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numbered

CONFIDENTIAL 2014N211143_00The GlaxoSmithKline group of companies BA1116891

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Division: Worldwide DevelopmentInformation Type: Clinical Pharmacology Study Report

Title: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers

Phase: I

Compound Number: GSK933776

Effective Date: 11-MAY-2015

Keywords: GSK933776, Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody, healthy volunteer study

Author(s): (CPSSO); (Clinical Statistics); (CPMS); (PTS); (Clinical Immunology);

(MPD); (Ophthalmology); (Ophthalmology)

Indication Studied: Healthy Volunteers supporting Geographic Atrophy secondary to Age-related Macular Degeneration

Initiation Date: 22-Jan-2014

Completion Date: 15-Jul-2014

Sponsor Signatory: (and Medical Officer)

, MDMedical Director, RD Alternative Discovery & DevelopmentGlaxoSmithKline

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. This study complies with US 21 CFR 312.120, as described in the Ethics and Good Clinical Practice section.

Copyright 2015 the group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

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Table of Contents Page TITLE PAGE .......................................................................................................... ABBREVIATIONS .................................................................................................. ETHICS AND GOOD CLINICAL PRACTICE ......................................................... 1. CENTER INFORMATION AND STUDY ADMINISTRATION ............................. 2. OBJECTIVES & ENDPOINTS ........................................................................... 3. INVESTIGATIONAL PLAN ................................................................................

3.1. Study Rationale ............................................................................................... 3.2. Study Design Discussion ................................................................................. 3.3. Protocol Amendments ..................................................................................... 3.4. Selection of Study Population ..........................................................................

3.4.1. Inclusion/Exclusion Criteria ......................................................................... 3.4.2. Lifestyle and/or Dietary Restrictions ............................................................ 3.4.3. Withdrawal Criteria ......................................................................................

3.5. Treatments ...................................................................................................... 3.5.1. Investigational Product(s) ............................................................................ 3.5.2. Treatment Assignment ................................................................................ 3.5.3. Masking ....................................................................................................... 3.5.4. Prior and Concomitant Medications and Non-Drug Therapies .................... 3.5.5. Compliance .................................................................................................

3.6. Study Assessments and Procedures ............................................................... 3.6.1. Safety Assessments .................................................................................... 3.6.2. Physical Exams ........................................................................................... 3.6.3. Vital Signs ................................................................................................... 3.6.4. Electrocardiogram (ECG) ............................................................................ 3.6.5. Clinical Laboratory Assessments ................................................................ 3.6.6. Pharmacokinetic Assessments .................................................................... 3.6.7. Pharmacodynamic Assessments ................................................................

3.7. Biomarker(s)/Pharmacodynamic Markers ........................................................ 3.7.1. Confirmed Biomarkers/Pharmacodynamic Markers ....................................

3.8. Immunogenicity................................................................................................ 3.9. Data Quality Assurance ................................................................................... 3.10. Data Analysis Methods ..................................................................................

3.10.1. Hypotheses and Treatment Comparisons ................................................. 3.10.2. Sample size considerations ....................................................................... 3.10.3. Analysis Populations .................................................................................

3.11. Interim Analyses ............................................................................................ 3.12. Final Analyses ...............................................................................................

3.12.1. Safety Analyses ......................................................................................... 3.12.2. Pharmacokinetic Analyses ........................................................................ 3.12.3. Pharmacokinetic/Pharmacodynamic Analyses .......................................... 3.12.4. Changes in Conduct of the Study or Planned Analyses ............................

4. STUDY POPULATION RESULTS ..................................................................... 4.1. Subject Disposition ..........................................................................................

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CONFIDENTIAL 2014N211143_00BA1116891

4.2. Protocol Deviations .......................................................................................... 4.3. Populations Analyzed ...................................................................................... 4.4. Demographic and Baseline Characteristics ..................................................... 4.5. Concomitant Medications ................................................................................ 4.6. Exposure and Treatment Compliance ............................................................. 4.7. Adverse Events ............................................................................................... 4.8. Serious and Significant Adverse Events ..........................................................

4.8.1. Deaths ......................................................................................................... 4.8.2. Serious Adverse Events .............................................................................. 4.8.3. Significant Adverse Events ..........................................................................

4.9. Clinical Laboratory Evaluations ....................................................................... 4.10. Other Safety Evaluations ............................................................................... 4.11. Pregnancies ...................................................................................................

5. PHARMACOKINETIC RESULTS ...................................................................... 5.1. Drug Concentration Data ................................................................................. 5.2. Plasma Pharmacokinetic Parameters .............................................................. 5.3. Statistical Analyses of Pharmacokinetic Parameters .......................................

5.3.1. Plasma PK Parameters Statistical Assessment .......................................... 5.3.2. Statistical Analysis Details ...........................................................................

6. PHARMACODYNAMIC AND BIOMARKER RESULTS .................................... 6.1. Pharmacodynamic Results ..............................................................................

Figure 7.1: Median Plasma Free Aβ1-22 Concentration-Time Plots ..................... Figure 7.2: Median Plasma Total Aβ18-35 Concentration-Time Plot..................... Figure 7.3: Median Plasma Total Aβ Concentration-Time Plot ..............................

6.2. Immunogenicity Results ................................................................................... 7. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS ...................................................................................................... 8. DISCUSSION AND CONCLUSIONS .................................................................

8.1. Discussion ....................................................................................................... 8.2. Conclusions .....................................................................................................

9. REFERENCES ................................................................................................... 10. POST-TEXT TABLES AND FIGURES .............................................................

10.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection) ...............................................

10.2. Time and Events Tables for Treatment Arm C (50 mg SQ injection) ............. 10.3. Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3 .............................. 10.4. Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up ...

11. CASE NARRATIVES ....................................................................................... STUDY POPULATION DATA SOURCE TABLES ................................................

Table 9.1 Summary of Study Population (Safety Population) ................................. Table 9.2 Summary of Subject Disposition (Safety Population) .............................. Table 9.3 Summary of Protocol Deviations (Safety Population) ............................. Table 9.4 Summary of Demographic Characteristics (Safety Population) .............. Table 9.5 Summary of Race and Racial Combination Details (Safety Population) . Table 9.6 Summary of Concomitant Medications (Safety Population) ....................

SAFETY DATA SOURCE TABLES .......................................................................

29293031313233333333333435363637393941424242434344

455151525354

54555657586060616263656667

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Table 10.1 Summary of All Adverse Events (Safety Population) ............................ Table 10.2 Summary of Adverse Events Related to Study Treatment (Safety

Population) ............................................................................................... Table 10.6 Summary of Vital Signs (Safety Population) ......................................... Table 10.7 Summary of Vital Signs Changes from Baseline (Safety Population) ... Table 10.8 Summary of ECG Findings (Safety Population) .................................... Table 10.9 Summary of ECG Values (Safety Population) ...................................... Table 10.10 Summary of Category of QTc Data by Treatment and Time (Safety

Population) ............................................................................................... Table 10.11 Summary of Category of QTc Change from Baseline by Treatment

and Time (Safety Population) .................................................................. Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver

Signal/Event (Safety Population) ............................................................. Table 10.13 Summary of Time on Treatment Before Liver Event (Safety

Population) ............................................................................................... Table 10.14 Summary of Liver Biopsy Details (Safety Population) ......................... Table 10.15 Summary of Liver Imaging Details (Safety Population) ....................... Table 10.301 Clinical Chemistry Laboratory Summary by Visit (Safety Population)

................................................................................................................. Table 10.302 Hematology Laboratory Summary by Visit (Safety Population) ........ Table 10.401 Summary of Abnormal Chemistry Laboratory Results (Safety

Population) ............................................................................................... Table 10.402 Summary of Abnormal Hematology Laboratory Results (Safety

Population) ............................................................................................... Table 10.501 Summary of Urinalysis Data (Character Result) (Safety Population) Table 10.502 Summary of Urinalysys Data (Numerical Result) (Safety Population)

................................................................................................................. PHARMACOKINETIC DATA SOURCE FIGURES ................................................

Figure 11.1 Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................

Figure 11.2 Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) ......

Figure 11.3 Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................

Figure 11.4 Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) .....

Figure 11.5 Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................

Figure 11.6 Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) ......

PHARMACOKINETIC DATA SOURCE TABLES .................................................. Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-

Time Data [ng/mL] (PK Concentration Population) .................................. Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic

Parameters (PK Parameter Population) ...................................................

67

697085

110111

115

117

119

120121122

123158

200

248296

308319

319

320

321

322

323

359395

395

399

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Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters (PK parameter Population) ...

Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters (PK Parameter Population) .......................

PHARMACODYNAMIC DATA SOURCE FIGURES .............................................. Figure 7.1 Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear

and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 7.2 Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear

and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 7.3 Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear

and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 12.1 Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)

(Pharmacodynamic Population) ............................................................... Figure 12.2 Mean Plasma PD Concentration Change from Baseline-Time Plot

(Linear and Semi-Log) (Pharmacodynamic Population) .......................... Figure 12.3 Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)

(Truncated) (Pharmacodynamic Population) ........................................... Figure 12.4 Mean Plasma PD Concentration Change from Baseline-Time Plot

(Linear and Semi-Log) (Truncated) (Pharmacodynamic Population) ....... Figure 12.5 Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)

(Pharmacodynamic Population) ............................................................... Figure 12.6 Median Plasma PD Concentration Change from Baseline-Time Plot

(Linear and Semi-Log) (Pharmacodynamic Population) .......................... Figure 12.7 Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)

(Truncated) (Pharmacodynamic Population) ........................................... Figure 12.8 Median Plasma PD Concentration Change from Baseline-Time Plot

(Linear and Semi-Log) (Truncated) (Pharmacodynamic Population) ....... Figure 12.9 Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)

(Pharmacodynamic Population) ............................................................... Figure 12.10 Individual Plasma PD Concentration-Time Plot (Linear and Semi-

Log) (Truncated) (Pharmacodynamic Population) ................................... PHARMACODYNAMIC DATA SOURCE TABLES ...............................................

Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL] (Pharmacodynamic Population) .........................................

Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL] (Pharmacodynamic Population) .........

Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data (Pharmacodynamic Population) ......................

Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data (Pharmacodynamic Population) .............................................

PHARMACOKINETIC AND PHARMACODYNAMIC DATA SOURCE FIGURES . Figure 13.1 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta

Concentration versus Nominal Time by Treatment (Pharmacokinetic/Pharmacodynamic Population) ...................................

406

407408

408

409

410

411

414

417

420

423

426

429

432

435

543651

651

660

669

678688

688

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Figure 13.2 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Pharmacokinetic/Pharmacodynamic Population) ..................

Figure 13.3 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time by Treatment (Truncated) (Pharmacokinetic/Pharmacodynamic Population) ...................................

Figure 13.4 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Truncated) (Pharmacokinetic/Pharmacodynamic Population) .................................................................................................................

692

696

700

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ABBREVIATIONS

z Terminal phase rate constant

AD Alzheimer’s diseaseADCC Antibody-dependent cellular cytotoxicityAE Adverse eventALT Alanine aminotransferase (SGPT)AMD Age-related macular degenerationANOVA Analysis of varianceAPTT/INR activated partial thromboplastin time /international normalized ratioARIA Amyloid related imaging abnormalitiesARIA-E ARIA-edema/effusionsARIA-H ARIA-hemosiderin depositsAST Aspartate aminotransferase (SGOT)AUC Area under concentration-time curve

AUC(0-) Area under the concentration-time curve over the dosing interval

AUC(0-inf) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time

AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration

Aβ or Abeta Amyloid betaBUN Blood urea nitrogenCDC Complement-dependent cytotoxicityCL Systemic clearance of parent drugCmax Maximum observed concentration CO2 Carbon dioxideCPK Creatine phosphokinaseCPMS Clinical Pharmacology Modelling & SimulationCP-RAP Clinical Pharmacology Reporting and Analysis PlanCPSSO Clinical Pharmacology Science and Study OperationsCRF Case Report FormCSF Cerebrospinal FluidCt Last observed quantifiable concentrationCV Coefficient of variationCVA Cerebrovascular accidentECG ElectrocardiogramECL ElectrochemiluminescentF Absolute bioavailability of drug FDA Food and Drug AdministrationFSH Follicle Stimulating HormoneGA Geographic atrophyGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGGT Gamma glutamyltransferaseGLP Good Laboratory PracticeGSK GlaxoSmithKline

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h/hr Hour(s)HBsAg Hepatitis B surface antigenHIV Human immunodeficiency virusIB Investigator’s BrochureICH International Conference on Harmonisation IDSL Integrated Data Standards LibraryIEC International Ethics CommitteeIM IntramuscularINR International Normalized RatioIP Investigational productIRB Institutional Review BoardIUD Intrauterine deviceIUS Intrauterine systemIV IntravenousKg KilogramL Literlbs PoundsLDH Lactate dehydrogenaseLFTs Liver function testsmAb Monoclonal antibodymg MilligrammL MillilitermmHg Millimeters of mercuryMRI Magnetic Resonance ImagingMSDS Material Safety Data Sheetmsec MillisecondsPCI Potential Clinical ImportancePD PharmacodynamicPK PharmacokineticPoC Proof of conceptQTcB QT duration corrected for heart rate by Bazett’s formulaQTcF QT duration corrected for heart rate by Fridericia’s formulaRBC Red blood cellsSAE Serious adverse event(s)SGOT Serum glutamic-oxaloacetic transaminaseSGPT Serum glutamic pyruvic transaminaseSOP Standard Operating ProcedureSPM Study Procedures ManualSQ SubcutaneousT½ Terminal phase half-lifeTmax Time of occurrence of CmaxULN Upper limit of normalVE Vasogenic edemaWBC White blood cellsτ Dosing interval

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Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

NONE RandAllWinNonlin

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ETHICS AND GOOD CLINICAL PRACTICE

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a institutional review board, in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements, including US 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of independent ethics committees. Ethics committee or institutional review board approvals are maintained in the Sponsor’s study file.

This study was conducted in accordance with ICH GCP and all applicable subject privacy requirements, and, the ethical principles that are outlined in the Declaration of Helsinki 2008. The study was monitored in accordance with ICH E6, Section 5.18.

Investigators were trained to conduct the study in accordance with GCPs and the study protocol as defined in ICH E3, Section 9.6. Written commitments were obtained from investigators to comply with GCP and to conduct the study in accordance with the protocol.

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The investigator agreed to provide the subject as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. (Electronic and/or paper) Case report forms were provided for each subject’s data to be recorded.

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1. CENTER INFORMATION AND STUDY ADMINISTRATION

This study was conducted at Quintiles, 6700 W. 115th Street, Overland Park, Kansas, 66211, United States. The first subject was enrolled on 22-Jan-2014 (first subject first visit) and the last subject completed on 15-Jul-2014 (last subject last visit).

Table 1 Study conduct

Name and Address Role/ResponsibilitiesInstitutional Review Board

United States

IRB Activities

Steering Committee None None

CROs/Companies and activities outsourced

Quintiles 6700 W. 115th StOverland Park, KS 66211 USA

Data Management Activities

Independent Data Monitoring Committee

None None

Monitor CCRA Site Monitoring

PK Laboratory Alliance Pharma, Inc17 Lee Boulavard, Malvern

PA 19355, USA

PK Sample Analysis

Biomarker/PD/ImmunologyLaboratory

GlaxoSmithKline709 Swedeland RoadKing of Prussia PA 19406, USA

PD/Biomarker/Immunology SampleAnalysis

Central Laboratory Quest Diagnostics26081 Avenue Hall, #150Valencia, CA 91355, USA

Liver Event Sample Analysis

Local Safety Laboratory Physicians Reference Laboratory (PRL)7800 West 110th St.Overland Park, KS 66210, USA

Hematology/Chemistry/Urinalysis Sample Analysis

Co-license or Joint Venture Agreement

None None

Contract medical writer None None

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2. OBJECTIVES & ENDPOINTS

Objectives Endpoints

Primary

To estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration

The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion (reference arm)

Secondary

To characterize the pharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration

Pharmacokinetic parameters including area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) if AUC(0-inf) is not reportable, Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit

To evaluate the safety and tolerability of GSK933776 following IV, IM and SQ administration

Clinical safety data from adverse event reporting (including injection site reactions), clinical observations, vital signs, ECG, and clinical laboratory parameters

To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker of interest

Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22, as data permit

To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration

Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status), as data permit

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3. INVESTIGATIONAL PLAN

3.1. Study Rationale

The route of administration in clinical studies of GSK933776 prior to conduct of this study was intravenous (IV) infusion; including two completed clinical studies evaluatingGSK933776 in patients with Alzheimer’s disease (AD) and one ongoing Phase 2 study in Geographic Atrophy patients.

This study was planned and executed to support possible transition to IM or SQ administration for subsequent studies with GSK933776, by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicityfollowing IM and SQ administration in healthy volunteers. Such alternative routes of administration would provide more options in the selection of an efficacious dose for later development in patients with geographic atrophy.

This study was conducted in healthy adult volunteers, between ages 18-50 years. Total dose was selected as 200mg, approximating the 3 mg/kg regimen administered by IV infusion.

Previously patients had received treatment over 3 months or longer with the 3 mg/kg IV regimen, the accrued safety profile of GSK933776 in these populations suggested tolerability of single dose of 200mg or four repeat doses of 50mg of GSK933776.

3.2. Study Design Discussion

Figure 1 Study Design/Schematic

• Duration: Approximately 85 days for subjects in Treatment Arms A, B and D; approximately 106 days for subjects in Treatment Arm C

• Follow up: 84 days following last dose administration

• Sample size: Planned evaluable subjects = 24. Enrolment will account for dropouts or non-evaluable subjects via replacement

Screening 1:1:1:1

Randomization

A: Single 200 mg IV infusion of GSK933776 (n=6)

B: Single 200 mg SQ dose of GSK933776 (n=6)

C: 4 weekly 50 mg SQ doses of GSK933776 (n=6)

D: Single 200 mg IM dose of GSK933776 (n=6)

Treatment Arms

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This was a single clinical center, randomized, open-label study conducted to investigate the relative bioavailability, pharmacokinetic (PK) profile, pharmacodynamic (PD)profile, safety and tolerability, and immunogenicity profile of GSK933776 administered by IV infusion and IM and SQ routes of administration in healthy volunteers. A total of 36 subjects were enrolled for this study.

Subjects were screened to determine eligibility to participate in the study after providing informed consent. Subjects were assigned to 1 of 4 below mentioned possible treatment regimens in 1:1:1:1 ratio

Arm A (1*): Single 200 mg IV infusion of GSK933776

Arm B (2*): Single 200 mg SQ dose of GSK933776

Arm C (3*): 4 weekly 50 mg SQ dose of GSK933776

Arm D (4*): Single 200 mg IM dose of GSK933776.

*Final Treatment codes in Source Documents and Datasets are numbered 1, 2,3,4 respectively.

Subjects remained in the unit for at least 6 hours post-dose for safety and tolerability assessments and samples for pharmacokinetic and pharmacodynamic determinationswere obtained. Subjects receiving GSK933776 by IM and SQ administration were monitored for injection site tolerability and immediate post-injection reactions for at least 6 hours after injection.

Subjects in treatment arms A, B and D were followed for approximately 84 days after dose administration and subjects in treatment arm C were followed for 84-day after the final [fourth] dose. The total duration of subject participation from screening to follow-up for treatment arms A, B and D (single dose of GSK933776), was approximately 113 days and for treatment arm C (weekly SQ administration for 4 doses), was approximately 134 days. Subjects returned for periodic visits over the approximate 84-day post dosing period for monitoring of safety, tolerability and immunogenicity and samples for PK and PD assessments were obtained.

The final clinic visit was scheduled for each subject, and assessments were performed based on the Time and Events Table (Table 13)

3.3. Protocol Amendments

This study was conducted using original protocol version 1.0 dated 05 Nov 2013. There was no protocol amendment for the study.

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3.4. Selection of Study Population

3.4.1. Inclusion/Exclusion Criteria

3.4.1.1. Inclusion Criteria

A subject was eligible for inclusion in this study only if all of the following criteria applied:

1. Male or female subject 18 – 50 years of age at the time of signing the informed consent

2. In general, subjects were in good health as determined by a physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied could be included only if the Investigator and the GSK Medical Monitor agreed that the condition was unlikely to introduce additional risk factors and did not interfere with the study procedures

3. Body weight ≥ 55 kg [121 lbs (pounds)] and ≤ 85 kg (187 lbs) with a body mass index (BMI) between 18.5 and 29 (inclusively) where

BMI = (weight in kg)(height in meters)2

at the time of signing the informed consent

4. A female subject was eligible to participate if she was of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/mL (<140 pmol/L) was confirmatory

5. Male subjects agreed to use one form of acceptable contraception methods listed in Section 3.4.2.1.1 if their partner was of childbearing potential. This criterion was to befollowed from the time of the screening visit through the follow-up visit (84 days after last dose of study medication)

6. Subjects were capable of giving written informed consent, which includedcompliance with the requirements and restrictions listed in the consent form.

3.4.1.2. Exclusion Criteria

A subject was not eligible for inclusion in this study if any of the following criteria applied:

3.4.1.2.1. Criteria Based Upon Medical Histories

1. Known risk history of:

a. Central nervous system (CNS) disorders:

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i. History and/or evidence by computerised tomography (CT) or Magnetic Resonance Imaging (MRI) scan performed within the past 12 months] of cerebral haemorrhage OR a known risk of cerebral haemorrhage, including uncontrolled hypertension, cerebrovascular malformation, coagulopathy, CNS vasculitis, degenerative or inflammatory/demyelinating CNS conditions or any other condition that the Investigator and/or the medical monitor considered a relevant risk factor for cerebral haemorrhage

ii. Transient ischemic attack (TIA)/cerebrovascular accident (CVA) in the previous year, or other uncontrolled risk factors for stroke

b. History of seizures (except febrile seizures in childhood) or recent unprovoked seizure

c. Uncontrolled type 2 diabetes mellitus [glycated haemoglobin (HbA1C) >10%], active cardiovascular disease (e.g., moderate-severe angina, unstable angina, myocardial infarction (MI) within the last 2 years, symptomatic congestive heart failure, clinically significant arrhythmia)

d. Current blood clotting or bleeding disorder or conditions that predispose to these (e.g. cancer)

e. Diagnosis of currently active, or, in remission but chronic relapsing, systemic autoimmune disease or condition (e.g. multiple sclerosis, lupus erythematosus etc) that the Investigator and/or the medical monitor considered as a relevant risk factor for concomitant administration of a therapeutic monoclonal antibody

2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

3. Use of prescription drugs or non-prescription drugs; including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication did not interfere with the study procedures or compromise subject safety

4. A positive pre-study drug/alcohol screen. Current or recent drug or alcohol abuse or dependence. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 units for males or >7 units for females. One drink was equivalent to 12 g of alcohol: 12 ounces (~360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Use of illegal drugs

5. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicated their participation

3.4.1.2.2. Criteria Based Upon Diagnostic Assessments

6. Seated systolic blood pressure > 140 mmHg or seated diastolic blood pressure of > 90 mmHg

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7. QTc > 450 millisecond (msec)

8. AST and ALT ≥ 2xULN; alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN was acceptable if bilirubin was fractionated and direct bilirubin <35%)

9. Significant abnormalities on hematology screen: clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for females), or platelet counts below 124 GI/L; INR > 2

10. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

11. A positive test for HIV antibody

3.4.1.2.3. Other Criteria

12. Where participation in the study resulted in donation of blood or blood products in excess of 500 mL within a 56 day period

13. Exposure to more than four new chemical entities within 12 months prior to screening

14. Prior allergic reactions to biological products (vaccines, antibodies) or known hypersensitivity to any of the components of the drug formulation

15. Prior participation in clinical investigations involving therapeutic monoclonal antibodies with a similar mode of action or proteins derived from monoclonal antibodies with any risk of cross- reactivity or any investigations of treatments or use of any other investigational medication or device within 2 months prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever was longer.

3.4.2. Lifestyle and/or Dietary Restrictions

3.4.2.1. Contraception Requirements

3.4.2.1.1. Male Subjects

Male subjects with female partners of child-bearing potential were asked to use one of the following contraceptive methods after the first dose of study treatment and until the follow-up visit, 84 days after the last dose of investigational product.

• Condom (during non-vaginal intercourse with any partner - male or female) OR

• Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)

• Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

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3.4.2.2. Meals and Dietary Restrictions

3.4.2.2.1. Caffeine, Alcohol, and Tobacco

During each dosing session, subjects were asked to abstain from alcohol for 24 hours prior to the start of dosing until collection of the final PK and/or PD sample during each session. An alcohol test was given as outlined in Time and Events Table (Table 13)

3.4.2.2.2. Activity

Subjects were asked to abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects were allowed to participate in light recreational activities during studies.

3.4.2.2.3. Other Restrictions

Subjects were asked to refrain from all recreational drugs throughout the study (screening to follow-up). Drugs of abuse tests were performed randomly throughout the study at the Investigator’s discretion. A positive result at any point may lead to exclusion from the study

One subject did test positive for Cannabis use during the study but subject was cleared to continue after approval from GSK Medical Monitor.

3.4.2.2.4. Screen and Baseline Failures

Data for screen and baseline failures was collected in source documentation at the site but was not transmitted to GSK in the study defined data capture system

3.4.3. Withdrawal Criteria

A subject could withdraw from study treatment at any time at his/her own request, or could be withdrawn at any time at the discretion of the Investigator for safety, behavioralor administrative reasons.

If a subject failed to attend the clinic for a required study visit, the site was to contact the subject and re-schedule the missed visit as soon as possible. The site also was to counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wished to and/or should continue in the study based on previous non-compliance. In cases where the subject did not return for the rescheduled visit or could not be reached to reschedule the missed visit, the site was to make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they could be appropriately withdrawn from the study.

These contact attempts were to be documented in the subject’s medical record. If subject continued to be unreachable, then and only then he/she was considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation wasrecorded in the eCRF.

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One subject was documented as “Lost to Follow-up” after all required steps were taken to contact the subject were exhausted.

3.4.3.1. Planned Dose Adjustments

This study did not allow alteration from the outlined doses for each cohort. The maximum total dose was not to exceed 200 mg in any subject or cohort.

All subjects received the correct dosage of 200 mg in clinic as randomized.

3.4.3.2. Subject Specific Dose Adjustment/Stopping Criteria

A subject could discontinue treatment and withdraw from the study at any time at his/her own request or could be withdrawn at any time for safety or administrative reasons at the discretion of the Investigator.

Two subjects withdrew early from the study. They did receive full dosing per protocol but missed follow-up visits. One subject withdrew early due to moving out of state. Another subject was Lost to Follow-up.

3.4.3.3. Allergic Reaction

Although humanization of the GSK933776 antibody was expected to reduce the risk of acute allergic reactions, all subjects were monitored carefully for evidence of acute allergic reactions and infusion reactions (for those subjects participation in the IV arm). It was important to recognize early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis should any event be noted during the study.

No subjects experienced signs of anaphylaxis or anaphylactic reactions.

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3.5. Treatments

3.5.1. Investigational Product(s)

Identity of Investigational Product

PRODUCT NAME:

GSK933776 (SQ ADMINISTRATION)

GSK933776 (IM ADMINISTRATION)

GSK933776 (IV ADMINISTRATION)

Formulation description:

Antibody solution Antibody solution Antibody solution

Dosage form: Solution for injection Solution for injection Solution for infusion

Unit dose strength(s)/Dosage level(s):

50 mg/mL (1 mL nominal volume) in a 3 mL glass vial



Route/Duration: Route: SubcutaneousDuration(Single Dose): 200 mg Duration(Repeat Dose): 50 mg weekly for 4 weeks

Route: IntramuscularDuration(Single Dose): 200 mg

Route: Intravenous Duration (Single Dose): 200 mg

Dosing instructions:

The dose was administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site was either the abdomen or the upper thigh. Injection site was documented and rotated

The dose was administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed)

The dose was administered through an IV catheter over approximately 1 hour

Method for individualizing dosage:

GSK933776 was drawn into a sterile disposable syringe.Study drug was then administered through a sterile needle (27GA).

GSK933776 was drawn into a sterile disposable syringe. Study drug was then administered through a sterile needle (23GA).

GSK933776 was prepared in 0.9% Sodium Chloride in infusion bags. Study drug was then administered using an IV delivery pump and a catheter.

Batch Numbers PK Lot ID: 132379262

Lot No: 091217577

PK Lot ID: 132379262

Lot No: 091217577

PK Lot ID: 132379262

Lot No: 091217577

3.5.2. Treatment Assignment

Subjects were assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio in accordance with the randomisation schedule generated using RandAll, a web-based clinical trials system, by QSci, Clinical Statistics Department at GlaxoSmithKline (GSK).

A description of each study regimen is provided below:

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TREATMENT ARM DESCRIPTIONA (1*) 200 mg GSK933776 administered by IV infusionB (2*) 200 mg GSK933776 administered by SQ injection C (3*) 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks

for a total monthly dose of 200 mg GSK933776D (4*) 200 mg GSK933776 administered by IM injection

*Final Treatment codes in Source Documents and Datasets are numbered 1, 2,3,4 respectively

3.5.3. Masking

This was an open-label study.

3.5.4. Prior and Concomitant Medications and Non-Drug Therapies

3.5.4.1. Permitted Medications:

Acetaminophen, at doses of 2 grams/day was permitted for use any time during the study. Other concomitant medication were to be considered on a case by case basis by the GSK Medical Monitor.

3.5.4.2. Prohibited Medications and Non-Drug Therapies

Subjects were asked to abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug was a potential enzyme inducer) or 5 half-lives (whichever was longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication did not interfere with the study.

3.5.4.3. Non-Drug Therapies

Subjects were asked to abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug was a potential enzyme inducer) or 5 half-lives (whichever was longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication didnot interfere with the study.

3.5.5. Compliance

When the individual dose for a subject was prepared from a bulk supply, the preparation of the dose was confirmed by a second member of the study site staff.

The subjects were dosed at the study site, they received study treatment directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic was recorded in the source documents. The dose of study treatment and study participant identification was confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.

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3.6. Study Assessments and Procedures

The planned time points for each assessment are outlined in the Time and Events Table(Table 13)

3.6.1. Safety Assessments

The safety assessments were the monitoring of adverse events (AEs), clinical laboratory tests, vital signs, ECGs, physical examinations and monitoring of allergic reactions.

Refer to Protocol Section 6.3 for full details of safety assessments.

The Investigator or site staff were responsible for detecting, documenting and reporting events that met the definition of an AE or SAE. AE information volunteered by the subject, discovered by Investigator questioning or detected by other means was collected from the start of study treatment until the follow-up contact. The following information on AEs was obtained:

Duration (start and stop dates)

Severity (mild, moderate, severe)

Causality (reasonable possibility yes/no)

Actions taken and outcome

The AE and SAE definitions are provided in the Protocol, Section 7.1.3 and Section7.1.4, respectively. The definition of laboratory and vital sign abnormalities of potential clinical importance are provided in the study RAP Section 8.6.

3.6.2. Physical Exams

A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height (at screening only) and weight was also measured and recorded.

3.6.3. Vital Signs

Vital sign measurements included systolic and diastolic blood pressure and pulse rate, and were recorded whilst the subject was in a semi-supine position having rested in sameposition for at least 5 minutes.

3.6.4. Electrocardiogram (ECG)

12-lead ECGs were obtained at the screening and follow-up visits using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTcB intervals.

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3.6.5. Clinical Laboratory Assessments

Hematology, clinical chemistry, urinalysis and additional parameters were tested. Details for the preparation and shipment of samples were provided by the local laboratory.Reference ranges for all safety parameters were provided to the site by the laboratory.

3.6.6. Pharmacokinetic Assessments

Pharmacokinetic samples were collected at time-points outlined in the Time and Events (Table 13). Samples were collected at nominal times relative to the proposed time ofGSK933776 dosing.

Blood samples were taken via an indwelling cannula (or by direct venipuncture). All blood samples were taken from the opposite arm to that of drug administration. Approximately 2mL of whole blood was collected into 2mL EDTA tubes (lavender cap) and was placed on ice. Approximately 1 ml plasma was collected into storage tube.

Within 30 minutes of collection, all blood samples were centrifuged in a refrigerated centrifuge at 2000g for 15 minutes at approximately 4°C. The resultant 1 ml plasma (clear liquid on top) was transferred to uniquely labeled 1.4mL matrix -tube (clear top) and frozen immediately on dry-ice. In the absence of dry ice, the sample was immediately placed into a freezer at or below -20°C without delay.

Human plasma samples were analyzed for GSK933776 by Alliance Pharma, Malvern, PA, USA using a validated analytical immunoassay method based on sample dilution, followed by immunoassay analysis [GlaxoSmithKline Document Number: 2013N182307_00]. The LLQ for GSK933776 was 100 ng/mL, using a 100 L aliquot of eleven-fold diluted human plasma, with a higher limit of quantification (HLQ) of 5000 ng/mL.

The immunoassay utilizes 1-16 beta amyloid peptide as the means of capture and therefore measures free GSK933776 antibody which is defined as the sum of bivalent and monovalent unbound forms of the GSK933776 antibody.

For each analytical batch, quality control (QC) samples, containing GSK933776 at three different concentrations were stored with study samples and analyzed with each batch of samples against separately prepared calibration standards. For the analysis to be acceptable, no more than one-third of the total QC results and no more than one-half of the results from each concentration level were to deviate from the nominal concentration by more than 20%. The applicable analytical runs met all predefined run acceptance criteria. All data are stored in the Good Laboratory Practice Archive, Alliance Pharma, Malvern, PA, USA.

3.6.7. Pharmacodynamic Assessments

PD sampling for Aβ and related fragments is included in this study to enrich the existing PK-PD dataset and allow for specific PK-PD modeling of SQ and IM administrations. It is anticipated that these data could be useful for development of a general model

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characterizing the GSK933776 PK-PD relationship across multiple populations (AD, GA,and healthy volunteers).

3.7. Biomarker(s)/Pharmacodynamic Markers

3.7.1. Confirmed Biomarkers/Pharmacodynamic Markers

The total and free levels of beta amyloid fragments were measured in plasma for each subject. Abeta1-22, Abeta18-35 and Abeta42 were evaluated using immuno-electrochemiluminescent (ECL) assays.

Blood samples were taken from all subjects in this study according to Time and Events (Table 13).

Before collecting the PD samples, a protease inhibitor solution was prepared the morning of collection of samples, and was added to the PD collection tubes before adding the plasma.

Approximately 4mL of whole blood was collected for free and total A assays. Blood was collected into 4ml EDTA tubes (polypropylene tubes containing EDTA K2 gel, lavender cap) and the tubes were placed on ice immediately. Once collected, all blood samples were centrifuged in a refrigerated centrifuge at 2000g for 15 minutes at approximately 4°C within 30 minutes. When the sample was removed from the centrifuge, the plasma sample was mixed gently and the resultant, approximately 2 ml, plasma, was separated into 4 aliquots, each aliquots of 0.5 ml plasma was added into each tube containing 20 microliters of protease inhibitor solution and samples were frozen upright on dry ice or in a freezer at or below -70°C.

3.8. Immunogenicity

Blood samples for determination of anti-GSK933776 antibodies were taken from all subjects in this study as a safety measurement for GSK933776 at the time-points specified in the Time and Events Table (Table 13)

Samples were analysed for the presence of anti-GSK933776 antibodies by ECL screening and neutralisation assays. If sera contained anti- GSK933776 antibodies as determined by the ECL screening assay, they were further analysed for specificity, titres of antibodies and the presence of neutralising antibodies. The immunogenicity assessment report included the incidence and titres of anti-GSK933776 binding and neutralising antibodies.

Approximately 3mL of whole blood was collected into serum-separator tubes. All blood samples were maintained at ambient temperature for at least 1 hour, but no more than 4 hours. In case, clotting stimulator was added, samples were held no more than 1 hour to allow for complete clotting prior to centrifugation. Once a sample was completely clotted, it was centrifuged at 2000g for 15 minutes at approximately 4°C. Approximately 1.5 mL of serum (clear liquid on top) was equally divided into 3 aliquots and transferred to clean, uniquely labelled 1.8 ml cryotubes and frozen at -70°C immediately.

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3.9. Data Quality Assurance

Subject data was entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK and combined with data provided from other sources (e.g., laboratory data) in a validated data system.

Verification of data accuracy and adherence to protocol requirements was achieved through regular monitoring visits at the investigational site. Subsequent data handling and reporting processes were performed according to processes detailed in GSK’s Standard Operating Procedures (SOPs). AEs and concomitant medications were coded using company standard dictionaries, Medical Dictionary for Regulatory Activities (MedDRA) and GSKDrug.

SAEs, consistent with the data collected for other AEs, was entered into the database and quality assured, including reconciliation with the GCSP database.

Investigator(s), responsible study site staff, sponsor representative(s) and study monitor(s) attended a study site initiation meeting to review study protocol procedures, study requirements, and GCP responsibilities. Investigators and staff were given opportunity to discuss any aspect of the study protocol and GCP requirements. Training records were reviewed to ensure Investigators and staff were qualified to conduct the study and to document training in GCP.. Documentation of GCP training was confirmed prior to staff participation in the study.

The Principal Investigator signed the Investigator page of the protocol to confirm their commitment to conduct the study in accord with the protocol and GCP. The signed documents have been archived within individual Investigator study files.

Study monitor(s) contacted the site prior to the start of the study and reviewed with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion included identification, agreement and documentation of data items for which the CRF served as the source document. The study was monitored to ensure that: (1) the data are authentic, accurate, and complete; (2) the safety and rights of subjects were protected; (3) the study was conducted in accordance with the currently approved protocol and any other study agreements, GCP and all applicable regulatory requirements.

3.10. Data Analysis Methods

3.10.1. Hypotheses and Treatment Comparisons

This study was designed to estimate the bioavailability of GSK933776 administered by SQ or IM injection relative to GSK933776 administered intravenously. No formal hypothesis was tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals were constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (SQGSK933776)/( IV GSK933776) and (IM GSK933776)/( IV GSK933776).

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3.10.2. Sample size considerations

The sample size for this study was based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. Variability estimates from previous studies with IV administration of GSK933776assured acceptable precision of PK parameters for the proposed sample size.

3.10.3. Analysis Populations

3.10.3.1. Safety Population

All patients enrolled in the study who received at least one dose of study drug wereincluded in the Safety Population. This population was used in the assessment of safety, and for listing and summarizing baseline/demographic and subject disposition data.

3.10.3.2. Pharmacokinetic Concentration Population

The PK Concentration Population consisted of all subjects in the Safety Population who underwent plasma PK sampling and had evaluable PK assay results. This population wasused for the concentration tables, listings, and figures.

3.10.3.3. Pharmacokinetic Parameter Population

The PK Parameter Population consisted of all subjects in the Pharmacokinetic Concentration Population for whom valid and evaluable pharmacokinetic parameters were derived. This population was used in the assessment and characterization of PK parameters. This population was also used for listing and statistical analysis of PK parameters.

3.10.3.4. Pharmacodynamic Population

The Pharmacodynamic (PD) Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). This population was used for listing, summarizing and plotting of plasma concentration-time data for biomarkers.

3.10.3.5. PK/PD Analysis Population

The PK/PD Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776. This population was used to explore the PK/PD relationship.

3.11. Interim Analyses

No interim analyses were conducted.

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3.12. Final Analyses

3.12.1. Safety Analyses

Safety data was summarized and listed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline. No formal statistical analysis of safety data was conducted.These tables used the “Safety” population unless otherwise specified.

3.12.2. Pharmacokinetic Analyses

Derivation of pharmacokinetic parameters was performed by, or under the direct auspices of, Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline.Statistical analysis of PK parameters was performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline. These tables used the PK concentration or parameter population unless otherwise specified.

The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin 6.3 or higher. Calculations were based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters were determined, as data permitted area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)), area under the plasma concentration-time curve (AUC) AUC(0-672hrs) (for Treatment Arms A and C only), AUC(0-168hrs) (for Treatment Arms A and C only), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), apparent terminal phase half-life (T1/2), apparent clearance (CL/F), apparent volume of distribution (V/F) (F=1 for Treatment Arm A). Pharmacokinetic data was presented in graphical and/or tabular form and was summarized descriptively. All pharmacokinetic data was stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.

Following loge-transformation, the PK parameters AUC(0-∞), AUC(0-672hrs) (Treatment Arms A and C only), AUC(0-168hrs) (Treatment Arms A and C only), Cmax, CL/F and V/F of GSK933776 was separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for Regimen. Point estimates and their associated 90% confidence intervals (CIs) was constructed for the differences, B – A, C –A and D - A. For the comparison of C - A the parameter AUC(0-168hrs) was dose normalized. The point estimates and their associated 90% confidence intervals was then back-transformed to provide point estimates and 90% confidence intervals for the ratios, B:A, C:A and D:A.

Tmax of GSK933776 was separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B – A, C - A and D - A.

3.12.3. Pharmacokinetic/Pharmacodynamic Analyses

The relationships between plasma concentration of GSK933776 and various biomarkers were explored via graphical and descriptive analyses.

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Pharmacodynamic /biomarker endpoints included plasma total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the amino acid sequence 1-22. PD/biomarker concentrations were listed by treatment, subject, visit, and actual plasma sampling time and summarized by treatment, visit, and nominal time. PD/biomarker concentration changes from baseline were also summarized. Standard summary statistics were calculated (i.e. mean, standard deviation, median, minimum and maximum). The immunogenicity endpoint included the measurement of antibodies to GSK933776 in serum samples. Immunogenicity data was summarized and a by-subject listing was provided.

These tables used the PD population unless otherwise specified.

3.12.4. Changes in Conduct of the Study or Planned Analyses

There were no changes in the conduct of the study but there were minor changes in planned analysis of the study as stated below.

Tmax and T1/2 of GSK933776 were originally planned to be analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B - A, C - A and D - A. Wilcoxon rank-sum test, an analysis of Wilcoxon scores in the linear rank statistic for two-sample data, produces the rank sum statistic, not the median differences.

In the final analyses, non-parametric Hodges-Lehmann (HL) estimation of location shift for two-sample data was employed. Hodges-Lehmann estimate of location shift for two-sample data is the median of all possible differences in outcomes between a subject in Arm B, C, or D and a subject in Arm A. The Hodges-Lehmann estimator of location shift is associated with the Wilcoxon linear rank statistic.

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4. STUDY POPULATION RESULTS

4.1. Subject Disposition

Thirty Six (36) healthy subjects were enrolled into the study and all were randomized to one of the 4 treatment groups. Allocation of subjects was 9 subjects per treatment group. Two subjects were ultimately withdrawn from the study with one subject lost to follow-up and the other moved out of the area.

Details of subject disposition can be found in Table 2.

Table 2 Subject Disposition

Number of Subjects: Treatment A (200mg

IV)

Treatment B (200mg

SQ)

Treatment C (50mg SQ X 4)

Treatment D (200mg

IM)Number of subjects planned, [N] 6 6 6 6 Number of subjects randomized, [N] 9 9 9 9Number of subjects included in All subjects (safety) population, [n (%)]

9 (100%) 9 (100%) 9 (100%) 9 (100%)

Number of subjects included in PK population, [n (%)]

9 (100%) 9 (100%) 9 (100%) 9 (100%)

Number of subjects completed as planned, [n (%)]

9 (100%) 9 (100%) 8 (89%) 8 (89%)

Number of subjects withdrawn (any reason), [n (%)]

0 0% 1 (11%) 1 (11%)

Number of subjects withdrawn for SAE, [n (%)]

0 0 0 0

Number of subjects withdrawn for AE, [n (%)]

0 0 0 0

Reasons for subject withdrawal, [n (%)]Lost to follow-up 0 0 1 (11%) 0Adverse events 0 0 0 0Protocol violation 0 0 0 0Other1 0 0 0 1 (11%)

1Other refers to subject moving out of the area

4.2. Protocol Deviations

There were 12 subjects with reportable protocol deviations. All were considered minor in nature and all subjects were deemed eligible for analysis. None of the deviations were related to inclusion or exclusion criteria. Most were due to out of window visits or missed/out of window assessments.

4.3. Populations Analyzed

All thirty-six subjects were included in the agreed study populations defined in the RAP as in Table 3.

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Table 3 Populations analyzed

Population Definition No. of Subjects Included Displays

All SubjectsAll Subjects who received at least one dose of study treatment

36 Safety

Pharmacokinetic Concentration Population

All Subjects who have at least one evaluable GSK933776 PK Assay Result

36Pharmacokinetic Concentration

Pharmacokinetic Parameter Population

All Subjects in the PK Concentration population who have at least one evaluable PK parameterderived

36Pharmacokinetic Parameters

Pharmacodynamic Population

All Subjects in the Safety population who have at least one evaluable Biomarker Concentration (including Immunogenicity)

36Pharmacodynamic & Biomarker

PK/PD Analysis Population

All Subjects in the Safety population who have at least one evaluable Biomarker Concentration as well as one evaluable PK Concentration

36Pharmacokinetic andPharmacodynamic Relationship

4.4. Demographic and Baseline Characteristics

The demographic characteristics were well balanced except for gender.

The thirty-six subjects recruited for this study comprised 35 males and 1 female, 2 were Hispanic/Latino and the remaining 34 subjects were Non Hispanic/Latino. Subjects were between 19 and 45 years inclusive. All subject’s weights were within the agreed limits of 55kg (121 lbs) and 85kg (187 lbs) with all meeting the inclusion BMI parameter between 18.5 and 29 inclusively.

A summary of the subject demographics is in Table 4.

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Table 4 Demographics

Demographics: Treatment A (200mg

IV)

Treatment B (200mg

SQ)


Treatment D (200mg

IM)Age in Years [Mean (SD)] 34.7 (8.86) 27.8 (7.71) 26.3 (6.18) 24.8 (6.10)

Sex [n (%)]Female 0 0 1 (11%) 0

Male 9 (100%) 9 (100%) 8 (89%) 9 (100%)BMI (kg/m2) [Mean (SD)] 25.19

(2.226)23.15

(2.068)23.72

(1.873)23.08

(2.329)Height (cm) [Mean (SD)] 176.69

(5.974))179.39 (4.739)

171.21 (7.710)

174.23 (4.224)

Weight (kg) [Mean (SD)] 78.41 (4.606)

74.37 (5.793)

69.53 (7.122)

70.02 (6.853)

Ethnicity [n (%)]Hispanic or Latino 1 (11%) 0 0 1 (11%)

Not Hispanic or Latino 8 (89%) 9 (100%) 9 (100%) 8 (89%)Race [n (%)]

African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%)American Indian or Alaskan Native 0 0 0 1 (11%)

Asian – Japanese Heritage 1 (11%) 0 0 0White – Arabic/North African Heritage 1 (11%) 0 0 0White – White/Caucasian/European

Heritage5 (56%) 5 (56%) 3 (33%) 2 (22%)

4.5. Concomitant Medications

Ten (10) subjects (28%) took concomitant medications during the study. The majority of these medications were taken for treatment emergent adverse events and were primarily antibiotics given for various infections and Tylenol given for pain.. The remaining medications were taken for prophylaxis, sleep aid, and/or for health maintenance.

One (1) subject tested positive for Cannabis use at Study Day 27 during the study. The subject admittedly self administered Cannabis one time during the study and thus it is listed as a concomitant medication. The subject was re-educated to abstain from illegal drugs while on study. It was agreed by the Primary Investigator and GSK Medical Monitor that the subject could continue in the study.

None of these medications were expected to affect the pharmacokinetic endpoints of the study.

4.6. Exposure and Treatment Compliance

Study Medication was administered by the study personnel in the Unit under the supervision of a physician. All subjects received the correct treatment as randomized and compliance with study medication was 100%.

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4.7. Adverse Events

Fifteen (15) subjects (42%) reported a total of 23 adverse events during the study – one of which was a serious adverse event. See Table 5 for a listing of all Adverse Events.

All the AEs except one were considered by the investigator to be unrelated to the investigational product . The one AE classified as having a relationship to the investigational product was Headache and started within 1 hour 11 minutes of investigational product administration and resolved the same day.None of the events were of sufficient clinical importance to warrant withdrawal from the study and all resolvedduring the study with the exception of the serious event which was not considered drug related and remained unresolved at time of study end.

Table 5 Adverse Events

Listing of all Adverse Events (Verbatim Text)

Treatment A (200mg IV)

Treatment B (200mg SQ)

Treatment C (50mg SQ x 4)

Treatment D (200mg IM)

Bruise to Lower Spine 1Cold 1Constipation 1Fatigue Feeling 1Gastroenteritis 1Generalized Itching 1Headache 2Headache/Congestion 1Hearing Voices 1Increased Urine White Blood Counts

1

Microhematuria 1Microscopic Hematuria 1Positive Chlamydia Asymptomatic Urethritis

1

Rash Penis 1Right Arm Erythema 1Slight Headache 1Strep Throat 1Swollen Mouth 1Upper Respiratory Infection 2Weight Loss 1Weight Loss Associated Increased Satiety

1

Total Number of AEs 5 10 6 2Number of Subjects Exposed 9 9 9 9Number of Subjects with AEs 4 (44%) 6 (67%) 3 (33%) 2 (22%)

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4.8. Serious and Significant Adverse Events

4.8.1. Deaths

There were no deaths in this study.

4.8.2. Serious Adverse Events

There was one serious adverse event reported on Day 27 of the study– this event was reported as Hearing Voices with a resulting diagnosis of Schizophrenia, Paranoid Type. The event was moderate in intensity and was considered not related to study treatment. The event was still ongoing at study end. The subject had a previous history of psychiatric disease, including hallucinations, as well as recently documented substance abuse.

4.8.3. Significant Adverse Events

None

4.9. Clinical Laboratory Evaluations

Clinical laboratory values were similar across the treatment groups. There were no trends or patterns identified across subjects or across groups.

Three subjects had haematology values reaching low levels of potential clinical importance [Table 6]. Three subjects had clinical chemistry values that exceeded the limits of potential clinical importance [Table 7]. There were no Urinalysis results meeting PCI criteria.

No haematology or clinical chemistry result was classified by the investigator as an adverse event and none gave cause for clinical concern.

Urinalysis results showed no clinically important changes or abnormalities overall.

Table 6 Haematology PCI Laboratory Evaluations

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Table 7 Chemistry Laboratory PCI Evaluations

4.10. Other Safety Evaluations

Vital Signs

Five (5) subjects had vital sign values exceeding the pre-set ranges of potential clinical importance [Table 8], however none were deemed clinically significant. All values returned to normal at subsequent measurements. There were no trends or changes over time noted between the treatment groups.

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Table 8 Vital Signs PCI Evaluations

ECG’s:

Three (3) subjects had abnormal findings but all were considered not clinically significant by the investigator and appear to be one-time events. These results also exceeded the pre-set ranges of potential clinical importance by GSK, however none were deemed clinically significant by the GSK Medical Monitor [Table 9]. There were also no trends or changes over time noted between the groups.

Table 9 ECG PCI Evaluations

4.11. Pregnancies

There was no pregnancy reported for the one female subject of childbearing potential or with any female partners of the 35 male subjects.

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5. PHARMACOKINETIC RESULTS

5.1. Drug Concentration Data

Individual plasma GSK933776 concentration listings and associated summary statistics are prepared. Individual plasma GSK933776 concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales (Source Data Figure 11.5) and with the actual times truncated to 1000 hours post dose (Source Data Figure 11.6).

Mean plasma GSK933776 concentration-time profiles are displayed with nominal time on both semi-logarithmic and linear scales (Source Data Figure 11.1, Figure 1) and truncated to 800 hours post-dose (Source Data Figure 11.2, Figure 2). Median plasma GSK933776 concentration-time profiles are displayed with nominal time on both semi-logarithmic and linear scales(Source Data Figure 11.3) and truncated to 800 hours post dose (Source Data Figure 11.4).

Descriptive statistics for plasma GSK933776 concentration data at each planned relative time are presented by treatment in Source Data Table 11.1.

Figure 2 Arithmetic Mean GSK933776 Plasma Concentration - Time (Linear and Semi-logarithmic Scales)

Source Data: Figure 11.1

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Figure 3 Arithmetic Mean GSK933776 Plasma Concentration - Time Truncated to 800 hours Postdose (Linear and Semi-logarithmic Scales)

Source Data: Figure 11.2

5.2. Plasma Pharmacokinetic Parameters

Plasma PK parameters following each treatment are summarized in Source Data Table 11.2 for GSK933776 and also in Table 10 .

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Table 10 Summary of Plasma GSK933776 Pharmacokinetic Parameters by Treatment

PK ParameterA

IV 200 mgN=9

BSQ 200 mg

N=9

CSQ 50 mg x 4

N=9

DIM 200 mg

N=9

AUC(0-168) (h*ug/mL) 5522 (9.23)NE

934.5 (19.48)NE

AUC(0-168)/D (h*ug/mL/mg)

27.6 (9.23)NE

18.7 (19.48)NE

AUC(0-672) (h*ug/mL) 12049 (10.66)NE

7220 (22.50)NE

AUC(0-inf) (h*ug/mL) 14899 (14.86) 12371 (20.56) 14197 (21.21) 12911 (22.69)

Cmax(ng/mL)

62.5 (14.05) 22.4 (16.61) 17.8 (27.94) 28.7 (22.56)

CL/F(mL/h)

13.42 (14.86) 16.15 (20.30) 3.53 (21.40) 15.48 (22.67)

Vz/F(mL)

5618 (10.86) 7013 (19.70) 1683 (27.49) 6425 (14.66)

t1/2(h)

286 313 320 286

(203, 357) (239, 367) (289, 424) (194, 344)

tmax(h)

2 117 599 96

(1, 3) (96, 120) (527, 601) (24, 120)

tlast(h)

1344 1343 1176 1344

(673, 1345) (697, 1346) (1010, 1849) (671, 1344)

Source Data: Table 11.2All parameter values are presented as geometric mean (%CVb) except t1/2, tmax and tlast are presented as median

(minimum and maximum). NE = not estimatedTreatment Key:A: single 200 mg dose of GSK933776 administered by IV infusion (reference arm)B: single 200 mg dose of GSK933776 administered SQC: 50 mg dose of GSK933776 administered SQ once weekly for 4 weeks (total dose = 200 mg)D: single 200 mg dose of GSK933776 administered IM

Following 200 mg IV administration, GSK933776 dose normalized geometric mean AUC(0-168) was 1.5-fold higher than after a single 50 mg SQ dose. The geometric mean AUC(0-672) for 200 mg IV GSK933776 was 1.7-fold higher than 4 weekly 50 mg SQ doses. Geometric mean AUC(0-inf) was comparable for the 200 mg IV dose and 4x50 mg SQ dose, and the 200 mg SQ dose was similar to the 200 mg IM dose. Geometric mean Cmax was 2.8-, 3.5- and 2.1-fold higher for the IV 200 mg dose compared to the 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively. Small to moderate between-subject variability was associated with these PK parameters.

The median t½ following the IV and IM doses were identical at 286 hours followed closely by the 200 mg SQ dose at 313 hours and the 4x50 mg SQ dose at 320 hours. The geometric mean clearance for the IV dose was 13.4 mL/hr and apparent CL/F for the 200 mg SQ dose was 16.2 mL/hr, approximately 4.6-fold higher than the 4x50 mg dose.

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Apparent CL/F for the 200 mg IM dose was 15.5 mL/hr. The Vz was 5618 mL for the 200 mg IV dose and Vz/F was 7013, 1683, and 6425 mL for the 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively.

Median tmax valuesof 2.0, 117, 599 and 96 hours for the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively.

5.3. Statistical Analyses of Pharmacokinetic Parameters

5.3.1. Plasma PK Parameters Statistical Assessment

Statistical assessments of GSK933776 parameters are presented in Source Data Table 11.3 and Table 11.4 and are reproduced below (Table 10 and Table 11).

Comparing the mean AUC(0-inf) for the 200 mg IV dose to the 200 mg IM dose resulted in relative bioavailability of 87%. Relative bioavailability of Cmax was 46% for the comparison of IV and IM doses.

Comparing the mean AUC(0-inf) for the 200 mg IV dose to the 200 mg SQ dose resulted in relative bioavailability of 83%. Relative bioavailability of Cmax was 36% for the comparison of IV and SQ doses.

Comparing the mean dose normalized AUC(0-168)/D (i.e., 7 days) and the mean AUC(0-672) (i.e., 28 days) for the 200 mg IV dose to the 4x50 mg SQ dose resulted in relative bioavailability of 68% and 60%, respectively. Relative bioavailability of Cmax was 28% for the comparison of IV and weekly SQ doses.

Statistical assessment of t½ between the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM doses showed the dosage forms to be comparable.

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Table 11 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters

__GeoMetric LS Mean__

ParameterComparison

Test Vs Reference n Test n RefRatio (%)(Test/Ref)

90% ConfidenceInterval for Ratio

AUC(0-168)/D (h*ug/mL/mg)

SQ_50mg*4 VS IV_200mg 9 18.7 9 27.6 67.70 (59.77, 76.67)

AUC(0-672) (h*ug/mL)

SQ_50mg*4 VS IV_200mg 9 7220 9 12049 59.92 (51.92, 69.16)

AUC(0-inf) (h*ug/mL)

IM_200mg VS IV_200mg 9 12911 9 14899 86.65 (73.96, 101.53)

SQ_200mg VS IV_200mg 9 12371 9 14899 83.03 (70.87, 97.29)

SQ_50mg*4 VS IV_200mg 9 14197 9 14899 95.28 (81.32, 111.64)

Cmax (ug/mL)

IM_200mg VS IV_200mg 9 28.7 9 62.5 45.99 (38.98, 54.26)

SQ_200mg VS IV_200mg 9 22.4 9 62.5 35.82 (30.36, 42.26)

SQ_50mg*4 VS IV_200mg 9 17.8 9 62.5 28.41 (24.08, 33.52)

CL/F (mL/h)

IM_200mg VS IV_200mg 9 15.47911 9 13.42335 115.31 (98.44, 135.09)

SQ_200mg VS IV_200mg 9 16.1524 9 13.42335 120.33 (102.72, 140.96)

SQ_50mg*4 VS IV_200mg 9 3.52867 9 13.42335 26.29 (22.44, 30.80)

Vz/F (mL)

IM_200mg VS IV_200mg 9 6424.608 9 5618.401 114.35 (98.28, 133.05)

SQ_200mg VS IV_200mg 9 7013.106 9 5618.401 124.82 (107.28, 145.24)

SQ_50mg*4 VS IV_200mg 9 1683.06 9 5618.401 29.96 (25.75, 34.85)

Source Data: Table 11.3

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Table 12 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters

-Median-

ParameterComparison

Test vs Referencen Test n Ref.

Difference(Test-Ref)

90% ConfidenceInterval forDifference

t1/2 (h)

SQ_200mg vs IV_200mg 9 313.20 9 286.19 7.96 (-28.99, 45.7)

SQ_50mg x 4 vs IV_200mg 9 320.00 9 286.19 31.3 (-2.46, 71.89)

IM_200mg vs IV_200mg 9 285.89 9 286.19 -3.25 (-40.27, 32.72)

tmax (h)

SQ_200mg vs IV_200mg 9 116.92 9 1.50 115.42 (94.42, 117.85)

SQ_50mg x 4 vs IV_200mg 9 598.73 9 1.50 596.8 (594.97, 598.07)

IM_200mg vs IV_200mg 9 95.63 9 1.50 93.7 (45.37, 94.42)

Source Data: Table 11.4

5.3.2. Statistical Analysis Details

Statistical analyses of pharmacokinetic data were performed under the direct auspices of Clinical Pharmacology Statistics & Programming, GlaxoSmithKline.

Data was released to CPSP by CPK via HARP. Main results of the summary statistics are presented to the accuracy of the raw data. All summary statistics were carried out using SAS 9.3 for LINUX running under the HARP environment.

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6. PHARMACODYNAMIC AND BIOMARKER RESULTS

6.1. Pharmacodynamic Results

Plasma A1-22 (free), A18–35 (total) and A42 (total) from the pharmacodynamic population were summarized, graphically presented, and listed. Individual subject plots of the plasma A parameters by time and route of administration can be seen in the source data (Source Figure 12.10) and summary overviews are presented graphically in Figure 7.1, Figure 7.2 and Figure 7.3 respectively.

As expected, free A1-22 levels decreased after dosing with GSK933776 for all routes of administration, but had the most marked effect with the 200 mg IV dose. The cohort receiving 200 mg IM also showed a reduction from baseline levels of free A1-22, and although not as significant as that of the IV dose, it was greater than that of either SQ dose. The SQ 4 x 50mg dose demonstrated the most variability and showed the greatest reduction in free amyloid beta at the end of the one month dosing interval (672 hours). Based on the present data, the likely levels of target engagement for GSK933776 based on route of administration is IV>IM>SQ. Figure 7.1 summarizes the free A1-22 concentration over time on linear and semi-log scales.

Figure 7.1: Median Plasma Free A1-22 Concentration-Time Plots

There was also an evident increase in both total A18–35 and A42 levels in plasma after the administration of GSK933776, which began immediately after the dosing. Levels of total A18–35 after the 200 mg IV administration were higher than both the 200 mg IM and SQ doses, which had similar concentration-time profiles (Figure 7.2) . The cohort receiving 4 x 50 mg GSK933776 showed a more gradual accumulation of A18-35 before a decline after the last dose.

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Figure 7.2: Median Plasma Total A18-35 Concentration-Time Plot

Levels of total A42 in plasma were on average highest after the IV dose, although both the 200 mg IM and SQ doses had similar concentration-time profiles. Subjects in the 4 X 50 mg group exhibited the lowest levels of A42 (Figure 7.3); however, all groups had lower measurements of total A in the A42 assay than seen in the A18-35 assay. This is consistent with reports in the literature (see references) that indicate A1-40, rather than the full-length A1-42, may be more relevant in the pathology of A-mediated disease.

Figure 7.3: Median Plasma Total A Concentration-Time Plot

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6.2. Immunogenicity Results

No antibodies were detected post dose against GSK933776 in serum samples collected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776

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7. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS

Mean plasma GSK933776 concentration-time profiles are plotted with mean Aβ1-22, Aβ18-35 or Aβ42 concentrations displayed with nominal time linear scales (Source Data Figure 13.3, Figure 3) truncated to 800 hours postdose. Mean plasma GSK933776concentration-time profiles are plotted with mean change from baseline Aβ1-22, Aβ18-35 or Aβ42 concentrations displayed with nominal time linear scales (Source Data Figure 13.4, Figure 4) truncated to 800 hours post-dose.

There appears to be an increase in plasma Aβ1-22 levels with decreasing GSK933776 concentrations. .In the SQ and IM arms, there appears to be an initial transient decrease in plasma Aβ1-22 levels that might be related to delay in drug distribution into the central compartment following SQ and IM administration. The mean Aβ18-35 or Aβ42 plasma concentrations appear to mimic the plasma GSK933776 levels. The change from baseline Aβ levels followed similar trends as un-corrected values.

Figure 4 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time by Treatment (Truncated)

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Data Source: Figure 13.3

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Figure 5 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Truncated)

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Data Source: Figure 13.4

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8. DISCUSSION AND CONCLUSIONS

8.1. Discussion

GSK933776 is a humanised, Fc-disabled IgG1 monoclonal antibody (mAb) directed against the N-terminal amino acid residues 1-5 of amyloid beta (Aβ). GSK933776 is currently being evaluated as a potential treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD); it has also previously been studied in patients with Alzheimer’s disease (AD). To date, all studies with GSK933776 have administered the dose by intravenous (IV) infusion. This study evaluated other potential routes of administration by establishing bioavailability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, tolerability and safety assessments for GSK933776 following IM and SQ administration. An IV infusion arm was included to estimate the relative bioavailability following IM and SQ administration.

The relative bioavailability of GSK933776 as measured by AUC(0-inf) following 50 mg repeat-dose SQ administration as compared with 200 mg IV administration were similar. In general, the exposure for the first 672 hours and 168 hours (dose normalized) following the 50 mg repeat-dose SQ administration as compared with 200 mg IV administration showed approximately 40% lower exposure. The Cmax following the 50 mg repeated-dose SQ was approximately 70% lower when compared with the 200 mg IV administered dose.

The relative bioavailability of GSK933776 as measured by AUC(0-inf) following 200 mg single-dose IM and SQ administration as compared to 200 mg IV administration showed approximately 15% lower exposure. The Cmax was 55% to 65% lower for the IM and SQ dosing, respectively.

Half-life was comparable across the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM routes of administration.

The Aβ 1-22 levels increased with decreasing GSK933776 concentrations, whereas the Aβ18-35 and Aβ42 in plasma mimicked GSK933776 concentrations.

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8.2. Conclusions

Compared to intravenous administration, the relative bioavailability of subcutaneous and intramuscular administrations of GSK933776 were 83% and 87% for AUC(0-inf) and 36% and 46% for Cmax, respectively.

Compared to intravenous administration, the relative bioavailability results indicate that 200 mg subcutaneous and intra-muscular administrations of GSK933776 produce comparable exposure profiles, with the relative bioavailability at approximately 82% and 85%, respectively, compared to IV administration.

Subcutaneous administration of GSK933776 50 mg weekly were 68% for dose normalized exposure over 7 days (i.e., AUC(0-168)/D) and 60% for exposure over 28 days (i.e., AUC(0-672), respectively. Cmax following 50 mg weekly dosing was substantially lower at 28% of that following 200 mg intravenous administration.

The median t½ was comparable across routes of administration.

Intravenous, subcutaneous and intra-muscular GSK933776 were well tolerated in this study. No significant safety findings could be attributed to investigational product. Vital signs, laboratory and electrocardiographic parameters fell within expected ranges

Plasma Abeta1-22 decreased, Abeta18-35 and Abeta42 increased followingGSK933776 dosing by all routes of administration.

No antibodies were detected post dose against GSK933776 in serum samplescollected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776.

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9. REFERENCES

Anderson, D.H., Talaga, K.C., Rivest, A.J., Barron, E., Hageman, G.S., Johnson, L.V., (2004). Characterization of β amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Experimental Eye Research, 78(2), 243-256.

Fonseca, A.C., Ferreiro, E., Oliveira, C.R., Cardoso, S.M. & Pereira, C.F. (2013). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta, 1832(12):2191-203. doi: 10.1016

GlaxoSmithKline Document Number 2013N182307_00 Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” 13-Nov-2013

Howlett DR, Hortobágyi T & Francis PT (2013). Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue, Brain Pathology, 23(6), 623-632.

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10. POST-TEXT TABLES AND FIGURES

10.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection)

Table 13 Time and Events Tables

DayScreena Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 10

Day 15

Day 22

Day 29

Day 57

Follow Up Day 85d

AssessmentsPre-dose

0h 0.25h 0.5h 0.75h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016h

Informed Consent XDemographics X

Physical Examination X X X XMedical history (inc. family cardiovascular history) XConcomitant Medications X X X X X XDose XAE/SAE Review ----------------------------------------------------------------------------------X------------------------------------------------------------------12-lead ECG X XVital Signs X X X X X X X X X X X X XUrine Drug/Alcoholc X Xc

Follicle stimulating hormone (FSH)/estradiol if indicated XHepatitis B, Hepatitis C, HIV (human immunodeficiency virus) X

Hematology, Chemistry, Urinalysis X X X X X X XHbA1c XPK Blood Sample X Xb Xb Xb Xb X Xb X X X X X X X X X X X XPD Blood Sample X Xb Xb Xb X X X X X X X XImmunogenicity Blood Sample X X X XSubjects were screened a minimum of 7 days, but no more than 30 days, prior to Day 1 Samples were drawn only for subjects in Arm A (IV infusion).Alcohol breathalyzer test night be done instead of urine test post screening visit

The follow up visit occured 3 days

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10.2. Time and Events Tables for Treatment Arm C (50 mg SQ injection)

Screening through Week 1

Day Screena Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Assessments Pre-dose 0h 0.5h 1h 2h 4h 6h 24h 48 h 72h 96h 120hInformed Consent XDemographics XPhysical Examination X XMedical history (includingfamily cardiovascular history)

X

Concomitant Medications X XDose XAE/SAE Review ------------------------------------------------------------------------------X----------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X XUrine Drug/Alcoholb

X Xb

Hepatitis B, Hepatitis C, HIV XHematology, Chemistry, Urinalysis X X XFSH, estradiol (if indicated) XHbA1c XPK Blood Sample X X X X X X XPD Blood Sample X X X X XImmunogenicity Blood Sample Xa. Subjects were screened a minimum of 7 days, but no more than 30 days, prior to Day 1b. Alcohol breathalyzer test may have been done instead of urine test post screening visit

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10.3. Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3

Day Day 8/15 Day 9/16

Day 10/17

Day 11/18 Day 12/19

Day 13/20

Assessments Predose 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120hConcomitant Medications XDose X

AE/SAE Review------------------------------------------------------------------------------------------X--------------------------------------------------------------------------

Vital Signs X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis XPK Blood Sample X X X X X X X

PD Blood SampleX X X X X

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10.4. Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up

Day Day 22Day23

Day 24

Day 25

Day 26

Day 27

Day 31

Day 36

Day 43

Day 50

Day 78

Follow Up Day 106a

Assessments

Pre-dos

e 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h1344

h 2016hPhysical Examination XConcomitant Medications X X X X XDose XAE/SAE Review ---------------------------------------------------------------------------------------------X-----------------------------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis X X X X XPK Blood Sample X X X X X X X X X X X X XPD Blood Sample X X X X X X X X X XImmunogenicity Blood Sample X X X X X

Follow up occured 3 days

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This section contained patient narratives which are textual descriptions of medical history,

treatment and outcome for individual patients who experienced a clinically important adverse

event including serious adverse events during the trial. They have been excluded to protect

patient privacy. This data may be made available subject to an approved research proposal and

a determination of the ability to provide information from the specific narratives whilst protecting

the patient’s privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.1 Summary of Study Population

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------------------------- Safety Population 9 9 9 9 36 Pharmacokinetic Concentration Population 9 9 9 9 36 Pharmacokinetic Parameter Population 9 9 9 9 36 Pharmacodynamic Population 9 9 9 9 36 Pharmacokinetic/Pharmacodynamic Analysis 9 9 9 9 36 Population

Subjects are included in the Safety Population if they have taken at least one dose of study medication.Subjects are included in the Pharmacokinetic (PK) Concentration Population if they have evaluableGSK933776 concentration.Subjects are included in the PK Parameter Population if they have evaluable GSK933776 PK parameter.Subjects are included in the Pharmacodynamic (PD) Population if they have evaluable biomarker concentration.Subjects are included in the PK/PD Analysis Population if they have evaluable GSK933776 concentrationand evaluable biomarker concentration.

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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.2 Summary of Subject Disposition

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------- Completion Status Completed 9 (100%) 9 (100%) 8 (89%) 8 (89%) 34 (94%) Prematurely Withdrawn 0 0 1 (11%) 1 (11%) 2 (6%) Primary Reason for Withdrawal Adverse Event 0 0 0 0 0 Lost to follow-up 0 0 1 (11%) 0 1 (3%) Protocol Violation 0 0 0 0 0 Subject decided to withdraw 0 0 0 0 0 from study Other 0 0 0 1 (11%) 1 (3%)

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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.3 Summary of Protocol Deviations

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Category (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------------

Any protocol deviations 1 (11%) 5 (56%) 5 (56%) 1 (11%) 12 (33%)

Assessments and/or procedures 0 1 (11%) 0 0 1 (3%) Missed assessment or procedure 1 (11%) 0 0 1 (11%) 2 (6%) Visit and/or Assessment window 0 4 (44%) 4 (44%) 0 8 (22%) Other protocol deviation category 0 0 2 (22%) 0 2 (6%)

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Protocol: BA1116891 Page 1 of 2Population: Safety Table 9.4 Summary of Demographic Characteristics

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36)------------------------------------------------------------------------------------------------------------Age (y) n 9 9 9 9 36 Mean 34.7 27.8 26.3 24.8 28.4 SD 8.86 7.71 6.18 6.10 7.97 Median 34.0 26.0 25.0 23.0 26.0 Min. 22 20 19 19 19 Max. 45 43 40 36 45

Sex n 9 9 9 9 36 Female 0 0 1 (11%) 0 1 (3%) Male 9 (100%) 9 (100%) 8 (89%) 9 (100%) 35 (97%)

Ethnicity n 9 9 9 9 36 Hispanic/ 1 (11%) 0 0 1 (11%) 2 (6%) Latino Not Hispanic/ 8 (89%) 9 (100%) 9 (100%) 8 (89%) 34 (94%) Latino

Height (cm) n 9.0 9.0 9.0 9.0 36.0 Mean 176.69 179.39 171.21 174.23 175.38 SD 5.974 4.739 7.710 4.224 6.351 Median 175.40 179.40 168.30 175.30 175.70 Min. 170.4 173.5 161.0 168.5 161.0 Max. 189.2 189.4 180.5 178.4 189.4

Weight (kg) n 9.0 9.0 9.0 9.0 36.0 Mean 78.41 74.37 69.53 70.02 73.08 SD 4.606 5.793 7.122 6.853 6.944 Median 79.20 76.20 69.10 71.40 73.80 Min. 68.0 63.5 57.5 61.7 57.5 Max. 83.3 80.6 79.5 83.5 83.5

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Protocol: BA1116891 Page 2 of 2Population: Safety Table 9.4 Summary of Demographic Characteristics

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36)------------------------------------------------------------------------------------------------------------BMI (kg/m^2) n 9.0 9.0 9.0 9.0 36.0 Mean 25.19 23.15 23.72 23.08 23.78 SD 2.226 2.068 1.873 2.329 2.212 Median 25.74 23.55 23.74 22.70 23.65 Min. 21.6 19.5 20.4 20.6 19.5 Max. 27.9 25.5 27.0 27.2 27.9

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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.5 Summary of Race and Racial Combination Details

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Race (N=9) (N=9) (N=9) (N=9) (N=36) ------------------------------------------------------------------------------------------------- n 9 9 9 9 36 African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%) 18 (50%) American Indian or Alaska Native 0 0 0 1 (11%) 1 (3%) Asian - Central/South Asian Heritage 0 0 0 0 0 Asian - East Asian Heritage 0 0 0 0 0 Asian - Japanese Heritage 1 (11%) 0 0 0 1 (3%) Asian - South East Asian Heritage 0 0 0 0 0 Asian - Mixed Race 0 0 0 0 0 Native Hawaiian or other Pacific 0 0 0 0 0 Islander White - Arabic/North African 1 (11%) 0 0 0 1 (3%) Heritage White - White/Caucasian/European 5 (56%) 5 (56%) 3 (33%) 2 (22%) 15 (42%) Heritage White - Mixed Race 0 0 0 0 0 Mixed Race 0 0 0 0 0

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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.6 Summary of Concomitant Medications

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Generic Term (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------- Any Medication 2 (22%) 3 (33%) 3 (33%) 2 (22%) 10 (28%)

Tylenol 1 (11%) 0 2 (22%) 0 3 (8%) Amoxil 0 1 (11%) 0 0 1 (3%) Cannabis 0 1 (11%) 0 0 1 (3%) Clemastine Fumarate 0 1 (11%) 0 0 1 (3%) Clindamycin 0 0 1 (11%) 0 1 (3%) Decadron 0 0 1 (11%) 0 1 (3%) Estazolam 0 0 1 (11%) 0 1 (3%) Flinstone Multi-Vitamin 1 (11%) 0 0 0 1 (3%) Risperdal 0 1 (11%) 0 0 1 (3%) Zithromax 0 0 0 1 (11%) 1 (3%) Zithromycin 0 0 0 1 (11%) 1 (3%)

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Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.1 Summary of All Adverse Events

System Organ Class IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------- ANY EVENT 4 (44%) 6 (67%) 3 (33%) 2 (22%) 15 (42%)

Infections and infestations Any event 0 3 (33%) 2 (22%) 1 (11%) 6 (17%) Upper respiratory tract 0 2 (22%) 1 (11%) 0 3 (8%) infection Gastroenteritis 0 1 (11%) 0 0 1 (3%) Pharyngitis streptococcal 0 0 1 (11%) 0 1 (3%) Tooth abscess 0 1 (11%) 0 0 1 (3%) Urethritis chlamydial 0 0 0 1 (11%) 1 (3%)

General disorders and administration site conditions Any event 2 (22%) 1 (11%) 0 0 3 (8%) Asthenia 1 (11%) 0 0 0 1 (3%) Catheter site erythema 1 (11%) 0 0 0 1 (3%) Early satiety 0 1 (11%) 0 0 1 (3%)

Renal and urinary disorders Any event 0 2 (22%) 0 1 (11%) 3 (8%) Haematuria 0 1 (11%) 0 1 (11%) 2 (6%) Pyuria 0 1 (11%) 0 0 1 (3%)

Nervous system disorders Any event 1 (11%) 0 1 (11%) 0 2 (6%) Headache 1 (11%) 0 1 (11%) 0 2 (6%)

Skin and subcutaneous tissue disorders Any event 1 (11%) 0 1 (11%) 0 2 (6%) Pruritus generalised 0 0 1 (11%) 0 1 (3%) Skin hypertrophy 1 (11%) 0 0 0 1 (3%)

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Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.1 Summary of All Adverse Events

System Organ Class IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------- Ear and labyrinth disorders Any event 1 (11%) 0 0 0 1 (3%) External ear pain 1 (11%) 0 0 0 1 (3%)

Gastrointestinal disorders Any event 0 0 1 (11%) 0 1 (3%) Constipation 0 0 1 (11%) 0 1 (3%)

Injury, poisoning and procedural complications Any event 0 0 1 (11%) 0 1 (3%) Contusion 0 0 1 (11%) 0 1 (3%)

Investigations Any event 0 1 (11%) 0 0 1 (3%) Weight decreased 0 1 (11%) 0 0 1 (3%)

Psychiatric disorders Any event 0 1 (11%) 0 0 1 (3%) Schizophrenia, paranoid type 0 1 (11%) 0 0 1 (3%)

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Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.2 Summary of Adverse Events Related to Study Treatment

System Organclass IV_200 mg SQ_200 mg SQ_50 mg x 4 IM_200 mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) ----------------------------------------------------------------------------------------------- ANY EVENT 1 (11%) 0 0 0 1 (3%)

Nervous system disorders 1 (11%) 0 0 0 1 (3%) Any event 1 (11%) 0 0 0 1 (3%) Headache 1 (11%) 0 0 0 1 (3%)

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Protocol: BA1116891 Page 1 of 15Population: Safety Table 10.6 Summary of Vital Signs

Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure IV_200mg 9 DAY 1 PREDOSE 9 83.0 4.53 84.0 77 92 (mmHg) 0.5 H 9 74.9 5.06 76.0 69 82 1 H 9 74.1 5.23 76.0 65 82 2 H 9 72.3 6.28 72.0 61 82 4 H 8 74.9 4.09 75.5 70 80 6 H 9 77.8 6.63 78.0 67 86 DAY 2 24 H 9 80.4 5.17 82.0 72 90 DAY 6 120 H 9 81.2 4.55 82.0 75 88 DAY 15 336 H 9 81.8 4.89 82.0 74 88 DAY 29 672 H 9 82.4 4.25 83.0 75 89 DAY 57 1344 H 9 81.4 5.55 80.0 75 93 FOLLOW-UP 2016 H 9 83.7 4.44 83.0 78 91

SQ_200mg 9 DAY 1 PREDOSE 9 76.1 5.73 75.0 67 85 0.5 H 9 73.9 8.80 71.0 64 90 1 H 9 73.3 5.48 75.0 65 82 2 H 9 70.8 6.24 73.0 57 77 4 H 9 73.6 5.90 74.0 65 83 6 H 9 79.2 14.61 74.0 67 107 DAY 2 24 H 9 69.8 10.20 71.0 49 81 DAY 6 120 H 9 73.6 5.55 73.0 65 83 DAY 15 336 H 9 76.0 10.65 75.0 61 94 DAY 29 672 H 9 75.7 7.91 75.0 66 92 DAY 57 1344 H 9 73.8 5.83 74.0 66 81 FOLLOW-UP 2016 H 9 73.0 7.05 71.0 64 84

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure SQ_50mg x 4 9 DAY 1 PREDOSE 9 77.8 9.18 74.0 64 92 (mmHg) 0.5 H 9 76.9 8.95 75.0 64 94 1 H 9 71.1 8.89 71.0 60 86 2 H 9 71.2 7.10 71.0 61 85 4 H 9 68.9 7.54 72.0 58 78 6 H 9 74.4 7.26 74.0 63 84 DAY 2 24 H 9 80.2 5.36 78.0 74 90 DAY 3 48 H 9 80.0 9.70 76.0 71 96 DAY 8 PREDOSE 9 77.0 8.54 79.0 58 86 0.5 H 9 74.2 7.24 74.0 62 89 1 H 9 75.3 7.95 76.0 59 87 2 H 9 75.9 8.54 78.0 60 90 4 H 9 73.6 9.49 75.0 53 87 6 H 9 78.1 8.08 78.0 61 91 DAY 9 24 H 9 81.8 12.84 81.0 57 103 DAY 15 PREDOSE 9 77.9 5.93 78.0 71 88 0.5 H 9 69.3 3.81 69.0 63 74 1 H 9 68.7 6.73 69.0 61 80 2 H 9 71.4 7.81 69.0 57 82 4 H 9 66.9 5.58 67.0 58 76 6 H 9 74.1 3.48 75.0 69 78 DAY 16 24 H 9 77.0 8.17 76.0 63 92 DAY 22 PREDOSE 9 78.6 7.99 79.0 68 93 0.5 H 9 75.9 9.18 76.0 61 93 1 H 9 73.9 6.58 73.0 64 85 2 H 9 74.4 9.26 71.0 65 92 4 H 9 70.6 7.97 70.0 56 85 6 H 9 76.7 9.86 74.0 67 101 DAY 23 24 H 9 77.8 10.21 75.0 62 93 DAY 27 120 H 9 77.6 6.54 76.0 68 87 DAY 36 336 H 9 79.8 10.27 76.0 66 96

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure SQ_50mg x 4 9 DAY 50 672 H 8 79.0 9.20 80.5 62 89 (mmHg) DAY 78 1344 H 8 79.6 8.72 78.5 69 93 FOLLOW-UP 2016 H 8 76.3 7.40 77.0 65 87

IM_200mg 9 DAY 1 PREDOSE 9 78.6 14.00 77.0 49 95 0.5 H 9 77.8 11.12 78.0 57 89 1 H 9 76.6 10.64 75.0 56 89 2 H 9 73.8 10.18 76.0 55 85 4 H 9 73.9 6.64 73.0 64 85 6 H 9 79.1 7.13 83.0 66 88 DAY 2 24 H 9 78.2 14.60 78.0 46 99 DAY 6 120 H 9 78.0 8.31 76.0 65 90 DAY 15 336 H 9 81.3 10.70 80.0 69 97 DAY 29 672 H 9 80.3 11.17 77.0 63 97 DAY 57 1344 H 8 81.9 7.22 82.0 72 92 FOLLOW-UP 2016 H 8 78.6 13.19 80.5 58 97

Systolic Blood Pressure IV_200mg 9 DAY 1 PREDOSE 9 122.9 7.66 122.0 112 134 (mmHg) 0.5 H 9 118.6 7.92 119.0 108 130 1 H 9 119.2 7.05 119.0 110 131 2 H 9 120.7 10.89 116.0 108 137 4 H 8 118.4 5.97 118.0 111 127 6 H 9 120.8 4.12 119.0 116 127 DAY 2 24 H 9 126.9 6.68 127.0 116 136 DAY 6 120 H 9 123.9 6.41 123.0 114 133 DAY 15 336 H 9 124.1 7.10 121.0 115 134 DAY 29 672 H 9 124.4 6.50 128.0 115 132 DAY 57 1344 H 9 125.7 6.00 124.0 118 138 FOLLOW-UP 2016 H 9 124.4 9.03 122.0 113 137

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_200mg 9 DAY 1 PREDOSE 9 122.4 5.27 123.0 113 129 (mmHg) 0.5 H 9 122.4 11.68 117.0 112 148 1 H 9 123.2 11.27 124.0 105 143 2 H 9 120.9 9.48 121.0 103 134 4 H 9 115.7 7.94 116.0 101 126 6 H 9 120.9 14.05 117.0 106 145 DAY 2 24 H 9 120.8 8.70 119.0 108 137 DAY 6 120 H 9 119.7 8.80 122.0 110 137 DAY 15 336 H 9 120.3 13.25 123.0 101 147 DAY 29 672 H 9 121.2 8.36 119.0 110 134 DAY 57 1344 H 9 118.1 6.92 120.0 107 128 FOLLOW-UP 2016 H 9 119.2 8.27 121.0 103 130

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_50mg x 4 9 DAY 1 PREDOSE 9 123.7 6.18 122.0 116 134 (mmHg) 0.5 H 9 120.7 7.42 119.0 108 133 1 H 9 120.6 7.30 123.0 108 129 2 H 9 122.3 4.74 123.0 116 128 4 H 9 119.7 8.46 118.0 110 132 6 H 9 122.0 6.16 123.0 110 129 DAY 2 24 H 9 128.2 6.70 128.0 119 138 DAY 3 48 H 9 127.1 8.30 125.0 115 141 DAY 8 PREDOSE 9 120.2 7.40 120.0 106 130 0.5 H 9 118.7 10.09 121.0 96 129 1 H 9 123.0 7.89 124.0 108 132 2 H 9 121.4 6.77 124.0 111 128 4 H 9 120.9 9.77 123.0 98 129 6 H 9 122.7 8.05 120.0 113 133 DAY 9 24 H 9 130.4 6.02 130.0 122 139 DAY 15 PREDOSE 9 122.6 8.79 124.0 111 135 0.5 H 9 118.4 7.97 119.0 106 131 1 H 9 118.0 4.44 119.0 110 125 2 H 9 122.0 4.80 123.0 111 128 4 H 9 115.4 5.03 117.0 106 121 6 H 9 121.3 5.63 119.0 116 132 DAY 16 24 H 9 123.1 7.01 125.0 111 131 DAY 22 PREDOSE 9 124.9 6.64 126.0 115 133 0.5 H 9 119.8 8.21 119.0 105 130 1 H 9 122.3 6.87 123.0 112 132 2 H 9 125.1 7.94 125.0 114 139 4 H 9 120.2 8.94 121.0 106 138 6 H 9 125.4 6.98 123.0 117 136 DAY 23 24 H 9 125.7 4.42 127.0 120 132 DAY 27 120 H 9 123.9 5.51 124.0 117 131 DAY 36 336 H 9 129.1 9.14 128.0 116 149

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_50mg x 4 9 DAY 50 672 H 8 127.5 6.74 126.0 118 138 (mmHg) DAY 78 1344 H 8 124.0 10.09 125.5 107 137 FOLLOW-UP 2016 H 8 122.9 5.99 122.0 116 133


Pulse Rate (BEATS/MIN) IV_200mg 9 DAY 1 PREDOSE 9 61.8 9.93 62.0 49 82 0.5 H 9 64.8 8.61 65.0 56 82 1 H 9 63.6 6.67 65.0 55 76 2 H 9 64.6 11.24 64.0 49 82 4 H 8 59.9 8.82 60.0 49 73 6 H 9 62.1 10.40 62.0 47 80 DAY 2 24 H 9 71.4 10.91 70.0 60 89 DAY 6 120 H 9 65.3 10.71 62.0 54 87 DAY 15 336 H 9 69.2 6.42 68.0 62 78 DAY 29 672 H 9 64.6 6.54 65.0 56 77 DAY 57 1344 H 9 64.8 9.27 62.0 55 77 FOLLOW-UP 2016 H 9 62.0 9.15 65.0 47 77

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_200mg 9 DAY 1 PREDOSE 9 70.7 14.04 73.0 54 93 0.5 H 9 71.1 14.76 68.0 52 97 1 H 9 72.8 17.28 64.0 55 104 2 H 9 73.0 16.91 65.0 56 108 4 H 9 66.2 15.92 62.0 52 106 6 H 9 71.8 15.52 79.0 52 93 DAY 2 24 H 9 72.8 17.47 67.0 49 104 DAY 6 120 H 9 70.6 7.67 68.0 61 83 DAY 15 336 H 9 66.8 12.12 66.0 49 89 DAY 29 672 H 9 70.3 14.80 65.0 53 98 DAY 57 1344 H 9 69.7 9.58 68.0 62 94 FOLLOW-UP 2016 H 9 71.6 12.60 68.0 56 93

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_50mg x 4 9 DAY 1 PREDOSE 9 65.0 10.54 66.0 51 76 0.5 H 9 58.1 4.96 59.0 53 67 1 H 9 59.7 11.05 54.0 50 86 2 H 9 63.9 9.39 62.0 54 86 4 H 9 61.1 8.84 60.0 48 79 6 H 9 59.1 9.14 55.0 52 81 DAY 2 24 H 9 73.4 11.61 73.0 58 88 DAY 3 48 H 9 70.2 13.75 67.0 53 92 DAY 8 PREDOSE 9 67.1 9.16 65.0 55 85 0.5 H 9 60.7 8.19 62.0 46 73 1 H 9 62.8 9.24 63.0 51 81 2 H 9 65.4 12.69 60.0 51 93 4 H 9 73.4 13.07 74.0 56 97 6 H 9 59.6 7.42 61.0 48 67 DAY 9 24 H 9 75.9 13.27 76.0 58 97 DAY 15 PREDOSE 9 63.9 13.82 61.0 48 93 0.5 H 9 62.1 9.89 60.0 52 85 1 H 9 60.6 5.61 61.0 54 70 2 H 9 61.4 8.31 61.0 51 79 4 H 9 67.3 13.25 63.0 52 90 6 H 9 60.9 7.17 62.0 49 74 DAY 16 24 H 9 67.4 11.46 64.0 56 92 DAY 22 PREDOSE 9 63.1 15.40 60.0 48 98 0.5 H 9 63.2 14.81 59.0 51 98 1 H 9 64.0 13.13 59.0 52 95 2 H 9 65.1 12.83 62.0 54 97 4 H 9 66.4 13.09 62.0 53 89 6 H 9 62.4 15.08 56.0 52 100 DAY 23 24 H 9 69.7 5.92 69.0 62 81 DAY 27 120 H 9 70.0 12.54 65.0 55 86 DAY 36 336 H 9 70.7 16.42 69.0 53 108 DAY 50 672 H 8 68.1 14.96 67.0 51 91

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_50mg x 4 9 DAY 78 1344 H 8 64.6 6.32 63.5 56 76 FOLLOW-UP 2016 H 8 65.8 10.26 67.0 53 82


Respiratory Rate IV_200mg 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.3 1.41 16.0 12 16 1 H 9 15.8 0.67 16.0 14 16 2 H 9 15.8 0.67 16.0 14 16 4 H 8 15.3 1.49 16.0 12 16 6 H 9 16.4 1.33 16.0 14 18 DAY 2 24 H 9 15.8 0.67 16.0 14 16 DAY 6 120 H 9 15.6 0.88 16.0 14 16 DAY 15 336 H 9 16.0 0.00 16.0 16 16 DAY 29 672 H 9 16.0 0.00 16.0 16 16 DAY 57 1344 H 9 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 9 16.4 1.33 16.0 16 20

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_200mg 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.6 1.33 16.0 14 18 1 H 9 16.2 1.56 16.0 14 20 2 H 9 16.0 1.00 16.0 14 18 4 H 9 16.2 1.86 16.0 14 20 6 H 9 16.2 1.20 16.0 14 18 DAY 2 24 H 9 16.0 0.00 16.0 16 16 DAY 6 120 H 9 16.2 1.20 16.0 14 18 DAY 15 336 H 9 16.0 0.00 16.0 16 16 DAY 29 672 H 9 16.0 0.00 16.0 16 16 DAY 57 1344 H 9 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 9 16.0 0.00 16.0 16 16

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.8 0.67 16.0 14 16 1 H 9 16.0 1.00 16.0 14 18 2 H 9 15.3 1.41 16.0 14 18 4 H 9 15.1 1.76 16.0 12 18 6 H 9 15.3 2.00 16.0 12 18 DAY 2 24 H 9 16.0 0.00 16.0 16 16 DAY 3 48 H 9 16.0 0.00 16.0 16 16 DAY 8 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 15.1 1.05 16.0 14 16 1 H 9 15.1 1.05 16.0 14 16 2 H 9 15.8 0.67 16.0 14 16 4 H 9 16.4 1.67 16.0 14 18 6 H 9 16.0 1.00 16.0 14 18 DAY 9 24 H 9 16.3 1.00 16.0 16 19 DAY 15 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 14.7 1.41 14.0 12 16 1 H 9 15.6 1.33 16.0 14 18 2 H 9 15.8 0.67 16.0 14 16 4 H 9 15.6 1.33 16.0 14 18 6 H 9 15.1 1.45 14.0 14 18 DAY 16 24 H 9 16.0 0.00 16.0 16 16 DAY 22 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 15.6 1.67 16.0 12 18 1 H 9 14.7 1.73 16.0 12 16 2 H 9 14.9 1.76 16.0 12 16 4 H 9 14.7 2.00 14.0 12 18 6 H 9 14.9 1.76 14.0 12 18 DAY 23 24 H 9 16.0 0.00 16.0 16 16 DAY 27 120 H 9 16.0 1.00 16.0 14 18 DAY 36 336 H 9 16.0 0.00 16.0 16 16

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 50 672 H 8 16.0 0.00 16.0 16 16 (BEATS/MIN) DAY 78 1344 H 8 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 8 16.0 0.00 16.0 16 16


Temperature (C) IV_200mg 9 DAY 1 PREDOSE 9 36.6 0.12 36.6 36 37 0.5 H 9 36.8 0.12 36.8 37 37 1 H 9 36.8 0.20 36.8 37 37 2 H 9 36.8 0.15 36.8 37 37 4 H 8 36.7 0.17 36.7 36 37 6 H 9 36.7 0.14 36.8 36 37 DAY 2 24 H 9 36.7 0.19 36.7 36 37 DAY 6 120 H 9 36.6 0.25 36.6 36 37 DAY 15 336 H 9 36.7 0.23 36.6 36 37 DAY 29 672 H 9 36.6 0.19 36.6 36 37 DAY 57 1344 H 9 36.7 0.24 36.8 36 37 FOLLOW-UP 2016 H 9 36.7 0.18 36.7 36 37

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_200mg 9 DAY 1 PREDOSE 9 36.7 0.18 36.7 36 37 0.5 H 9 36.9 0.29 36.9 36 37 1 H 9 36.9 0.23 36.9 37 37 2 H 9 36.9 0.17 36.9 37 37 4 H 9 36.9 0.15 36.8 37 37 6 H 9 36.9 0.23 36.9 36 37 DAY 2 24 H 9 36.8 0.20 36.9 37 37 DAY 6 120 H 9 36.8 0.12 36.8 37 37 DAY 15 336 H 9 36.7 0.30 36.7 36 37 DAY 29 672 H 9 36.7 0.22 36.7 36 37 DAY 57 1344 H 9 36.7 0.29 36.6 36 37 FOLLOW-UP 2016 H 9 36.9 0.19 36.9 37 37

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 1 PREDOSE 9 36.6 0.17 36.6 36 37 0.5 H 9 36.8 0.18 36.7 37 37 1 H 9 36.8 0.13 36.8 37 37 2 H 9 36.7 0.21 36.8 36 37 4 H 9 36.8 0.15 36.9 37 37 6 H 9 36.9 0.20 36.9 37 37 DAY 2 24 H 9 36.7 0.15 36.8 36 37 DAY 3 48 H 9 36.6 0.20 36.6 36 37 DAY 8 PREDOSE 9 36.6 0.16 36.6 36 37 0.5 H 9 36.9 0.24 36.8 37 37 1 H 9 36.8 0.16 36.8 37 37 2 H 9 36.8 0.25 36.9 36 37 4 H 9 36.9 0.18 36.9 37 37 6 H 9 36.9 0.21 36.8 37 37 DAY 9 24 H 9 36.7 0.23 36.7 36 37 DAY 15 PREDOSE 9 36.6 0.20 36.6 36 37 0.5 H 9 36.8 0.12 36.8 37 37 1 H 9 36.8 0.17 36.8 37 37 2 H 9 36.8 0.17 36.8 37 37 4 H 9 36.8 0.12 36.9 37 37 6 H 9 36.8 0.23 36.8 36 37 DAY 16 24 H 9 36.7 0.29 36.8 36 37 DAY 22 PREDOSE 9 36.7 0.22 36.6 36 37 0.5 H 9 36.7 0.10 36.7 37 37 1 H 9 36.7 0.09 36.7 37 37 2 H 9 36.7 0.11 36.7 37 37 4 H 9 36.8 0.13 36.8 37 37 6 H 9 36.8 0.18 36.8 37 37 DAY 23 24 H 9 36.8 0.20 36.8 36 37 DAY 27 120 H 9 36.8 0.28 36.8 36 37 DAY 36 336 H 9 36.8 0.24 36.9 37 37 DAY 50 672 H 8 36.7 0.18 36.8 37 37

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Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 78 1344 H 8 36.8 0.24 36.8 36 37 FOLLOW-UP 2016 H 8 36.9 0.17 36.8 37 37


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Protocol: BA1116891 Page 1 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline

Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood IV_200mg 9 DAY 1 0.5 H 9 -8.1 4.91 -9.0 -15 1 Pressure (mmHg) 1 H 9 -8.9 6.11 -9.0 -19 1 2 H 9 -10.7 6.10 -10.0 -23 -5 4 H 8 -8.0 7.23 -9.0 -16 2 6 H 9 -5.2 8.12 0.0 -17 1

DAY 2 24 H 9 -2.6 3.94 -2.0 -7 5

DAY 6 120 H 9 -1.8 4.60 -3.0 -9 5

DAY 15 336 H 9 -1.2 7.92 1.0 -12 11

DAY 29 672 H 9 -0.6 6.33 -1.0 -8 12

DAY 57 1344 H 9 -1.6 8.66 -5.0 -11 16

FOLLOW-UP 2016 H 9 0.7 5.20 4.0 -7 6

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Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_200mg 9 DAY 1 0.5 H 9 -2.2 5.76 -4.0 -11 7 Pressure (mmHg) 1 H 9 -2.8 5.76 -3.0 -11 7 2 H 9 -5.3 5.61 -5.0 -16 3 4 H 9 -2.6 3.57 -2.0 -11 1 6 H 9 3.1 13.35 -1.0 -8 34

DAY 2 24 H 9 -6.3 8.41 -4.0 -27 1

DAY 6 120 H 9 -2.6 3.97 -2.0 -10 3

DAY 15 336 H 9 -0.1 6.83 -1.0 -12 9

DAY 29 672 H 9 -0.4 6.29 0.0 -9 8

DAY 57 1344 H 9 -2.3 4.15 -1.0 -9 3

FOLLOW-UP 2016 H 9 -3.1 7.36 -5.0 -14 8

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Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_50mg x 4 9 DAY 1 0.5 H 9 -0.9 6.13 2.0 -9 8 Pressure (mmHg) 1 H 9 -6.7 5.61 -6.0 -17 0 2 H 9 -6.6 8.57 -4.0 -27 4 4 H 9 -8.9 8.75 -7.0 -23 4 6 H 9 -3.3 7.16 -4.0 -14 8

DAY 2 24 H 9 2.4 7.30 4.0 -10 11

DAY 3 48 H 9 2.2 4.44 2.0 -8 7

DAY 8 PREDOSE 9 -0.8 7.93 1.0 -15 8 0.5 H 9 -3.6 9.33 -1.0 -16 7 1 H 9 -2.4 6.54 -2.0 -13 6 2 H 9 -1.9 12.04 4.0 -28 9 4 H 9 -4.2 10.47 -1.0 -21 9 6 H 9 0.3 7.94 3.0 -10 10

DAY 9 24 H 9 4.0 17.26 8.0 -31 33

DAY 15 PREDOSE 9 0.1 6.39 0.0 -13 8 0.5 H 9 -8.4 8.34 -7.0 -25 0 1 H 9 -9.1 11.16 -5.0 -31 6 2 H 9 -6.3 11.70 -5.0 -35 4 4 H 9 -10.9 11.85 -6.0 -34 -1 6 H 9 -3.7 8.06 -4.0 -17 5

DAY 16 24 H 9 -0.8 9.01 2.0 -20 12

DAY 22 PREDOSE 9 0.8 9.95 -1.0 -10 20 0.5 H 9 -1.9 9.74 4.0 -15 11 1 H 9 -3.9 9.03 0.0 -18 7

87



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_50mg x 4 9 DAY 22 2 H 9 -3.3 13.19 -4.0 -23 19 Pressure (mmHg) 4 H 9 -7.2 7.81 -8.0 -19 3 6 H 9 -1.1 12.34 3.0 -21 19

DAY 23 24 H 9 0.0 7.76 3.0 -12 9

DAY 27 120 H 9 -0.2 4.94 2.0 -9 5

DAY 36 336 H 9 2.0 8.37 2.0 -13 14

DAY 50 672 H 8 0.6 5.29 -1.5 -6 8

DAY 78 1344 H 8 1.3 8.15 4.0 -12 13

FOLLOW-UP 2016 H 8 -2.1 8.71 -0.5 -19 8

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Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood IM_200mg 9 DAY 1 0.5 H 9 -0.8 5.21 -2.0 -7 8 Pressure (mmHg) 1 H 9 -2.0 5.70 -1.0 -13 7 2 H 9 -4.8 8.41 -8.0 -19 8 4 H 9 -4.7 12.20 -4.0 -20 15 6 H 9 0.6 8.16 -3.0 -7 17

DAY 2 24 H 9 -0.3 4.00 1.0 -6 4

DAY 6 120 H 9 -0.6 11.49 -3.0 -16 18

DAY 15 336 H 9 2.8 9.26 1.0 -10 20

DAY 29 672 H 9 1.8 7.07 3.0 -10 14

DAY 57 1344 H 8 2.4 12.56 -3.0 -5 31

FOLLOW-UP 2016 H 8 -0.9 10.40 -4.0 -14 17

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Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood IV_200mg 9 DAY 1 0.5 H 9 -4.3 6.32 -6.0 -12 8 Pressure (mmHg) 1 H 9 -3.7 6.56 -3.0 -14 10 2 H 9 -2.2 8.06 -3.0 -15 15 4 H 8 -3.5 4.99 -3.0 -10 4 6 H 9 -2.1 6.74 -1.0 -15 7

DAY 2 24 H 9 4.0 6.86 4.0 -5 19

DAY 6 120 H 9 1.0 6.98 1.0 -13 9

DAY 15 336 H 9 1.2 9.73 0.0 -14 18

DAY 29 672 H 9 1.6 6.67 1.0 -7 15

DAY 57 1344 H 9 2.8 6.28 1.0 -4 14

FOLLOW-UP 2016 H 9 1.6 8.72 3.0 -18 13

90



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_200mg 9 DAY 1 0.5 H 9 0.0 11.19 -4.0 -10 24 Pressure (mmHg) 1 H 9 0.8 9.40 1.0 -16 19 2 H 9 -1.6 10.16 2.0 -25 10 4 H 9 -6.8 6.59 -7.0 -20 3 6 H 9 -1.6 10.71 -7.0 -14 16

DAY 2 24 H 9 -1.7 8.63 -4.0 -14 13

DAY 6 120 H 9 -2.8 7.36 -4.0 -11 10

DAY 15 336 H 9 -2.1 11.12 -3.0 -21 18

DAY 29 672 H 9 -1.2 6.89 -1.0 -12 7

DAY 57 1344 H 9 -4.3 5.96 -4.0 -15 4

FOLLOW-UP 2016 H 9 -3.2 9.60 -1.0 -19 10

91



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_50mg x 4 9 DAY 1 0.5 H 9 -3.0 8.14 0.0 -16 8 Pressure (mmHg) 1 H 9 -3.1 8.12 -5.0 -13 9 2 H 9 -1.3 6.02 1.0 -11 6 4 H 9 -4.0 10.98 -7.0 -16 16 6 H 9 -1.7 7.16 -1.0 -11 7

DAY 2 24 H 9 4.6 6.88 4.0 -6 13

DAY 3 48 H 9 3.4 7.84 5.0 -13 12

DAY 8 PREDOSE 9 -3.4 6.41 -3.0 -16 4 0.5 H 9 -5.0 9.26 -5.0 -22 10 1 H 9 -0.7 8.79 -1.0 -10 11 2 H 9 -2.2 6.16 -2.0 -15 6 4 H 9 -2.8 12.19 2.0 -28 8 6 H 9 -1.0 10.94 -4.0 -15 16

DAY 9 24 H 9 6.8 5.04 6.0 -4 14

DAY 15 PREDOSE 9 -1.1 7.79 1.0 -12 9 0.5 H 9 -5.2 11.26 -6.0 -26 7 1 H 9 -5.7 7.65 -6.0 -17 9 2 H 9 -1.7 10.22 0.0 -21 12 4 H 9 -8.2 9.52 -5.0 -26 2 6 H 9 -2.3 7.78 -2.0 -13 8

DAY 16 24 H 9 -0.6 5.59 -1.0 -9 8

DAY 22 PREDOSE 9 1.2 7.07 2.0 -8 14 0.5 H 9 -3.9 9.27 -5.0 -16 8 1 H 9 -1.3 10.12 1.0 -20 10

92



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_50mg x 4 9 DAY 22 2 H 9 1.4 11.08 3.0 -15 17 Pressure (mmHg) 4 H 9 -3.4 8.86 -5.0 -12 16 6 H 9 1.8 9.59 2.0 -15 14

DAY 23 24 H 9 2.0 5.17 5.0 -7 7

DAY 27 120 H 9 0.2 5.87 1.0 -12 9

DAY 36 336 H 9 5.4 9.61 3.0 -8 24

DAY 50 672 H 8 3.1 8.61 4.0 -9 16

DAY 78 1344 H 8 -0.4 11.86 2.5 -18 13

FOLLOW-UP 2016 H 8 -1.5 7.15 -1.5 -12 7

93



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood IM_200mg 9 DAY 1 0.5 H 9 -1.3 9.87 -1.0 -16 15 Pressure (mmHg) 1 H 9 -0.6 10.04 -2.0 -14 22 2 H 9 -4.3 11.25 -5.0 -16 23 4 H 9 -5.3 14.08 -8.0 -27 23 6 H 9 -1.3 8.09 -2.0 -13 13

DAY 2 24 H 9 2.2 12.32 4.0 -22 20

DAY 6 120 H 9 -4.1 14.00 -6.0 -18 27

DAY 15 336 H 9 -0.7 6.16 -3.0 -7 12

DAY 29 672 H 9 5.4 6.02 7.0 -4 11

DAY 57 1344 H 8 -0.5 8.28 -1.0 -10 16

FOLLOW-UP 2016 H 8 -5.1 8.49 -9.0 -14 9

94



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate IV_200mg 9 DAY 1 0.5 H 9 3.0 9.35 2.0 -9 24 (BEATS/MIN) 1 H 9 1.8 8.27 3.0 -14 13 2 H 9 2.8 8.64 0.0 -4 24 4 H 8 -1.8 6.27 -2.0 -9 11 6 H 9 0.3 9.18 0.0 -8 22

DAY 2 24 H 9 9.7 13.03 11.0 -12 25

DAY 6 120 H 9 3.6 9.94 3.0 -6 24

DAY 15 336 H 9 7.4 9.40 10.0 -7 23

DAY 29 672 H 9 2.8 10.13 -1.0 -14 18

DAY 57 1344 H 9 3.0 9.75 6.0 -13 19

FOLLOW-UP 2016 H 9 0.2 11.79 1.0 -17 16

95



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_200mg 9 DAY 1 0.5 H 9 0.4 7.00 0.0 -9 11 (BEATS/MIN) 1 H 9 2.1 8.75 1.0 -9 18 2 H 9 2.3 7.68 0.0 -10 15 4 H 9 -4.4 13.19 -1.0 -33 13 6 H 9 1.1 5.69 0.0 -8 10

DAY 2 24 H 9 2.1 14.43 8.0 -24 17

DAY 6 120 H 9 -0.1 13.75 2.0 -19 21

DAY 15 336 H 9 -3.9 14.26 -1.0 -36 12

DAY 29 672 H 9 -0.3 16.99 1.0 -32 25

DAY 57 1344 H 9 -1.0 11.63 1.0 -23 14

FOLLOW-UP 2016 H 9 0.9 15.27 -3.0 -25 23

96



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_50mg x 4 9 DAY 1 0.5 H 9 -6.9 7.37 -9.0 -16 2 (BEATS/MIN) 1 H 9 -5.3 8.06 -6.0 -15 10 2 H 9 -1.1 8.45 1.0 -13 10 4 H 9 -3.9 11.48 -3.0 -17 21 6 H 9 -5.9 8.13 -5.0 -19 5

DAY 2 24 H 9 8.4 11.13 11.0 -14 21

DAY 3 48 H 9 5.2 13.32 9.0 -20 24

DAY 8 PREDOSE 9 2.1 8.27 4.0 -12 12 0.5 H 9 -4.3 8.11 -4.0 -18 8 1 H 9 -2.2 12.05 -4.0 -15 27 2 H 9 0.4 8.47 0.0 -15 17 4 H 9 8.4 16.57 6.0 -10 43 6 H 9 -5.4 9.51 -8.0 -18 13

DAY 9 24 H 9 10.9 15.88 12.0 -9 43

DAY 15 PREDOSE 9 -1.1 15.64 -6.0 -21 18 0.5 H 9 -2.9 13.72 -7.0 -15 27 1 H 9 -4.4 8.79 -5.0 -16 7 2 H 9 -3.6 11.91 -8.0 -14 21 4 H 9 2.3 12.41 0.0 -12 32 6 H 9 -4.1 7.57 -6.0 -13 8

DAY 16 24 H 9 2.4 7.00 2.0 -7 16

DAY 22 PREDOSE 9 -1.9 11.23 0.0 -15 22 0.5 H 9 -1.8 12.74 -4.0 -16 22 1 H 9 -1.0 9.70 -2.0 -13 19

97



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_50mg x 4 9 DAY 22 2 H 9 0.1 10.49 3.0 -13 21 (BEATS/MIN) 4 H 9 1.4 13.50 2.0 -13 31 6 H 9 -2.6 12.95 -2.0 -21 24

DAY 23 24 H 9 4.7 11.36 8.0 -11 18

DAY 27 120 H 9 5.0 19.76 4.0 -20 30

DAY 36 336 H 9 5.7 13.11 3.0 -16 32

DAY 50 672 H 8 1.9 10.99 3.5 -15 16

DAY 78 1344 H 8 -1.6 9.72 -2.5 -14 12

FOLLOW-UP 2016 H 8 -0.5 7.67 0.0 -9 11

98



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate IM_200mg 9 DAY 1 0.5 H 9 3.6 18.17 3.0 -23 42 (BEATS/MIN) 1 H 9 7.1 19.90 0.0 -18 44 2 H 9 2.2 13.43 4.0 -20 26 4 H 9 8.1 15.50 9.0 -23 30 6 H 9 4.9 16.39 -3.0 -13 34

DAY 2 24 H 9 10.1 13.88 8.0 -4 44

DAY 6 120 H 9 13.9 19.25 13.0 -17 41

DAY 15 336 H 9 14.6 14.66 10.0 -4 41

DAY 29 672 H 9 7.6 15.44 7.0 -8 41

DAY 57 1344 H 8 6.4 17.62 1.0 -15 33

FOLLOW-UP 2016 H 8 8.8 13.74 7.5 -11 26

99



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate IV_200mg 9 DAY 1 0.5 H 9 -0.7 1.41 0.0 -4 0 (BEATS/MIN) 1 H 9 -0.2 0.67 0.0 -2 0 2 H 9 -0.2 0.67 0.0 -2 0 4 H 8 -0.8 1.49 0.0 -4 0 6 H 9 0.4 1.33 0.0 -2 2

DAY 2 24 H 9 -0.2 0.67 0.0 -2 0

DAY 6 120 H 9 -0.4 0.88 0.0 -2 0

DAY 15 336 H 9 0.0 0.00 0.0 0 0

DAY 29 672 H 9 0.0 0.00 0.0 0 0

DAY 57 1344 H 9 0.0 0.00 0.0 0 0

FOLLOW-UP 2016 H 9 0.4 1.33 0.0 0 4

100



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_200mg 9 DAY 1 0.5 H 9 -0.4 1.33 0.0 -2 2 (BEATS/MIN) 1 H 9 0.2 1.56 0.0 -2 4 2 H 9 0.0 1.00 0.0 -2 2 4 H 9 0.2 1.86 0.0 -2 4 6 H 9 0.2 1.20 0.0 -2 2

DAY 2 24 H 9 0.0 0.00 0.0 0 0

DAY 6 120 H 9 0.2 1.20 0.0 -2 2

DAY 15 336 H 9 0.0 0.00 0.0 0 0

DAY 29 672 H 9 0.0 0.00 0.0 0 0

DAY 57 1344 H 9 0.0 0.00 0.0 0 0

FOLLOW-UP 2016 H 9 0.0 0.00 0.0 0 0

101



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 1 0.5 H 9 -0.2 0.67 0.0 -2 0 (BEATS/MIN) 1 H 9 0.0 1.00 0.0 -2 2 2 H 9 -0.7 1.41 0.0 -2 2 4 H 9 -0.9 1.76 0.0 -4 2 6 H 9 -0.7 2.00 0.0 -4 2

DAY 2 24 H 9 0.0 0.00 0.0 0 0

DAY 3 48 H 9 0.0 0.00 0.0 0 0

DAY 8 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -0.9 1.05 0.0 -2 0 1 H 9 -0.9 1.05 0.0 -2 0 2 H 9 -0.2 0.67 0.0 -2 0 4 H 9 0.4 1.67 0.0 -2 2 6 H 9 0.0 1.00 0.0 -2 2

DAY 9 24 H 9 0.3 1.00 0.0 0 3

DAY 15 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -1.3 1.41 -2.0 -4 0 1 H 9 -0.4 1.33 0.0 -2 2 2 H 9 -0.2 0.67 0.0 -2 0 4 H 9 -0.4 1.33 0.0 -2 2 6 H 9 -0.9 1.45 -2.0 -2 2

DAY 16 24 H 9 0.0 0.00 0.0 0 0

DAY 22 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -0.4 1.67 0.0 -4 2 1 H 9 -1.3 1.73 0.0 -4 0

102



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 22 2 H 9 -1.1 1.76 0.0 -4 0 (BEATS/MIN) 4 H 9 -1.3 2.00 -2.0 -4 2 6 H 9 -1.1 1.76 -2.0 -4 2

DAY 23 24 H 9 0.0 0.00 0.0 0 0

DAY 27 120 H 9 0.0 1.00 0.0 -2 2

DAY 36 336 H 9 0.0 0.00 0.0 0 0

DAY 50 672 H 8 0.0 0.00 0.0 0 0

DAY 78 1344 H 8 0.0 0.00 0.0 0 0

FOLLOW-UP 2016 H 8 0.0 0.00 0.0 0 0

103



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate IM_200mg 9 DAY 1 0.5 H 9 -0.2 1.56 0.0 -2 2 (BEATS/MIN) 1 H 9 -0.4 1.33 0.0 -2 2 2 H 9 -0.2 1.20 0.0 -2 2 4 H 9 -0.7 1.41 0.0 -2 2 6 H 9 -0.2 1.86 0.0 -4 2

DAY 2 24 H 9 0.0 0.00 0.0 0 0

DAY 6 120 H 9 0.4 0.88 0.0 0 2

DAY 15 336 H 9 0.0 0.00 0.0 0 0

DAY 29 672 H 9 0.0 0.00 0.0 0 0

DAY 57 1344 H 8 0.0 0.00 0.0 0 0

FOLLOW-UP 2016 H 8 -0.3 0.71 0.0 -2 0

104



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) IV_200mg 9 DAY 1 0.5 H 9 0.2 0.16 0.2 -0 0 1 H 9 0.2 0.20 0.2 -0 1 2 H 9 0.2 0.17 0.1 0 1 4 H 8 0.1 0.19 0.0 -0 0 6 H 9 0.1 0.15 0.0 -0 0

DAY 2 24 H 9 0.1 0.23 0.1 -0 1

DAY 6 120 H 9 0.0 0.31 0.0 -0 1

DAY 15 336 H 9 0.1 0.22 0.0 -0 1

DAY 29 672 H 9 -0.0 0.21 0.0 -0 0

DAY 57 1344 H 9 0.1 0.30 0.2 -1 1

FOLLOW-UP 2016 H 9 0.1 0.23 0.2 -0 0

105



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_200mg 9 DAY 1 0.5 H 9 0.2 0.31 0.3 -0 1 1 H 9 0.2 0.14 0.2 0 0 2 H 9 0.2 0.13 0.2 0 0 4 H 9 0.2 0.12 0.2 0 0 6 H 9 0.2 0.12 0.2 0 0

DAY 2 24 H 9 0.1 0.29 0.1 -0 1

DAY 6 120 H 9 0.1 0.19 0.1 -0 0

DAY 15 336 H 9 0.0 0.34 0.1 -0 1

DAY 29 672 H 9 -0.0 0.15 0.0 -0 0

DAY 57 1344 H 9 0.0 0.33 0.0 -0 1

FOLLOW-UP 2016 H 9 0.2 0.21 0.2 -0 0

106



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 1 0.5 H 9 0.2 0.13 0.2 -0 0 1 H 9 0.2 0.23 0.2 -0 1 2 H 9 0.1 0.30 0.1 -0 1 4 H 9 0.2 0.23 0.2 -0 0 6 H 9 0.3 0.26 0.2 -0 1

DAY 2 24 H 9 0.1 0.27 0.1 -1 0

DAY 3 48 H 9 -0.1 0.28 0.0 -1 0

DAY 8 PREDOSE 9 -0.1 0.23 -0.1 -0 1 0.5 H 9 0.2 0.33 0.1 -0 1 1 H 9 0.2 0.22 0.2 -0 1 2 H 9 0.2 0.26 0.2 -0 1 4 H 9 0.3 0.26 0.3 -0 1 6 H 9 0.2 0.23 0.3 -0 1

DAY 9 24 H 9 0.1 0.26 0.1 -0 0

DAY 15 PREDOSE 9 -0.0 0.16 -0.1 -0 0 0.5 H 9 0.1 0.21 0.1 -0 0 1 H 9 0.1 0.28 0.1 -0 0 2 H 9 0.2 0.25 0.1 -0 1 4 H 9 0.2 0.24 0.2 -0 1 6 H 9 0.1 0.26 0.1 -0 1

DAY 16 24 H 9 0.1 0.25 0.1 -0 0

DAY 22 PREDOSE 9 0.0 0.23 0.0 -0 1 0.5 H 9 0.0 0.19 -0.1 -0 0 1 H 9 0.1 0.16 0.0 -0 0 2 H 9 0.1 0.17 0.1 -0 0

107



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 22 4 H 9 0.1 0.20 0.1 -0 1 6 H 9 0.2 0.19 0.2 -0 1

DAY 23 24 H 9 0.1 0.32 0.1 -1 1

DAY 27 120 H 9 0.1 0.30 0.1 -0 1

DAY 36 336 H 9 0.2 0.23 0.1 -0 1

DAY 50 672 H 8 0.1 0.18 0.0 -0 0

DAY 78 1344 H 8 0.1 0.33 0.0 -0 1

FOLLOW-UP 2016 H 8 0.2 0.22 0.2 -0 1

108



Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) IM_200mg 9 DAY 1 0.5 H 9 0.2 0.17 0.2 0 1 1 H 9 0.3 0.27 0.2 0 1 2 H 9 0.3 0.10 0.3 0 1 4 H 9 0.1 0.17 0.1 -0 0 6 H 9 0.3 0.21 0.2 0 1

DAY 2 24 H 9 0.2 0.20 0.2 -0 0

DAY 6 120 H 9 0.1 0.32 0.2 -1 0

DAY 15 336 H 9 0.0 0.14 0.0 -0 0

DAY 29 672 H 9 0.1 0.16 0.1 -0 0

DAY 57 1344 H 8 0.0 0.27 0.1 -1 0

FOLLOW-UP 2016 H 8 0.0 0.29 0.0 -1 1

109


Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.8 Summary of ECG Findings

IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Category (N=9) (N=9) (N=9) (N=9) -------------------------------------------------------------------------------------------- SCREENING n 9 9 9 9 Normal 2 (22.2%) 3 (33.3%) 4 (44.4%) 0 Abnormal - Not Clinically 7 (77.8%) 6 (66.7%) 5 (55.6%) 9 (100.0%) Significant Abnormal - Clinically 0 0 0 0 Significant

FOLLOW-UP n 9 9 8 8 Normal 3 (33.3%) 5 (55.6%) 2 (25.0%) 2 (25.0%) Abnormal - Not Clinically 6 (66.7%) 4 (44.4%) 6 (75.0%) 6 (75.0%) Significant Abnormal - Clinically 0 0 0 0 Significant

110


Protocol: BA1116891 Page 1 of 4Population: Safety Table 10.9 Summary of ECG Values

Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Heart Rate IV_200mg 9 SCREENING 9 57.3 8.20 58.0 48 76 (bpm) FOLLOW-UP 9 58.8 7.79 58.0 49 71

SQ_200mg 9 SCREENING 9 64.0 9.21 64.0 51 76 FOLLOW-UP 9 67.1 11.96 63.0 53 92

SQ_50mg x 4 9 SCREENING 9 61.1 7.36 62.0 49 69 FOLLOW-UP 8 66.8 8.71 67.5 53 80

IM_200mg 9 SCREENING 9 62.0 7.02 60.0 52 73 FOLLOW-UP 8 64.8 10.02 64.5 47 78

PR Interval IV_200mg 9 SCREENING 9 167.2 16.77 163.0 143 195 (msec) FOLLOW-UP 9 167.9 14.40 164.0 151 196




111



Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QRS Duration IV_200mg 9 SCREENING 9 98.6 6.97 99.0 89 109 (msec) FOLLOW-UP 9 98.0 9.76 93.0 85 114




QTcB IV_200mg 9 SCREENING 9 394.7 10.69 394.0 379 417 (msec) FOLLOW-UP 9 396.0 20.04 391.0 375 432




112



Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QTcF IV_200mg 9 SCREENING 9 397.9 11.75 399.0 381 417 (msec) FOLLOW-UP 9 397.6 15.30 393.0 379 424




QT,Corrected IV_200mg 9 SCREENING 9 397.4 11.16 398.0 382 417 (msec) FOLLOW-UP 9 396.8 14.76 394.0 379 423




113



Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QT Interval IV_200mg 9 SCREENING 9 405.0 24.99 417.0 355 432 (msec) FOLLOW-UP 9 401.0 19.46 398.0 375 434




114


Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.10 Summary of Category of QTc Data by Treatment and Time

Planned 451 to 481 to Treatment N Visit Time n <=450 <=480 <=500 >500 --------------------------------------------------------------------------------------------------------- QT, IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 Corrected (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0

SQ_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0

SQ_50mg x 4 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0

IM_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0

QTcB IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0




115


Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.10 Summary of Category of QTc Data by Treatment and Time

Planned 451 to 481 to Treatment N Visit Time n <=450 <=480 <=500 >500 --------------------------------------------------------------------------------------------------------- QTcF IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0




116


Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.11 Summary of Category of QTc Change from Baseline by Treatment and Time

Planned Treatment N Visit Time n <=30 31 to <=60 >61 -------------------------------------------------------------------------------------------------------- QT, IV_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 Corrected (msec)

SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0

SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0

IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0

QTcB IV_200mg 9 FOLLOW-UP 2016 H 9 8 (88.9%) 1 (11.1%) 0 (msec)

SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0

SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 7 (87.5%) 1 (12.5%) 0

IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0

117


Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.11 Summary of Category of QTc Change from Baseline by Treatment and Time

Planned Treatment N Visit Time n <=30 31 to <=60 >61 -------------------------------------------------------------------------------------------------------- QTcF IV_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 (msec)

SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0

SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0

IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0

118


Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event

No data to report

119


Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.13 Summary of Time on Treatment Before Liver Event

No data to report

120


Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.14 Summary of Liver Biopsy Details

No data to report

121


Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.15 Summary of Liver Imaging Details

No data to report

122


Protocol: BA1116891 Page 1 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit

Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alanine IV_200mg 9 DAY 1 PREDOSE 9 24.1 5.80 24.0 17 33 Aminotrans ferase (U/L)

DAY 5 96 H 9 24.9 5.90 25.0 17 36

DAY 15 336 H 9 25.4 7.14 25.0 17 36

DAY 29 672 H 9 22.7 3.91 21.0 18 29

DAY 57 1344 H 9 27.7 9.01 28.0 13 42

FOLLOW-UP 2016 H 9 23.2 4.87 24.0 15 31

SQ_200mg 9 DAY 1 PREDOSE 9 21.8 5.67 20.0 14 32

DAY 5 96 H 9 21.7 7.25 19.0 11 34

DAY 15 336 H 9 20.3 6.82 19.0 8 28

DAY 29 672 H 9 18.4 3.61 18.0 15 27

DAY 57 1344 H 9 22.1 12.60 16.0 12 50

FOLLOW-UP 2016 H 9 22.1 6.85 21.0 13 36

SQ_50mg x 4 9 DAY 1 PREDOSE 9 30.7 10.81 28.0 17 49

DAY 6 120 H 9 32.0 13.77 35.0 15 56

123



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alanine SQ_50mg x 4 9 DAY 8 PREDOSE 9 32.0 14.36 33.0 13 57 Aminotrans ferase (U/L)

DAY 15 PREDOSE 9 29.2 14.16 31.0 12 58

DAY 22 PREDOSE 9 31.1 18.38 24.0 12 64

DAY 31 216 H 9 30.8 15.66 26.0 14 65

DAY 50 672 H 8 32.1 16.77 31.5 11 67

DAY 78 1344 H 8 29.4 13.95 26.5 12 60

FOLLOW-UP 2016 H 8 26.6 12.99 24.5 13 56

IM_200mg 9 DAY 1 PREDOSE 9 18.8 5.89 19.0 11 31

DAY 5 96 H 9 20.4 3.97 20.0 16 29

DAY 15 336 H 9 20.4 6.56 17.0 14 32

DAY 29 672 H 9 20.2 5.24 18.0 15 31

DAY 57 1344 H 8 25.5 10.43 25.5 15 48

FOLLOW-UP 2016 H 8 18.3 5.65 19.0 10 27

124



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Albumin IV_200mg 9 DAY 1 PREDOSE 9 43.0 3.71 44.0 34 47 (g/L)

DAY 5 96 H 9 43.6 3.71 45.0 36 47

DAY 15 336 H 9 43.9 3.41 44.0 37 49

DAY 29 672 H 9 43.0 3.81 44.0 34 47

DAY 57 1344 H 9 43.3 3.50 43.0 36 47

FOLLOW-UP 2016 H 9 43.8 3.67 44.0 36 48

SQ_200mg 9 DAY 1 PREDOSE 9 41.9 2.32 41.0 38 45

DAY 5 96 H 9 44.2 1.79 44.0 42 48

DAY 15 336 H 9 43.6 2.24 44.0 40 47

DAY 29 672 H 9 44.7 2.29 45.0 42 49

DAY 57 1344 H 9 43.2 2.77 44.0 38 48

FOLLOW-UP 2016 H 9 41.7 1.94 41.0 38 45


DAY 6 120 H 9 45.6 2.83 45.0 42 51

DAY 8 PREDOSE 9 44.4 2.79 44.0 41 49

125



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Albumin SQ_50mg x 4 9 DAY 15 PREDOSE 9 43.9 2.37 44.0 40 47 (g/L)

DAY 22 PREDOSE 9 43.9 1.76 44.0 41 47

DAY 31 216 H 9 45.6 2.40 46.0 40 49

DAY 50 672 H 8 44.9 2.23 45.0 41 48

DAY 78 1344 H 8 44.8 2.49 44.5 41 48

FOLLOW-UP 2016 H 8 43.9 2.17 43.5 40 47

IM_200mg 9 DAY 1 PREDOSE 9 43.9 2.76 45.0 39 47

DAY 5 96 H 9 45.1 3.33 45.0 40 51

DAY 15 336 H 9 44.7 3.08 45.0 38 49

DAY 29 672 H 9 44.0 3.28 44.0 39 48

DAY 57 1344 H 8 44.8 2.19 44.0 42 49

FOLLOW-UP 2016 H 8 44.5 2.98 43.5 41 50

Alkaline IV_200mg 9 DAY 1 PREDOSE 9 74.7 14.97 78.0 55 93 Phosphatas e (U/L)

126



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alkaline IV_200mg 9 DAY 5 96 H 9 79.8 18.71 79.0 57 116 Phosphatas e (U/L)

DAY 15 336 H 9 76.8 13.34 81.0 53 90

DAY 29 672 H 9 75.0 14.97 69.0 57 103

DAY 57 1344 H 9 75.9 12.15 74.0 61 99

FOLLOW-UP 2016 H 9 77.1 12.26 83.0 59 90

SQ_200mg 9 DAY 1 PREDOSE 9 65.2 14.32 67.0 40 89

DAY 5 96 H 9 64.2 11.91 62.0 43 80

DAY 15 336 H 9 64.7 11.92 65.0 41 78

DAY 29 672 H 9 65.9 11.25 69.0 40 77

DAY 57 1344 H 9 61.0 9.82 60.0 43 77

FOLLOW-UP 2016 H 9 61.9 11.25 64.0 46 81


DAY 6 120 H 9 68.7 15.43 70.0 47 91

DAY 8 PREDOSE 9 66.3 15.33 67.0 44 98

127



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alkaline SQ_50mg x 4 9 DAY 15 PREDOSE 9 62.7 14.65 61.0 43 84 Phosphatas e (U/L)

DAY 22 PREDOSE 9 62.2 14.94 62.0 38 85

DAY 31 216 H 9 65.2 15.25 64.0 42 94

DAY 50 672 H 8 64.5 16.63 60.0 44 91

DAY 78 1344 H 8 70.3 20.40 70.5 41 97

FOLLOW-UP 2016 H 8 64.4 14.20 65.5 39 79

IM_200mg 9 DAY 1 PREDOSE 9 72.1 19.60 65.0 45 107

DAY 5 96 H 9 79.0 24.79 68.0 53 126

DAY 15 336 H 9 76.7 22.62 66.0 48 112

DAY 29 672 H 9 75.2 23.40 63.0 50 111

DAY 57 1344 H 8 81.0 21.26 72.5 56 114

FOLLOW-UP 2016 H 8 80.6 20.11 77.0 56 111

128



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Aspartate IV_200mg 9 DAY 1 PREDOSE 9 24.9 2.15 25.0 21 28 Aminotrans ferase (U/L)

DAY 5 96 H 9 25.2 4.38 23.0 21 33

DAY 15 336 H 9 26.8 2.68 27.0 21 29

DAY 29 672 H 9 24.6 3.28 25.0 19 29

DAY 57 1344 H 9 28.3 5.41 27.0 23 39

FOLLOW-UP 2016 H 9 26.3 4.09 26.0 21 34

SQ_200mg 9 DAY 1 PREDOSE 9 24.2 6.10 23.0 17 35

DAY 5 96 H 9 24.7 8.72 23.0 17 45

DAY 15 336 H 9 25.3 7.30 23.0 16 39

DAY 29 672 H 9 24.0 5.29 22.0 18 33

DAY 57 1344 H 9 27.2 11.42 23.0 18 49

FOLLOW-UP 2016 H 9 24.1 7.04 22.0 17 39


DAY 6 120 H 9 27.4 6.44 26.0 18 37

129



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Aspartate SQ_50mg x 4 9 DAY 8 PREDOSE 9 27.1 6.97 25.0 15 35 Aminotrans ferase (U/L)

DAY 15 PREDOSE 9 27.2 7.28 31.0 16 34

DAY 22 PREDOSE 9 26.1 8.52 23.0 15 40

DAY 31 216 H 9 27.6 6.75 28.0 17 39

DAY 50 672 H 8 28.1 8.32 27.0 15 42

DAY 78 1344 H 8 26.9 8.04 26.5 15 40

FOLLOW-UP 2016 H 8 29.6 9.35 26.0 21 46

IM_200mg 9 DAY 1 PREDOSE 9 22.8 2.95 23.0 19 27

DAY 5 96 H 9 24.3 5.59 23.0 16 35

DAY 15 336 H 9 24.4 4.56 25.0 17 33

DAY 29 672 H 9 26.1 4.65 26.0 18 34

DAY 57 1344 H 8 38.1 26.01 30.5 20 100

FOLLOW-UP 2016 H 8 23.5 7.11 22.5 12 35

130



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Bilirubin IV_200mg 9 DAY 1 PREDOSE 9 11.780 6.0121 8.550 5.13 22.23 (umol/L)

DAY 5 96 H 9 11.780 6.4802 10.260 3.42 25.65

DAY 15 336 H 9 15.200 14.5963 13.680 5.13 53.01

DAY 29 672 H 9 12.350 5.8477 10.260 6.84 25.65

DAY 57 1344 H 9 11.400 4.8366 10.260 5.13 20.52

FOLLOW-UP 2016 H 9 14.060 6.3280 13.680 5.13 25.65

SQ_200mg 9 DAY 1 PREDOSE 9 9.690 3.4200 8.550 5.13 15.39

DAY 5 96 H 9 13.300 4.2560 13.680 6.84 20.52

DAY 15 336 H 9 12.540 3.3114 11.970 8.55 18.81

DAY 29 672 H 9 11.210 3.5368 10.260 6.84 17.10

DAY 57 1344 H 9 12.730 2.4350 11.970 8.55 15.39

FOLLOW-UP 2016 H 9 12.730 4.1103 11.970 5.13 18.81

SQ_50mg x 4 9 DAY 1 PREDOSE 9 7.600 3.0959 6.840 3.42 11.97

DAY 6 120 H 9 9.310 1.9330 8.550 6.84 13.68

DAY 8 PREDOSE 9 7.790 2.7187 8.550 5.13 13.68

131



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Bilirubin SQ_50mg x 4 9 DAY 15 PREDOSE 9 7.410 2.5650 6.840 3.42 11.97 (umol/L)

DAY 22 PREDOSE 9 7.410 1.7100 6.840 5.13 10.26

DAY 31 216 H 9 8.740 2.6276 6.840 6.84 13.68

DAY 50 672 H 8 10.474 2.6550 10.260 6.84 13.68

DAY 78 1344 H 8 8.764 1.6947 8.550 6.84 11.97

FOLLOW-UP 2016 H 8 8.550 3.1663 9.405 3.42 11.97

IM_200mg 9 DAY 1 PREDOSE 9 9.880 6.0323 8.550 5.13 22.23

DAY 5 96 H 9 9.690 4.6830 10.260 3.42 17.10

DAY 15 336 H 9 9.500 2.9755 8.550 5.13 13.68

DAY 29 672 H 9 11.020 5.4150 8.550 5.13 20.52

DAY 57 1344 H 8 11.115 4.9222 9.405 5.13 18.81

FOLLOW-UP 2016 H 8 10.688 6.0458 8.550 5.13 23.94

Blood Urea IV_200mg 9 DAY 1 PREDOSE 9 4.9583 1.06270 4.6410 3.213 7.140 Nitrogen (mmol/L)

132



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Blood Urea IV_200mg 9 DAY 5 96 H 9 4.6410 1.07100 4.9980 3.213 6.426 Nitrogen (mmol/L)

DAY 15 336 H 9 4.4427 1.23811 4.6410 2.856 6.069

DAY 29 672 H 9 4.4427 1.01150 4.6410 2.499 6.069

DAY 57 1344 H 9 4.5617 1.48034 4.2840 2.499 6.426

FOLLOW-UP 2016 H 9 4.7997 0.82015 5.3550 3.570 5.712

SQ_200mg 9 DAY 1 PREDOSE 9 5.1963 1.32513 5.3550 2.499 6.783

DAY 5 96 H 9 4.1650 1.18404 4.6410 2.142 6.069

DAY 15 336 H 9 4.7203 1.53321 5.3550 2.499 6.426

DAY 29 672 H 9 4.5220 1.60650 4.6410 2.142 6.783

DAY 57 1344 H 9 4.2443 1.17654 4.2840 2.142 5.712

FOLLOW-UP 2016 H 9 4.6013 1.74387 4.2840 2.142 7.140


DAY 6 120 H 9 5.3550 0.96125 4.9980 4.284 7.497

DAY 8 PREDOSE 9 5.7913 1.18104 5.7120 4.284 7.854

133



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Blood Urea SQ_50mg x 4 9 DAY 15 PREDOSE 9 4.9980 0.91017 4.6410 3.927 6.426 Nitrogen (mmol/L)

DAY 22 PREDOSE 9 5.0773 1.69131 4.9980 2.142 8.211

DAY 31 216 H 9 4.9583 0.60386 4.9980 3.927 6.069

DAY 50 672 H 8 4.7749 0.83042 4.9980 3.213 5.712

DAY 78 1344 H 8 5.0426 0.90390 4.9980 3.927 6.426

FOLLOW-UP 2016 H 8 5.2658 1.09204 4.9980 3.927 7.497

IM_200mg 9 DAY 1 PREDOSE 9 5.4740 1.56633 5.3550 2.856 7.497

DAY 5 96 H 9 5.3550 0.85606 5.3550 3.927 6.783

DAY 15 336 H 9 5.1170 0.97768 4.6410 3.927 6.426

DAY 29 672 H 9 4.7600 1.54586 4.9980 2.856 8.211

DAY 57 1344 H 8 4.4625 0.80960 4.2840 3.570 5.355

FOLLOW-UP 2016 H 8 5.1765 1.09620 5.1765 3.570 7.140

Calcium IV_200mg 9 DAY 1 PREDOSE 9 2.3222 0.10929 2.3500 2.125 2.450 (mmol/L)

134



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Calcium IV_200mg 9 DAY 5 96 H 9 2.3111 0.08580 2.3250 2.150 2.450 (mmol/L)

DAY 15 336 H 9 2.3167 0.06847 2.3000 2.225 2.450

DAY 29 672 H 9 2.2778 0.10112 2.3000 2.100 2.425

DAY 57 1344 H 9 2.2944 0.09336 2.3250 2.125 2.425

FOLLOW-UP 2016 H 9 2.2944 0.11711 2.3000 2.125 2.500

SQ_200mg 9 DAY 1 PREDOSE 9 2.3472 0.07949 2.3750 2.225 2.475

DAY 5 96 H 9 2.4111 0.05017 2.4250 2.350 2.475

DAY 15 336 H 9 2.3639 0.09610 2.3750 2.250 2.550

DAY 29 672 H 9 2.3889 0.04526 2.3750 2.325 2.450

DAY 57 1344 H 9 2.3528 0.06548 2.3500 2.275 2.475

FOLLOW-UP 2016 H 9 2.3167 0.06731 2.3250 2.225 2.425


DAY 6 120 H 9 2.3889 0.06509 2.4000 2.300 2.500

DAY 8 PREDOSE 9 2.3722 0.06548 2.3750 2.250 2.475

DAY 15 PREDOSE 9 2.3417 0.06495 2.3500 2.250 2.425

135



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Calcium SQ_50mg x 4 9 DAY 22 PREDOSE 9 2.3556 0.05559 2.3500 2.300 2.475 (mmol/L)

DAY 31 216 H 9 2.3889 0.07615 2.3750 2.225 2.475

DAY 50 672 H 8 2.3750 0.07196 2.3750 2.275 2.500

DAY 78 1344 H 8 2.3844 0.07433 2.4000 2.225 2.475

FOLLOW-UP 2016 H 8 2.3156 0.04989 2.3125 2.250 2.400

IM_200mg 9 DAY 1 PREDOSE 9 2.3806 0.07683 2.3750 2.300 2.575

DAY 5 96 H 9 2.3722 0.07336 2.3750 2.250 2.475

DAY 15 336 H 9 2.3500 0.07906 2.3500 2.200 2.475

DAY 29 672 H 9 2.3528 0.06548 2.3500 2.250 2.475

DAY 57 1344 H 8 2.3656 0.08958 2.3375 2.225 2.500

FOLLOW-UP 2016 H 8 2.3500 0.07319 2.3625 2.250 2.475

Carbon IV_200mg 9 DAY 1 PREDOSE 9 31.6 1.42 32.0 30 34 Dioxide (mmol/L)

DAY 5 96 H 9 31.4 1.67 31.0 30 35

136



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Carbon IV_200mg 9 DAY 15 336 H 9 30.4 1.13 30.0 29 32 Dioxide (mmol/L)

DAY 29 672 H 9 30.9 1.45 31.0 28 33

DAY 57 1344 H 9 29.7 1.50 30.0 28 32

FOLLOW-UP 2016 H 9 30.4 1.88 31.0 26 32

SQ_200mg 9 DAY 1 PREDOSE 9 31.0 1.50 31.0 29 34

DAY 5 96 H 9 31.7 1.58 31.0 29 34

DAY 15 336 H 9 30.3 2.12 31.0 26 32

DAY 29 672 H 9 30.8 1.92 30.0 28 34

DAY 57 1344 H 9 29.9 1.76 30.0 28 33

FOLLOW-UP 2016 H 9 30.9 2.32 31.0 28 34


DAY 6 120 H 9 30.1 1.54 30.0 28 33

DAY 8 PREDOSE 9 30.2 2.11 30.0 26 33

DAY 15 PREDOSE 9 29.9 2.76 31.0 23 32

137



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Carbon SQ_50mg x 4 9 DAY 22 PREDOSE 9 29.4 1.51 30.0 26 31 Dioxide (mmol/L)

DAY 31 216 H 9 30.6 2.40 31.0 26 34

DAY 50 672 H 8 29.0 2.83 29.5 23 32

DAY 78 1344 H 8 28.8 2.25 29.5 25 32

FOLLOW-UP 2016 H 8 29.1 2.17 29.0 26 32

IM_200mg 9 DAY 1 PREDOSE 9 31.3 1.66 31.0 29 34

DAY 5 96 H 9 31.2 0.83 31.0 30 32

DAY 15 336 H 9 30.3 1.87 30.0 27 33

DAY 29 672 H 9 30.8 1.92 30.0 28 34

DAY 57 1344 H 8 29.4 2.07 30.0 27 32

FOLLOW-UP 2016 H 8 30.5 2.07 31.0 28 34

Chloride IV_200mg 9 DAY 1 PREDOSE 9 104.2 2.44 103.0 102 109 (mmol/L)

DAY 5 96 H 9 104.7 2.50 104.0 101 108

138



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Chloride IV_200mg 9 DAY 15 336 H 9 105.3 2.29 106.0 101 108 (mmol/L)

DAY 29 672 H 9 105.1 2.71 105.0 102 111

DAY 57 1344 H 9 105.2 1.99 105.0 102 108

FOLLOW-UP 2016 H 9 104.6 3.61 104.0 99 110

SQ_200mg 9 DAY 1 PREDOSE 9 104.3 1.50 104.0 102 106

DAY 5 96 H 9 103.8 1.79 104.0 101 106

DAY 15 336 H 9 103.9 3.10 104.0 99 108

DAY 29 672 H 9 103.7 1.73 104.0 101 106

DAY 57 1344 H 9 103.7 3.71 104.0 95 108

FOLLOW-UP 2016 H 9 105.1 2.09 106.0 102 108


DAY 6 120 H 9 105.1 1.90 105.0 102 108

DAY 8 PREDOSE 9 105.1 2.03 104.0 103 109

DAY 15 PREDOSE 9 105.9 2.47 105.0 103 111

DAY 22 PREDOSE 9 106.1 1.62 106.0 104 109

139



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Chloride SQ_50mg x 4 9 DAY 31 216 H 9 105.4 2.07 105.0 102 110 (mmol/L)

DAY 50 672 H 8 105.6 2.00 106.0 102 108

DAY 78 1344 H 8 105.9 2.42 106.0 102 110

FOLLOW-UP 2016 H 8 106.3 1.91 106.5 103 109

IM_200mg 9 DAY 1 PREDOSE 9 104.3 1.22 104.0 103 107

DAY 5 96 H 9 104.8 1.48 104.0 103 108

DAY 15 336 H 9 104.7 2.40 105.0 101 109

DAY 29 672 H 9 104.8 2.59 106.0 101 108

DAY 57 1344 H 8 105.1 1.25 105.0 104 107

FOLLOW-UP 2016 H 8 104.8 2.12 105.5 102 107

Creatine SQ_200mg 9 DAY 57 1344 H 1 799.0 799.0 799 799 Kinase BB (U/L)

SQ_50mg x 4 9 DAY 22 PREDOSE 1 405.0 405.0 405 405

FOLLOW-UP 2016 H 1 974.0 974.0 974 974

140



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatine SQ_200mg 9 DAY 57 1344 H 1 4.50 4.50 4.5 4.5 Kinase MB (ug/L)

SQ_50mg x 4 9 DAY 22 PREDOSE 1 1.10 1.10 1.1 1.1

FOLLOW-UP 2016 H 1 1.30 1.30 1.3 1.3

Creatine IM_200mg 9 DAY 57 1344 H 1 6462.0 6462.0 6462 6462 Kinase (U/L)

Creatinine IV_200mg 9 DAY 1 PREDOSE 9 81.52629 10.624598 79.56180 61.881 97.242 (umol/L)

DAY 5 96 H 9 78.57956 11.220826 79.56180 53.041 88.402

DAY 15 336 H 9 77.59731 14.510979 79.56180 53.041 97.242

DAY 29 672 H 9 74.65058 10.926780 79.56180 53.041 88.402

DAY 57 1344 H 9 77.59731 7.366833 79.56180 61.881 88.402

FOLLOW-UP 2016 H 9 75.63282 16.004859 79.56180 44.201 97.242

SQ_200mg 9 DAY 1 PREDOSE 9 80.54404 18.983002 79.56180 44.201 106.082

141



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatinine SQ_200mg 9 DAY 5 96 H 9 79.56180 18.752896 79.56180 53.041 114.922 (umol/L)

DAY 15 336 H 9 78.57956 16.207033 79.56180 53.041 97.242

DAY 29 672 H 9 78.57956 12.844513 79.56180 53.041 97.242

DAY 57 1344 H 9 78.57956 19.490809 79.56180 44.201 114.922

FOLLOW-UP 2016 H 9 78.57956 20.468664 70.72160 53.041 106.082


DAY 6 120 H 9 80.54404 19.490809 88.40200 44.201 97.242

DAY 8 PREDOSE 9 81.52629 16.406717 88.40200 44.201 97.242

DAY 15 PREDOSE 9 79.56180 17.118974 79.56180 44.201 106.082

DAY 22 PREDOSE 9 79.56180 17.118974 79.56180 44.201 97.242

DAY 31 216 H 9 80.54404 12.844513 79.56180 53.041 97.242

DAY 50 672 H 8 78.45678 14.516321 79.56180 53.041 97.242

DAY 78 1344 H 8 78.45678 17.321572 79.56180 53.041 106.082

FOLLOW-UP 2016 H 8 77.35175 18.752896 75.14170 53.041 106.082

IM_200mg 9 DAY 1 PREDOSE 9 76.61507 6.250965 79.56180 70.721 88.402

142



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatinine IM_200mg 9 DAY 5 96 H 9 79.56180 7.655838 79.56180 70.721 88.402 (umol/L)

DAY 15 336 H 9 77.59731 8.591130 79.56180 61.881 88.402

DAY 29 672 H 9 78.57956 6.910702 79.56180 70.721 88.402

DAY 57 1344 H 8 77.35175 6.250965 79.56180 70.721 88.402

FOLLOW-UP 2016 H 8 75.14170 8.184435 75.14170 61.881 88.402

Direct IV_200mg 9 DAY 1 PREDOSE 9 3.800 2.0552 3.420 1.71 6.84 Bilirubin (umol/L)

DAY 5 96 H 9 4.180 1.7336 5.130 1.71 6.84

DAY 15 336 H 9 4.750 3.0563 5.130 1.71 11.97

DAY 29 672 H 9 3.990 2.2621 3.420 1.71 8.55

DAY 57 1344 H 9 3.990 2.0943 3.420 1.71 8.55

FOLLOW-UP 2016 H 9 4.940 2.3328 5.130 1.71 8.55

SQ_200mg 9 DAY 1 PREDOSE 9 3.420 1.2092 3.420 1.71 5.13

DAY 5 96 H 9 4.370 1.2423 5.130 1.71 5.13

143



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Direct SQ_200mg 9 DAY 15 336 H 9 4.370 1.2423 3.420 3.42 6.84 Bilirubin (umol/L)

DAY 29 672 H 9 3.800 0.7540 3.420 3.42 5.13

DAY 57 1344 H 9 4.370 0.9012 5.130 3.42 5.13

FOLLOW-UP 2016 H 9 4.370 1.5081 5.130 1.71 6.84


DAY 6 120 H 9 3.230 1.0276 3.420 1.71 5.13

DAY 8 PREDOSE 9 2.850 1.2092 3.420 1.71 5.13

DAY 15 PREDOSE 9 2.470 0.9012 1.710 1.71 3.42

DAY 22 PREDOSE 9 2.470 0.9012 1.710 1.71 3.42

DAY 31 216 H 9 2.850 1.4809 1.710 1.71 5.13

DAY 50 672 H 8 3.420 1.2926 3.420 1.71 5.13

DAY 78 1344 H 8 3.420 0.0000 3.420 3.42 3.42

FOLLOW-UP 2016 H 8 3.206 1.0959 3.420 1.71 5.13

IM_200mg 9 DAY 1 PREDOSE 9 3.610 2.3328 3.420 1.71 8.55

144



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Direct IM_200mg 9 DAY 5 96 H 9 3.610 1.8025 3.420 1.71 6.84 Bilirubin (umol/L)

DAY 15 336 H 9 3.420 1.2092 3.420 1.71 5.13

DAY 29 672 H 9 3.610 1.5868 3.420 1.71 6.84

DAY 57 1344 H 8 3.848 1.7700 3.420 1.71 6.84

FOLLOW-UP 2016 H 8 3.634 1.6947 3.420 1.71 6.84

Gamma IV_200mg 9 DAY 1 PREDOSE 9 23.6 9.07 22.0 14 40 Glutamyl Transferas e (U/L)

DAY 5 96 H 9 23.4 8.79 22.0 13 37

DAY 15 336 H 9 22.7 8.31 20.0 14 37

DAY 29 672 H 9 21.0 7.07 20.0 12 29

DAY 57 1344 H 9 23.1 13.73 19.0 13 56

FOLLOW-UP 2016 H 9 24.9 16.66 16.0 12 65

SQ_200mg 9 DAY 1 PREDOSE 9 17.1 11.60 12.0 6 44

145



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Gamma SQ_200mg 9 DAY 5 96 H 9 19.2 12.15 13.0 9 46 Glutamyl Transferas e (U/L)

DAY 15 336 H 9 17.9 12.40 11.0 8 46

DAY 29 672 H 9 17.4 12.17 13.0 4 46

DAY 57 1344 H 9 18.8 11.41 14.0 7 43

FOLLOW-UP 2016 H 9 17.6 11.02 12.0 9 43


DAY 6 120 H 9 21.7 10.63 18.0 9 43

DAY 8 PREDOSE 9 21.2 11.14 19.0 9 44

DAY 15 PREDOSE 9 18.6 12.12 16.0 6 47

DAY 22 PREDOSE 9 18.7 9.95 15.0 7 39

DAY 31 216 H 9 21.9 12.99 17.0 7 43

DAY 50 672 H 8 20.5 13.34 15.5 10 51

DAY 78 1344 H 8 21.9 14.52 19.5 6 53

FOLLOW-UP 2016 H 8 20.1 13.09 16.5 8 48

146



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Gamma IM_200mg 9 DAY 1 PREDOSE 9 21.7 12.00 19.0 10 51 Glutamyl Transferas e (U/L)

DAY 5 96 H 9 22.6 10.98 21.0 11 49

DAY 15 336 H 9 22.8 10.34 23.0 11 47

DAY 29 672 H 9 22.0 10.34 20.0 11 47

DAY 57 1344 H 8 25.4 9.93 24.0 16 48

FOLLOW-UP 2016 H 8 25.3 11.30 21.5 19 53

Glucose IV_200mg 9 DAY 1 PREDOSE 9 4.93333 0.354771 4.99500 4.440 5.439 (mmol/L)

DAY 5 96 H 9 4.72983 0.359443 4.71750 4.051 5.439

DAY 15 336 H 9 4.93333 0.470479 5.05050 4.051 5.494

DAY 29 672 H 9 4.81000 0.330679 4.66200 4.495 5.439

DAY 57 1344 H 9 4.80383 0.383624 4.77300 4.162 5.494

FOLLOW-UP 2016 H 9 4.61267 0.495199 4.44000 4.107 5.605

SQ_200mg 9 DAY 1 PREDOSE 9 4.90250 0.374368 4.99500 4.384 5.494

147



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Glucose SQ_200mg 9 DAY 5 96 H 9 4.67433 0.427005 4.66200 4.218 5.494 (mmol/L)

DAY 15 336 H 9 4.72983 0.415118 4.82850 3.885 5.161

DAY 29 672 H 9 4.69283 0.229019 4.66200 4.384 5.217

DAY 57 1344 H 9 4.68667 0.471024 4.71750 3.996 5.328

FOLLOW-UP 2016 H 9 4.91483 0.773081 4.66200 4.051 6.604


DAY 6 120 H 9 5.11833 0.725639 4.99500 4.273 6.660

DAY 8 PREDOSE 9 4.82850 0.401177 4.93950 4.162 5.328

DAY 15 PREDOSE 9 4.91483 0.357653 4.88400 4.329 5.439

DAY 22 PREDOSE 9 5.26017 1.750402 4.71750 4.218 9.823

DAY 31 216 H 9 4.75450 0.374368 4.77300 4.162 5.272

DAY 50 672 H 8 4.65506 0.414728 4.55100 4.218 5.328

DAY 78 1344 H 8 4.73138 0.377295 4.71750 4.329 5.383

FOLLOW-UP 2016 H 8 4.87706 0.561650 4.82850 4.218 6.105

IM_200mg 9 DAY 1 PREDOSE 9 5.09367 0.446402 4.93950 4.384 5.827

148



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Glucose IM_200mg 9 DAY 5 96 H 9 4.75450 0.686497 4.77300 3.663 6.216 (mmol/L)

DAY 15 336 H 9 4.85317 0.400323 4.93950 3.996 5.217

DAY 29 672 H 9 4.90250 0.383513 4.88400 4.107 5.328

DAY 57 1344 H 8 4.68281 0.342045 4.82850 4.051 5.050

FOLLOW-UP 2016 H 8 4.56488 0.261583 4.52325 4.218 4.939

Potassium IV_200mg 9 DAY 1 PREDOSE 9 4.17 0.194 4.10 4.0 4.6 (mmol/L)

DAY 5 96 H 9 4.09 0.220 4.10 3.7 4.4

DAY 15 336 H 9 4.20 0.292 4.20 3.8 4.7

DAY 29 672 H 9 4.21 0.190 4.20 3.8 4.4

DAY 57 1344 H 9 4.23 0.224 4.20 3.9 4.7

FOLLOW-UP 2016 H 9 4.33 0.265 4.40 3.9 4.7

SQ_200mg 9 DAY 1 PREDOSE 9 4.11 0.276 4.10 3.7 4.4

DAY 5 96 H 9 4.20 0.180 4.20 4.0 4.4

DAY 15 336 H 9 4.33 0.287 4.40 3.9 4.7

149



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Potassium SQ_200mg 9 DAY 29 672 H 9 4.24 0.364 4.20 3.8 4.9 (mmol/L)

DAY 57 1344 H 9 4.01 0.237 3.90 3.7 4.4

FOLLOW-UP 2016 H 9 4.29 0.276 4.30 3.7 4.6


DAY 6 120 H 9 4.22 0.222 4.20 3.9 4.6

DAY 8 PREDOSE 9 4.14 0.194 4.20 3.7 4.3

DAY 15 PREDOSE 9 4.04 0.292 4.00 3.6 4.7

DAY 22 PREDOSE 9 4.10 0.250 4.00 3.8 4.6

DAY 31 216 H 9 4.17 0.173 4.10 3.9 4.4

DAY 50 672 H 8 4.21 0.309 4.30 3.7 4.6

DAY 78 1344 H 8 4.29 0.336 4.20 3.9 5.0

FOLLOW-UP 2016 H 8 4.24 0.192 4.25 4.0 4.5

IM_200mg 9 DAY 1 PREDOSE 9 4.12 0.291 4.10 3.7 4.7

DAY 5 96 H 9 4.20 0.274 4.10 3.9 4.7

DAY 15 336 H 9 4.14 0.279 4.10 3.8 4.6

150



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Potassium IM_200mg 9 DAY 29 672 H 9 4.20 0.212 4.20 3.9 4.6 (mmol/L)

DAY 57 1344 H 8 4.21 0.280 4.30 3.8 4.6

FOLLOW-UP 2016 H 8 4.21 0.242 4.20 3.9 4.7

Protein/Cr SQ_200mg 9 DAY 5 96 H 1 0.030 0.030 0.03 0.03 eatinine (Ratio)

DAY 29 672 H 1 0.040 0.040 0.04 0.04

DAY 57 1344 H 1 0.020 0.020 0.02 0.02

IM_200mg 9 DAY 5 96 H 1 0.030 0.030 0.03 0.03

FOLLOW-UP 2016 H 2 0.185 0.2192 0.185 0.03 0.34

Protein IV_200mg 9 DAY 1 PREDOSE 9 71.0 7.16 72.0 54 80 (g/L)

DAY 5 96 H 9 71.2 6.28 72.0 57 77

DAY 15 336 H 9 71.7 6.48 72.0 57 81

DAY 29 672 H 9 70.1 6.83 72.0 53 76

151



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Protein IV_200mg 9 DAY 57 1344 H 9 70.2 6.85 70.0 55 79 (g/L)

FOLLOW-UP 2016 H 9 70.9 7.91 73.0 54 79

SQ_200mg 9 DAY 1 PREDOSE 9 71.9 4.23 73.0 65 79

DAY 5 96 H 9 74.7 5.05 75.0 67 82

DAY 15 336 H 9 74.1 5.13 74.0 64 83

DAY 29 672 H 9 75.1 4.23 76.0 69 80

DAY 57 1344 H 9 72.7 5.07 75.0 65 80

FOLLOW-UP 2016 H 9 68.9 2.71 69.0 65 74


DAY 6 120 H 9 74.3 4.44 73.0 68 84

DAY 8 PREDOSE 9 72.9 5.11 74.0 64 82

DAY 15 PREDOSE 9 70.3 3.74 72.0 64 75

DAY 22 PREDOSE 9 70.7 3.28 69.0 67 75

DAY 31 216 H 9 74.7 4.58 75.0 65 80

DAY 50 672 H 8 72.5 3.30 73.0 68 77

152



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Protein SQ_50mg x 4 9 DAY 78 1344 H 8 72.0 3.59 72.5 65 77 (g/L)

FOLLOW-UP 2016 H 8 70.3 4.13 71.0 63 75

IM_200mg 9 DAY 1 PREDOSE 9 72.4 5.13 71.0 64 81

DAY 5 96 H 9 73.3 5.83 73.0 63 81

DAY 15 336 H 9 73.8 6.30 74.0 61 84

DAY 29 672 H 9 72.1 6.39 72.0 61 80

DAY 57 1344 H 8 72.1 4.42 72.5 65 80

FOLLOW-UP 2016 H 8 72.3 4.71 71.5 67 81

Sodium IV_200mg 9 DAY 1 PREDOSE 9 141.6 1.24 142.0 139 143 (mmol/L)

DAY 5 96 H 9 141.3 1.80 141.0 139 145

DAY 15 336 H 9 141.6 2.13 141.0 139 145

DAY 29 672 H 9 141.1 1.96 141.0 138 145

DAY 57 1344 H 9 140.9 1.76 140.0 138 144

FOLLOW-UP 2016 H 9 140.8 2.05 141.0 136 143

153



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Sodium SQ_200mg 9 DAY 1 PREDOSE 9 141.4 1.01 142.0 140 143 (mmol/L)

DAY 5 96 H 9 140.7 2.12 140.0 138 143

DAY 15 336 H 9 140.7 2.83 142.0 135 144

DAY 29 672 H 9 140.4 1.33 140.0 139 143

DAY 57 1344 H 9 140.6 2.35 141.0 135 143

FOLLOW-UP 2016 H 9 141.0 1.73 141.0 138 143


DAY 6 120 H 9 141.0 0.71 141.0 140 142

DAY 8 PREDOSE 9 141.0 1.73 141.0 138 143

DAY 15 PREDOSE 9 141.4 1.01 141.0 140 143

DAY 22 PREDOSE 9 141.9 1.17 142.0 140 144

DAY 31 216 H 9 141.8 1.09 142.0 140 143

DAY 50 672 H 8 141.4 1.06 141.5 140 143

DAY 78 1344 H 8 141.1 1.96 141.0 139 144

FOLLOW-UP 2016 H 8 142.6 1.92 143.0 139 145

154



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Sodium IM_200mg 9 DAY 1 PREDOSE 9 141.9 1.05 142.0 141 144 (mmol/L)

DAY 5 96 H 9 141.8 1.79 142.0 140 145

DAY 15 336 H 9 141.4 1.94 141.0 138 144

DAY 29 672 H 9 141.1 2.09 140.0 139 144

DAY 57 1344 H 8 141.5 1.20 141.5 140 143

FOLLOW-UP 2016 H 8 141.4 1.60 141.0 139 144

Thyrotropi SQ_200mg 9 DAY 29 672 H 1 1.9400 1.9400 1.940 1.940 n (mIU/L)

Thyroxine, SQ_200mg 9 DAY 29 672 H 1 15.4440 15.4440 15.444 15.444 Free (pmol/L)

Triiodothy SQ_200mg 9 DAY 29 672 H 1 0.04620 0.04620 0.046 0.046 ronine, Free (nmol/L)

155



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Urate IV_200mg 9 DAY 1 PREDOSE 9 331.878 80.4779 321.300 208.25 464.10 (umol/L)

DAY 5 96 H 9 341.794 57.5423 357.000 226.10 404.60

DAY 15 336 H 9 335.844 76.3197 362.950 238.00 452.20

DAY 29 672 H 9 329.233 55.0174 303.450 243.95 410.55

DAY 57 1344 H 9 319.978 56.4292 315.350 226.10 404.60

FOLLOW-UP 2016 H 9 331.217 93.5116 339.150 226.10 487.90

SQ_200mg 9 DAY 1 PREDOSE 9 362.289 63.1404 357.000 279.65 464.10

DAY 5 96 H 9 349.728 53.3660 333.200 279.65 440.30

DAY 15 336 H 9 349.728 60.3696 327.250 285.60 476.00

DAY 29 672 H 9 351.050 69.0687 327.250 267.75 481.95

DAY 57 1344 H 9 345.100 62.4750 321.300 285.60 458.15

FOLLOW-UP 2016 H 9 364.272 27.5533 362.950 327.25 404.60


DAY 6 120 H 9 304.111 48.1035 315.350 202.30 368.90

DAY 8 PREDOSE 9 309.400 57.9934 327.250 184.45 392.70

156



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Urate SQ_50mg x 4 9 DAY 15 PREDOSE 9 277.667 51.0973 285.600 184.45 339.15 (umol/L)

DAY 22 PREDOSE 9 296.839 54.4063 297.500 196.35 368.90

DAY 31 216 H 9 289.567 57.3025 309.400 166.60 362.95

DAY 50 672 H 8 310.887 72.9937 318.325 184.45 404.60

DAY 78 1344 H 8 311.631 68.9450 327.250 220.15 380.80

FOLLOW-UP 2016 H 8 325.019 61.0056 327.250 238.00 404.60

IM_200mg 9 DAY 1 PREDOSE 9 266.428 46.9238 273.700 172.55 309.40

DAY 5 96 H 9 288.244 59.7309 273.700 202.30 398.65

DAY 15 336 H 9 288.244 51.2798 321.300 220.15 357.00

DAY 29 672 H 9 286.261 41.1631 297.500 202.30 327.25

DAY 57 1344 H 8 287.088 41.6803 288.575 220.15 345.10

FOLLOW-UP 2016 H 8 302.706 64.9798 294.525 220.15 392.70

157


Protocol: BA1116891 Page 1 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit

Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils IV_200mg 9 DAY 1 PREDOSE 9 0.01 0.033 0.00 0.0 0.1 (10^9/L)

DAY 5 96 H 9 0.02 0.044 0.00 0.0 0.1

DAY 15 336 H 9 0.00 0.000 0.00 0.0 0.0

DAY 29 672 H 9 0.02 0.044 0.00 0.0 0.1

DAY 57 1344 H 9 0.01 0.033 0.00 0.0 0.1

FOLLOW-UP 2016 H 9 0.01 0.033 0.00 0.0 0.1

SQ_200mg 9 DAY 1 PREDOSE 9 0.00 0.000 0.00 0.0 0.0

DAY 5 96 H 9 0.01 0.033 0.00 0.0 0.1

DAY 15 336 H 9 0.00 0.000 0.00 0.0 0.0

DAY 29 672 H 9 0.01 0.033 0.00 0.0 0.1

DAY 57 1344 H 9 0.00 0.000 0.00 0.0 0.0

FOLLOW-UP 2016 H 9 0.01 0.033 0.00 0.0 0.1


DAY 6 120 H 9 0.00 0.000 0.00 0.0 0.0

DAY 8 PREDOSE 9 0.00 0.000 0.00 0.0 0.0

158



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.00 0.000 0.00 0.0 0.0 (10^9/L)

DAY 22 PREDOSE 9 0.01 0.033 0.00 0.0 0.1

DAY 31 216 H 9 0.00 0.000 0.00 0.0 0.0

DAY 50 672 H 8 0.00 0.000 0.00 0.0 0.0

DAY 78 1344 H 8 0.00 0.000 0.00 0.0 0.0

FOLLOW-UP 2016 H 8 0.00 0.000 0.00 0.0 0.0

IM_200mg 9 DAY 1 PREDOSE 9 0.00 0.000 0.00 0.0 0.0

DAY 5 96 H 9 0.00 0.000 0.00 0.0 0.0

DAY 15 336 H 9 0.01 0.033 0.00 0.0 0.1

DAY 29 672 H 9 0.01 0.033 0.00 0.0 0.1

DAY 57 1344 H 8 0.01 0.035 0.00 0.0 0.1

FOLLOW-UP 2016 H 8 0.00 0.000 0.00 0.0 0.0

Basophils/Le IV_200mg 9 DAY 1 PREDOSE 9 0.0053 0.00187 0.0050 0.002 0.008 ukocytes (1)

DAY 5 96 H 9 0.0056 0.00296 0.0040 0.003 0.012

159



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils/Le IV_200mg 9 DAY 15 336 H 9 0.0044 0.00167 0.0040 0.003 0.008 ukocytes (1)

DAY 29 672 H 9 0.0068 0.00286 0.0070 0.003 0.011

DAY 57 1344 H 9 0.0061 0.00440 0.0040 0.002 0.014

FOLLOW-UP 2016 H 9 0.0053 0.00194 0.0050 0.003 0.009

SQ_200mg 9 DAY 1 PREDOSE 9 0.0046 0.00194 0.0040 0.003 0.009

DAY 5 96 H 9 0.0051 0.00276 0.0040 0.002 0.010

DAY 15 336 H 9 0.0029 0.00183 0.0030 0.000 0.005

DAY 29 672 H 9 0.0059 0.00190 0.0050 0.004 0.010

DAY 57 1344 H 9 0.0043 0.00265 0.0040 0.000 0.010

FOLLOW-UP 2016 H 9 0.0060 0.00541 0.0050 0.002 0.020


DAY 6 120 H 9 0.0049 0.00196 0.0050 0.002 0.009

DAY 8 PREDOSE 9 0.0059 0.00285 0.0060 0.002 0.011

DAY 15 PREDOSE 9 0.0059 0.00310 0.0060 0.003 0.012

DAY 22 PREDOSE 9 0.0066 0.00559 0.0050 0.002 0.020

160



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils/Le SQ_50mg x 4 9 DAY 31 216 H 9 0.0051 0.00302 0.0040 0.002 0.012 ukocytes (1)

DAY 50 672 H 8 0.0049 0.00223 0.0045 0.003 0.010

DAY 78 1344 H 8 0.0050 0.00245 0.0045 0.002 0.010

FOLLOW-UP 2016 H 8 0.0058 0.00362 0.0050 0.002 0.013

IM_200mg 9 DAY 1 PREDOSE 9 0.0051 0.00190 0.0050 0.002 0.008

DAY 5 96 H 9 0.0043 0.00141 0.0040 0.002 0.006

DAY 15 336 H 9 0.0057 0.00474 0.0040 0.002 0.017

DAY 29 672 H 9 0.0051 0.00369 0.0040 0.001 0.014

DAY 57 1344 H 8 0.0054 0.00475 0.0050 0.001 0.016

FOLLOW-UP 2016 H 8 0.0053 0.00403 0.0040 0.002 0.014

Eosinophils IV_200mg 9 DAY 1 PREDOSE 9 0.13 0.050 0.10 0.1 0.2 (10^9/L)

DAY 5 96 H 9 0.14 0.073 0.10 0.1 0.3

DAY 15 336 H 9 0.12 0.097 0.10 0.0 0.3

DAY 29 672 H 9 0.14 0.088 0.10 0.0 0.3

161



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils IV_200mg 9 DAY 57 1344 H 9 0.14 0.101 0.10 0.0 0.3 (10^9/L)

FOLLOW-UP 2016 H 9 0.13 0.100 0.10 0.0 0.3

SQ_200mg 9 DAY 1 PREDOSE 9 0.29 0.237 0.20 0.1 0.9

DAY 5 96 H 9 0.22 0.192 0.20 0.1 0.7

DAY 15 336 H 9 0.19 0.105 0.20 0.1 0.4

DAY 29 672 H 9 0.21 0.226 0.10 0.1 0.8

DAY 57 1344 H 9 0.21 0.127 0.20 0.1 0.5

FOLLOW-UP 2016 H 9 0.23 0.166 0.20 0.1 0.6


DAY 6 120 H 9 0.14 0.101 0.10 0.0 0.3

DAY 8 PREDOSE 9 0.18 0.097 0.20 0.0 0.3

DAY 15 PREDOSE 9 0.21 0.105 0.20 0.1 0.4

DAY 22 PREDOSE 9 0.22 0.148 0.20 0.0 0.5

DAY 31 216 H 9 0.17 0.122 0.20 0.0 0.3

DAY 50 672 H 8 0.15 0.053 0.15 0.1 0.2

162



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils SQ_50mg x 4 9 DAY 78 1344 H 8 0.23 0.139 0.20 0.1 0.5 (10^9/L)

FOLLOW-UP 2016 H 8 0.15 0.120 0.15 0.0 0.3

IM_200mg 9 DAY 1 PREDOSE 9 0.18 0.083 0.20 0.1 0.3

DAY 5 96 H 9 0.14 0.113 0.10 0.0 0.4

DAY 15 336 H 9 0.17 0.141 0.10 0.0 0.5

DAY 29 672 H 9 0.12 0.083 0.10 0.0 0.2

DAY 57 1344 H 8 0.16 0.106 0.15 0.0 0.3

FOLLOW-UP 2016 H 8 0.16 0.092 0.20 0.0 0.3

Eosinophils/ IV_200mg 9 DAY 1 PREDOSE 9 0.0249 0.01159 0.0220 0.012 0.042 Leukocytes (1)

DAY 5 96 H 9 0.0261 0.01793 0.0210 0.010 0.059

DAY 15 336 H 9 0.0222 0.01660 0.0180 0.004 0.054

DAY 29 672 H 9 0.0274 0.01781 0.0210 0.010 0.065

DAY 57 1344 H 9 0.0283 0.01676 0.0240 0.007 0.063

163



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils/ IV_200mg 9 FOLLOW-UP 2016 H 9 0.0241 0.01621 0.0220 0.007 0.051 Leukocytes (1)

SQ_200mg 9 DAY 1 PREDOSE 9 0.0458 0.03713 0.0310 0.012 0.135

DAY 5 96 H 9 0.0404 0.03741 0.0360 0.008 0.135

DAY 15 336 H 9 0.0311 0.02059 0.0240 0.010 0.080

DAY 29 672 H 9 0.0347 0.03035 0.0270 0.010 0.112

DAY 57 1344 H 9 0.0369 0.03252 0.0290 0.015 0.120

FOLLOW-UP 2016 H 9 0.0389 0.03157 0.0300 0.015 0.120


DAY 6 120 H 9 0.0333 0.02137 0.0370 0.007 0.071

DAY 8 PREDOSE 9 0.0374 0.02149 0.0430 0.009 0.076

DAY 15 PREDOSE 9 0.0399 0.02621 0.0430 0.009 0.091

DAY 22 PREDOSE 9 0.0367 0.02086 0.0370 0.007 0.067

DAY 31 216 H 9 0.0332 0.02126 0.0230 0.007 0.058

DAY 50 672 H 8 0.0258 0.00848 0.0265 0.012 0.040

164



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils/ SQ_50mg x 4 9 DAY 78 1344 H 8 0.0406 0.03348 0.0300 0.010 0.110 Leukocytes (1)

FOLLOW-UP 2016 H 8 0.0281 0.02461 0.0205 0.005 0.077

IM_200mg 9 DAY 1 PREDOSE 9 0.0272 0.01419 0.0300 0.010 0.046

DAY 5 96 H 9 0.0276 0.02192 0.0220 0.008 0.080

DAY 15 336 H 9 0.0313 0.03158 0.0240 0.007 0.110

DAY 29 672 H 9 0.0260 0.01547 0.0240 0.008 0.055

DAY 57 1344 H 8 0.0329 0.02114 0.0295 0.012 0.073

FOLLOW-UP 2016 H 8 0.0324 0.02025 0.0305 0.012 0.071

Hematocrit IV_200mg 9 DAY 1 PREDOSE 9 0.4454 0.03211 0.4470 0.406 0.500 (1)

DAY 5 96 H 9 0.4383 0.02165 0.4350 0.401 0.473

DAY 15 336 H 9 0.4410 0.03351 0.4400 0.398 0.504

DAY 29 672 H 9 0.4402 0.02393 0.4380 0.409 0.483

DAY 57 1344 H 9 0.4490 0.02800 0.4400 0.417 0.496

165



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hematocrit IV_200mg 9 FOLLOW-UP 2016 H 9 0.4517 0.03391 0.4530 0.407 0.525 (1)

SQ_200mg 9 DAY 1 PREDOSE 9 0.4257 0.01527 0.4220 0.396 0.447

DAY 5 96 H 9 0.4441 0.01985 0.4500 0.409 0.468

DAY 15 336 H 9 0.4366 0.02064 0.4370 0.410 0.468

DAY 29 672 H 9 0.4403 0.01728 0.4420 0.412 0.465

DAY 57 1344 H 9 0.4427 0.02354 0.4330 0.418 0.481

FOLLOW-UP 2016 H 9 0.4440 0.02978 0.4430 0.393 0.496


DAY 6 120 H 9 0.4567 0.02971 0.4680 0.389 0.486

DAY 8 PREDOSE 9 0.4490 0.03012 0.4580 0.374 0.474

DAY 15 PREDOSE 9 0.4377 0.02251 0.4410 0.401 0.464

DAY 22 PREDOSE 9 0.4317 0.03206 0.4310 0.372 0.470

DAY 31 216 H 9 0.4484 0.03810 0.4590 0.387 0.498

DAY 50 672 H 8 0.4475 0.02115 0.4520 0.406 0.477

DAY 78 1344 H 8 0.4628 0.02855 0.4680 0.408 0.500

166



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hematocrit SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 0.4504 0.03898 0.4610 0.373 0.498 (1)

IM_200mg 9 DAY 1 PREDOSE 9 0.4471 0.01443 0.4530 0.422 0.462

DAY 5 96 H 9 0.4416 0.02020 0.4450 0.409 0.465

DAY 15 336 H 9 0.4451 0.01608 0.4450 0.417 0.469

DAY 29 672 H 9 0.4407 0.01755 0.4380 0.422 0.483

DAY 57 1344 H 8 0.4508 0.01585 0.4470 0.432 0.474

FOLLOW-UP 2016 H 8 0.4456 0.01496 0.4515 0.420 0.461

Hemoglobin IV_200mg 9 DAY 1 PREDOSE 9 150.0 9.54 149.0 140 168 (g/L)

DAY 5 96 H 9 151.9 7.36 152.0 140 164

DAY 15 336 H 9 150.2 11.64 148.0 134 173

DAY 29 672 H 9 150.9 10.60 149.0 139 170

DAY 57 1344 H 9 153.6 10.94 154.0 138 171

FOLLOW-UP 2016 H 9 151.8 13.72 149.0 134 180

167



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hemoglobin SQ_200mg 9 DAY 1 PREDOSE 9 145.3 5.98 145.0 137 155 (g/L)

DAY 5 96 H 9 152.9 7.88 153.0 141 167

DAY 15 336 H 9 148.6 6.58 147.0 141 158

DAY 29 672 H 9 150.4 4.80 148.0 147 161

DAY 57 1344 H 9 152.2 9.11 151.0 139 167

FOLLOW-UP 2016 H 9 151.0 10.59 153.0 136 164


DAY 6 120 H 9 155.2 10.39 159.0 134 171

DAY 8 PREDOSE 9 152.0 11.34 156.0 125 164

DAY 15 PREDOSE 9 148.0 7.91 152.0 134 156

DAY 22 PREDOSE 9 146.6 11.17 149.0 127 161

DAY 31 216 H 9 151.7 12.99 154.0 130 170

DAY 50 672 H 8 151.3 8.84 154.5 135 160

DAY 78 1344 H 8 154.8 12.42 155.0 130 171

FOLLOW-UP 2016 H 8 150.4 13.39 152.0 129 170

168



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hemoglobin IM_200mg 9 DAY 1 PREDOSE 9 150.6 4.48 150.0 143 157 (g/L)

DAY 5 96 H 9 150.4 7.62 148.0 137 160

DAY 15 336 H 9 150.7 4.47 150.0 142 157

DAY 29 672 H 9 148.1 7.79 146.0 136 164

DAY 57 1344 H 8 153.4 7.67 153.5 144 164

FOLLOW-UP 2016 H 8 149.4 5.80 149.0 141 158

Lymphocytes IV_200mg 9 DAY 1 PREDOSE 9 2.04 0.425 2.00 1.5 2.8 (10^9/L)

DAY 5 96 H 9 2.02 0.552 1.80 1.6 3.3

DAY 15 336 H 9 1.87 0.505 1.70 1.2 2.7

DAY 29 672 H 9 1.86 0.461 1.80 1.3 2.7

DAY 57 1344 H 9 1.89 0.535 1.70 1.3 2.6

FOLLOW-UP 2016 H 9 1.94 0.602 1.70 1.2 2.9

SQ_200mg 9 DAY 1 PREDOSE 9 2.18 0.531 2.30 1.4 2.9

DAY 5 96 H 9 1.83 0.512 1.60 1.3 2.7

169



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes SQ_200mg 9 DAY 15 336 H 9 1.89 0.619 1.70 1.3 3.1 (10^9/L)

DAY 29 672 H 9 1.89 0.537 1.80 1.4 2.8

DAY 57 1344 H 9 1.92 0.698 1.80 1.1 3.1

FOLLOW-UP 2016 H 9 1.83 0.656 1.70 0.8 3.2


DAY 6 120 H 9 1.79 0.426 1.90 1.3 2.4

DAY 8 PREDOSE 9 2.23 0.587 2.00 1.8 3.7

DAY 15 PREDOSE 9 2.33 0.424 2.20 1.5 2.9

DAY 22 PREDOSE 9 2.32 0.507 2.10 1.9 3.5

DAY 31 216 H 9 2.01 0.376 1.90 1.6 2.8

DAY 50 672 H 8 1.96 0.389 1.90 1.6 2.7

DAY 78 1344 H 8 2.11 0.422 2.10 1.6 2.8

FOLLOW-UP 2016 H 8 1.94 0.307 1.85 1.6 2.4

IM_200mg 9 DAY 1 PREDOSE 9 2.09 0.643 2.10 1.0 2.9

DAY 5 96 H 9 1.87 0.510 1.70 1.3 2.8

170



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes IM_200mg 9 DAY 15 336 H 9 1.78 0.380 1.70 1.3 2.4 (10^9/L)

DAY 29 672 H 9 1.78 0.406 1.80 1.1 2.3

DAY 57 1344 H 8 1.94 0.463 1.85 1.3 2.8

FOLLOW-UP 2016 H 8 1.85 0.571 1.65 1.3 2.8

Lymphocytes SQ_200mg 9 DAY 15 336 H 1 0.0 0.0 0 0 Atypical (10^9/L)

Lymphocytes SQ_200mg 9 DAY 15 336 H 1 0.010 0.010 0.01 0.01 Atypical/Leu kocytes (1)

Lymphocytes/ IV_200mg 9 DAY 1 PREDOSE 9 0.3812 0.06778 0.3860 0.294 0.477 Leukocytes (1)

DAY 5 96 H 9 0.3710 0.06090 0.3660 0.308 0.497

DAY 15 336 H 9 0.3028 0.08745 0.3360 0.146 0.401

DAY 29 672 H 9 0.3729 0.05075 0.3620 0.327 0.484

171



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes/ IV_200mg 9 DAY 57 1344 H 9 0.3647 0.10094 0.3560 0.193 0.586 Leukocytes (1)

FOLLOW-UP 2016 H 9 0.3303 0.07970 0.3180 0.201 0.504

SQ_200mg 9 DAY 1 PREDOSE 9 0.3363 0.07341 0.3000 0.244 0.465

DAY 5 96 H 9 0.3097 0.06941 0.2990 0.198 0.426

DAY 15 336 H 9 0.3324 0.10718 0.3020 0.194 0.510

DAY 29 672 H 9 0.3349 0.08319 0.3350 0.243 0.480

DAY 57 1344 H 9 0.3102 0.09172 0.3200 0.142 0.414

FOLLOW-UP 2016 H 9 0.2937 0.07240 0.2940 0.165 0.386


DAY 6 120 H 9 0.3614 0.07518 0.3840 0.206 0.476

DAY 8 PREDOSE 9 0.3948 0.07545 0.4320 0.283 0.471

DAY 15 PREDOSE 9 0.4059 0.09263 0.3690 0.298 0.549

DAY 22 PREDOSE 9 0.3733 0.08586 0.3360 0.286 0.515

DAY 31 216 H 9 0.3958 0.07671 0.3940 0.319 0.563

172



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes/ SQ_50mg x 4 9 DAY 50 672 H 8 0.3699 0.07672 0.3705 0.261 0.504 Leukocytes (1)

DAY 78 1344 H 8 0.3703 0.03993 0.3540 0.326 0.434

FOLLOW-UP 2016 H 8 0.3679 0.06949 0.3505 0.304 0.479

IM_200mg 9 DAY 1 PREDOSE 9 0.3703 0.11408 0.3820 0.161 0.542

DAY 5 96 H 9 0.3681 0.08418 0.3930 0.235 0.511

DAY 15 336 H 9 0.3489 0.08806 0.3230 0.216 0.494

DAY 29 672 H 9 0.3760 0.09169 0.4210 0.241 0.514

DAY 57 1344 H 8 0.3954 0.09418 0.4275 0.229 0.526

FOLLOW-UP 2016 H 8 0.3698 0.09179 0.3670 0.229 0.527

Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 29.73 1.477 29.90 26.7 31.9 Corpuscular Hemoglobin (pg)

DAY 5 96 H 9 30.51 1.346 30.60 27.4 31.9

DAY 15 336 H 9 30.18 1.620 30.70 26.4 31.9

173



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 29 672 H 9 30.26 1.415 30.80 27.0 31.5 Corpuscular Hemoglobin (pg)

DAY 57 1344 H 9 29.99 1.352 30.00 27.1 31.5

FOLLOW-UP 2016 H 9 30.13 1.388 30.10 27.1 31.4

SQ_200mg 9 DAY 1 PREDOSE 9 30.52 1.460 30.60 27.6 32.6

DAY 5 96 H 9 31.00 1.708 30.80 27.8 33.9

DAY 15 336 H 9 30.64 1.426 30.70 28.1 32.9

DAY 29 672 H 9 30.72 1.456 31.00 28.1 32.7

DAY 57 1344 H 9 30.98 1.527 31.30 28.2 33.3

FOLLOW-UP 2016 H 9 31.30 1.527 31.80 28.4 33.2


DAY 6 120 H 9 29.82 1.504 30.10 27.3 31.5

DAY 8 PREDOSE 9 29.66 1.599 29.80 27.1 31.7

DAY 15 PREDOSE 9 29.56 1.526 30.00 26.9 31.4

DAY 22 PREDOSE 9 29.60 1.530 30.00 27.0 31.7

174



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 31 216 H 9 29.67 1.309 30.10 27.1 31.1 Corpuscular Hemoglobin (pg)

DAY 50 672 H 8 29.58 1.614 30.15 26.7 31.1

DAY 78 1344 H 8 29.39 1.503 29.70 26.7 31.1

FOLLOW-UP 2016 H 8 29.71 1.678 29.90 27.1 31.9

IM_200mg 9 DAY 1 PREDOSE 9 30.39 1.697 30.20 28.1 33.0

DAY 5 96 H 9 30.84 1.913 30.50 28.6 33.6

DAY 15 336 H 9 30.57 1.551 30.20 28.6 33.3

DAY 29 672 H 9 30.49 1.472 30.30 28.6 33.0

DAY 57 1344 H 8 30.89 1.801 30.35 28.8 33.5

FOLLOW-UP 2016 H 8 30.89 1.730 30.65 28.3 33.9

Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 336.7 7.14 337.0 324 348 Corpuscular HGB Concentratio n (g/L)

175



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 5 96 H 9 346.4 5.46 347.0 334 352 Corpuscular HGB Concentratio n (g/L)

DAY 15 336 H 9 340.8 9.24 344.0 320 349

DAY 29 672 H 9 342.6 7.20 342.0 331 352

DAY 57 1344 H 9 341.7 5.85 342.0 331 350

FOLLOW-UP 2016 H 9 335.8 9.52 331.0 324 354

SQ_200mg 9 DAY 1 PREDOSE 9 341.4 10.27 342.0 326 360

DAY 5 96 H 9 344.2 8.67 345.0 328 358

DAY 15 336 H 9 340.9 11.10 339.0 324 356

DAY 29 672 H 9 341.6 9.41 343.0 328 358

DAY 57 1344 H 9 343.7 8.60 342.0 332 357

FOLLOW-UP 2016 H 9 340.1 14.92 339.0 313 361


DAY 6 120 H 9 339.4 7.35 339.0 325 351

176



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 8 PREDOSE 9 338.1 7.11 337.0 328 352 Corpuscular HGB Concentratio n (g/L)

DAY 15 PREDOSE 9 338.4 6.19 338.0 330 351

DAY 22 PREDOSE 9 339.3 5.77 342.0 328 347

DAY 31 216 H 9 337.7 5.81 336.0 332 351

DAY 50 672 H 8 338.0 8.25 338.0 325 348

DAY 78 1344 H 8 333.5 8.57 335.0 318 343

FOLLOW-UP 2016 H 8 333.5 10.60 337.0 318 345

IM_200mg 9 DAY 1 PREDOSE 9 337.0 14.39 340.0 312 355

DAY 5 96 H 9 340.3 10.87 340.0 327 360

DAY 15 336 H 9 338.4 10.57 345.0 321 352

DAY 29 672 H 9 336.2 9.76 334.0 318 350

DAY 57 1344 H 8 340.1 12.70 337.5 324 362

FOLLOW-UP 2016 H 8 335.4 13.37 333.0 321 361

177



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 88.21 3.146 88.80 82.4 91.6 Corpuscular Volume (fL)

DAY 5 96 H 9 88.03 3.066 89.00 81.8 91.2

DAY 15 336 H 9 88.56 3.194 89.20 82.6 92.7

DAY 29 672 H 9 88.30 3.523 89.60 81.8 92.6

DAY 57 1344 H 9 87.81 3.756 88.30 80.7 92.3

FOLLOW-UP 2016 H 9 89.80 4.619 90.90 83.7 95.3

SQ_200mg 9 DAY 1 PREDOSE 9 89.43 4.577 88.20 81.6 94.1

DAY 5 96 H 9 90.01 4.139 89.70 82.7 94.8

DAY 15 336 H 9 89.92 3.689 90.70 82.9 94.3

DAY 29 672 H 9 89.97 4.169 90.00 82.0 94.4

DAY 57 1344 H 9 90.16 4.241 91.10 82.6 96.4

FOLLOW-UP 2016 H 9 92.14 5.485 92.70 80.9 99.7


DAY 6 120 H 9 87.88 4.101 89.60 80.8 91.5

178



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 8 PREDOSE 9 87.66 4.374 89.20 80.5 92.0 Corpuscular Volume (fL)

DAY 15 PREDOSE 9 87.36 4.052 89.00 79.7 92.1

DAY 22 PREDOSE 9 87.27 4.168 88.80 80.6 92.7

DAY 31 216 H 9 87.92 4.314 89.50 80.3 92.8

DAY 50 672 H 8 87.45 4.518 88.85 79.5 92.3

DAY 78 1344 H 8 88.11 5.071 89.55 80.9 96.2

FOLLOW-UP 2016 H 8 89.11 5.169 90.65 80.8 95.5

IM_200mg 9 DAY 1 PREDOSE 9 90.24 4.790 90.80 82.4 96.9

DAY 5 96 H 9 90.58 4.881 90.60 83.1 99.0

DAY 15 336 H 9 90.38 4.716 91.30 82.7 96.7

DAY 29 672 H 9 90.73 4.920 90.80 83.1 97.2

DAY 57 1344 H 8 90.81 4.341 91.10 82.1 96.2

FOLLOW-UP 2016 H 8 92.10 4.334 92.40 85.7 97.6

179



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes IV_200mg 9 DAY 1 PREDOSE 9 0.37 0.050 0.40 0.3 0.4 (10^9/L)

DAY 5 96 H 9 0.32 0.067 0.30 0.2 0.4

DAY 15 336 H 9 0.39 0.093 0.40 0.3 0.6

DAY 29 672 H 9 0.30 0.071 0.30 0.2 0.4

DAY 57 1344 H 9 0.33 0.112 0.30 0.2 0.6

FOLLOW-UP 2016 H 9 0.41 0.105 0.40 0.3 0.6

SQ_200mg 9 DAY 1 PREDOSE 9 0.43 0.122 0.50 0.2 0.6

DAY 5 96 H 9 0.38 0.083 0.40 0.3 0.5

DAY 15 336 H 9 0.40 0.112 0.40 0.2 0.6

DAY 29 672 H 9 0.37 0.141 0.40 0.1 0.6

DAY 57 1344 H 9 0.46 0.101 0.50 0.3 0.6

FOLLOW-UP 2016 H 9 0.36 0.124 0.30 0.2 0.5


DAY 6 120 H 9 0.27 0.100 0.30 0.1 0.4

DAY 8 PREDOSE 9 0.33 0.071 0.30 0.2 0.4

180



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.33 0.071 0.30 0.2 0.4 (10^9/L)

DAY 22 PREDOSE 9 0.37 0.087 0.40 0.2 0.5

DAY 31 216 H 9 0.29 0.078 0.30 0.2 0.4

DAY 50 672 H 8 0.31 0.064 0.30 0.2 0.4

DAY 78 1344 H 8 0.35 0.107 0.40 0.2 0.5

FOLLOW-UP 2016 H 8 0.35 0.107 0.30 0.2 0.5

IM_200mg 9 DAY 1 PREDOSE 9 0.33 0.071 0.30 0.2 0.4

DAY 5 96 H 9 0.28 0.067 0.30 0.2 0.4

DAY 15 336 H 9 0.33 0.071 0.30 0.3 0.5

DAY 29 672 H 9 0.29 0.060 0.30 0.2 0.4

DAY 57 1344 H 8 0.29 0.083 0.30 0.2 0.4

FOLLOW-UP 2016 H 8 0.33 0.089 0.35 0.2 0.4

Monocytes/Le IV_200mg 9 DAY 1 PREDOSE 9 0.0696 0.01129 0.0690 0.055 0.090 ukocytes (1)

DAY 5 96 H 9 0.0621 0.00955 0.0640 0.045 0.074

181



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes/Le IV_200mg 9 DAY 15 336 H 9 0.0606 0.01792 0.0550 0.042 0.096 ukocytes (1)

DAY 29 672 H 9 0.0647 0.01563 0.0590 0.046 0.095

DAY 57 1344 H 9 0.0668 0.01132 0.0720 0.050 0.082

FOLLOW-UP 2016 H 9 0.0678 0.01746 0.0650 0.045 0.090

SQ_200mg 9 DAY 1 PREDOSE 9 0.0644 0.01290 0.0620 0.053 0.091

DAY 5 96 H 9 0.0644 0.01318 0.0690 0.049 0.079

DAY 15 336 H 9 0.0732 0.02934 0.0650 0.041 0.140

DAY 29 672 H 9 0.0636 0.01210 0.0620 0.050 0.086

DAY 57 1344 H 9 0.0723 0.02357 0.0650 0.044 0.110

FOLLOW-UP 2016 H 9 0.0591 0.01115 0.0610 0.042 0.077


DAY 6 120 H 9 0.0559 0.01737 0.0560 0.029 0.093

DAY 8 PREDOSE 9 0.0608 0.01652 0.0610 0.038 0.091

DAY 15 PREDOSE 9 0.0580 0.01638 0.0520 0.038 0.092

DAY 22 PREDOSE 9 0.0596 0.01654 0.0570 0.032 0.087

182



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes/Le SQ_50mg x 4 9 DAY 31 216 H 9 0.0559 0.00872 0.0580 0.043 0.070 ukocytes (1)

DAY 50 672 H 8 0.0604 0.01384 0.0590 0.043 0.082

DAY 78 1344 H 8 0.0621 0.01424 0.0585 0.046 0.089

FOLLOW-UP 2016 H 8 0.0673 0.01618 0.0665 0.047 0.089

IM_200mg 9 DAY 1 PREDOSE 9 0.0609 0.00929 0.0630 0.045 0.071

DAY 5 96 H 9 0.0556 0.00635 0.0570 0.044 0.064

DAY 15 336 H 9 0.0653 0.01576 0.0610 0.050 0.104

DAY 29 672 H 9 0.0623 0.01044 0.0630 0.046 0.082

DAY 57 1344 H 8 0.0583 0.00969 0.0565 0.041 0.072

FOLLOW-UP 2016 H 8 0.0661 0.01152 0.0650 0.053 0.089

Neutrophils IV_200mg 9 DAY 1 PREDOSE 9 2.86 0.823 2.80 1.7 4.0 (10^9/L)

DAY 5 96 H 9 2.96 0.702 2.80 1.7 4.2

DAY 15 336 H 9 3.88 1.122 3.60 2.3 6.2

DAY 29 672 H 9 2.62 0.659 2.40 1.8 3.8

183



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils IV_200mg 9 DAY 57 1344 H 9 2.91 1.257 2.20 1.4 5.4 (10^9/L)

FOLLOW-UP 2016 H 9 3.53 1.474 2.90 2.2 5.9

SQ_200mg 9 DAY 1 PREDOSE 9 3.70 1.233 3.80 1.6 5.5

DAY 5 96 H 9 3.57 1.222 3.70 1.6 5.9

DAY 15 336 H 9 3.42 1.332 4.00 1.0 4.8

DAY 29 672 H 9 3.24 0.879 3.50 1.2 4.0

DAY 57 1344 H 9 3.92 1.950 4.10 1.4 7.3

FOLLOW-UP 2016 H 9 4.01 1.738 4.10 1.4 6.7


DAY 6 120 H 9 2.86 1.114 2.90 1.6 4.6

DAY 8 PREDOSE 9 3.00 1.168 2.60 1.6 4.5

DAY 15 PREDOSE 9 3.14 1.535 3.10 1.3 5.0

DAY 22 PREDOSE 9 3.40 1.007 3.70 1.8 4.5

DAY 31 216 H 9 2.66 0.716 2.60 1.2 3.5

DAY 50 672 H 8 2.94 0.865 2.65 2.2 4.7

184



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils SQ_50mg x 4 9 DAY 78 1344 H 8 3.05 0.823 2.90 1.6 4.3 (10^9/L)

FOLLOW-UP 2016 H 8 3.01 1.303 3.10 1.1 4.8

IM_200mg 9 DAY 1 PREDOSE 9 3.16 1.061 3.00 1.6 4.9

DAY 5 96 H 9 2.80 0.669 2.60 1.9 3.8

DAY 15 336 H 9 2.83 0.723 2.80 1.6 4.1

DAY 29 672 H 9 2.60 0.758 2.50 1.6 4.0

DAY 57 1344 H 8 2.58 0.812 2.55 1.4 3.8

FOLLOW-UP 2016 H 8 2.70 0.898 2.70 1.5 4.2

Neutrophils/ IV_200mg 9 DAY 1 PREDOSE 9 0.5191 0.06886 0.5300 0.424 0.613 Leukocytes (1)

DAY 5 96 H 9 0.5351 0.06387 0.5580 0.415 0.605

DAY 15 336 H 9 0.6094 0.09050 0.5850 0.496 0.784

DAY 29 672 H 9 0.5286 0.05857 0.5520 0.412 0.590

DAY 57 1344 H 9 0.5340 0.10116 0.5540 0.312 0.691

185



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils/ IV_200mg 9 FOLLOW-UP 2016 H 9 0.5726 0.08626 0.5860 0.387 0.691 Leukocytes (1)

SQ_200mg 9 DAY 1 PREDOSE 9 0.5488 0.07088 0.5350 0.421 0.646

DAY 5 96 H 9 0.5804 0.08659 0.5820 0.465 0.702

DAY 15 336 H 9 0.5592 0.12333 0.5980 0.350 0.714

DAY 29 672 H 9 0.5610 0.08906 0.5620 0.420 0.673

DAY 57 1344 H 9 0.5762 0.12721 0.5930 0.380 0.780

FOLLOW-UP 2016 H 9 0.6028 0.08536 0.5940 0.514 0.767


DAY 6 120 H 9 0.5446 0.07694 0.5330 0.402 0.684

DAY 8 PREDOSE 9 0.5011 0.09084 0.4800 0.374 0.628

DAY 15 PREDOSE 9 0.4906 0.11792 0.5130 0.317 0.616

DAY 22 PREDOSE 9 0.5243 0.09617 0.5820 0.375 0.637

DAY 31 216 H 9 0.5099 0.08880 0.5030 0.308 0.604

DAY 50 672 H 8 0.5394 0.07790 0.5225 0.410 0.657

186



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils/ SQ_50mg x 4 9 DAY 78 1344 H 8 0.5221 0.05778 0.5345 0.389 0.582 Leukocytes (1)

FOLLOW-UP 2016 H 8 0.5311 0.10267 0.5575 0.341 0.636

IM_200mg 9 DAY 1 PREDOSE 9 0.5361 0.10968 0.5360 0.372 0.738

DAY 5 96 H 9 0.5444 0.07921 0.5280 0.418 0.692

DAY 15 336 H 9 0.5486 0.09138 0.5370 0.418 0.706

DAY 29 672 H 9 0.5306 0.09326 0.4870 0.413 0.672

DAY 57 1344 H 8 0.5081 0.09818 0.5025 0.394 0.682

FOLLOW-UP 2016 H 8 0.5264 0.08835 0.5255 0.394 0.678

Platelets IV_200mg 9 DAY 1 PREDOSE 9 204.6 42.55 200.0 146 278 (10^9/L)

DAY 5 96 H 9 214.0 37.32 211.0 148 284

DAY 15 336 H 9 217.9 42.81 209.0 161 278

DAY 29 672 H 9 210.7 49.10 214.0 127 294

DAY 57 1344 H 9 214.8 51.88 214.0 144 301

187



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Platelets IV_200mg 9 FOLLOW-UP 2016 H 9 206.0 45.69 198.0 149 314 (10^9/L)

SQ_200mg 9 DAY 1 PREDOSE 9 222.2 63.97 189.0 162 333

DAY 5 96 H 9 230.7 75.97 198.0 163 386

DAY 15 336 H 9 236.9 84.25 217.0 153 408

DAY 29 672 H 9 236.2 85.60 198.0 160 422

DAY 57 1344 H 9 223.3 66.85 217.0 154 377

FOLLOW-UP 2016 H 9 214.3 70.10 195.0 134 344


DAY 6 120 H 8 187.4 32.03 177.5 159 261

DAY 8 PREDOSE 9 188.0 30.68 188.0 143 251

DAY 15 PREDOSE 9 197.9 32.98 190.0 158 272

DAY 22 PREDOSE 8 189.0 38.71 182.0 149 276

DAY 31 216 H 9 189.1 36.49 192.0 147 272

DAY 50 672 H 7 190.4 38.98 178.0 141 266

DAY 78 1344 H 8 186.5 17.66 184.0 163 216

188



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Platelets SQ_50mg x 4 9 FOLLOW-UP 2016 H 7 186.1 38.43 184.0 148 267 (10^9/L)

IM_200mg 9 DAY 1 PREDOSE 9 225.1 25.21 216.0 186 268

DAY 5 96 H 9 222.4 31.06 228.0 178 268

DAY 15 336 H 9 220.8 40.41 223.0 162 281

DAY 29 672 H 9 222.3 36.43 230.0 173 271

DAY 57 1344 H 8 218.9 33.66 215.5 180 268

FOLLOW-UP 2016 H 8 209.8 39.58 191.5 171 282

Platelet SQ_50mg x 4 9 DAY 6 120 H 1 260.0 260.0 260 260 Count (Lt Blue) (10^9/L)

DAY 8 PREDOSE 1 241.0 241.0 241 241

DAY 15 PREDOSE 1 242.0 242.0 242 242

DAY 22 PREDOSE 1 252.0 252.0 252 252

DAY 31 216 H 1 227.0 227.0 227 227

189



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes IV_200mg 9 DAY 1 PREDOSE 9 5.061 0.4550 4.960 4.44 5.70 (10^12/L)

DAY 5 96 H 9 4.990 0.3721 4.810 4.57 5.61

DAY 15 336 H 9 4.986 0.4471 4.890 4.30 5.73

DAY 29 672 H 9 4.996 0.3903 4.870 4.49 5.53

DAY 57 1344 H 9 5.126 0.4139 5.110 4.60 5.72

FOLLOW-UP 2016 H 9 5.042 0.4926 4.990 4.30 5.97

SQ_200mg 9 DAY 1 PREDOSE 9 4.770 0.2644 4.720 4.50 5.16

DAY 5 96 H 9 4.938 0.2491 4.940 4.42 5.34

DAY 15 336 H 9 4.862 0.3024 4.850 4.48 5.34

DAY 29 672 H 9 4.901 0.2358 4.910 4.60 5.31

DAY 57 1344 H 9 4.923 0.3855 4.780 4.34 5.52

FOLLOW-UP 2016 H 9 4.829 0.3519 4.820 4.35 5.51


DAY 6 120 H 9 5.207 0.3714 5.320 4.26 5.48

DAY 8 PREDOSE 9 5.139 0.4651 5.200 4.07 5.79

190



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 5.018 0.3517 5.030 4.36 5.68 (10^12/L)

DAY 22 PREDOSE 9 4.963 0.5022 5.020 4.01 5.84

DAY 31 216 H 9 5.119 0.5556 5.270 4.17 6.03

DAY 50 672 H 8 5.140 0.4982 5.055 4.40 6.00

DAY 78 1344 H 8 5.278 0.5496 5.255 4.24 6.04

FOLLOW-UP 2016 H 8 5.074 0.5746 5.130 4.02 5.81

IM_200mg 9 DAY 1 PREDOSE 9 4.964 0.2485 4.960 4.68 5.37

DAY 5 96 H 9 4.889 0.3670 4.750 4.53 5.60

DAY 15 336 H 9 4.930 0.2209 4.860 4.66 5.30

DAY 29 672 H 9 4.868 0.2842 4.770 4.53 5.29

DAY 57 1344 H 8 4.969 0.2503 4.865 4.76 5.49

FOLLOW-UP 2016 H 8 4.846 0.2369 4.800 4.59 5.32

Erythrocytes IV_200mg 9 DAY 1 PREDOSE 9 0.1314 0.00700 0.1310 0.123 0.147 Distribution Width (1)

191



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes IV_200mg 9 DAY 5 96 H 9 0.1308 0.00703 0.1300 0.123 0.145 Distribution Width (1)

DAY 15 336 H 9 0.1321 0.00713 0.1300 0.125 0.149

DAY 29 672 H 9 0.1314 0.00826 0.1310 0.122 0.149

DAY 57 1344 H 9 0.1304 0.00621 0.1290 0.125 0.146

FOLLOW-UP 2016 H 9 0.1314 0.00954 0.1290 0.120 0.154

SQ_200mg 9 DAY 1 PREDOSE 9 0.1291 0.00580 0.1270 0.123 0.138

DAY 5 96 H 9 0.1292 0.00554 0.1270 0.123 0.137

DAY 15 336 H 9 0.1291 0.00558 0.1290 0.123 0.137

DAY 29 672 H 9 0.1294 0.00510 0.1290 0.121 0.137

DAY 57 1344 H 9 0.1318 0.00565 0.1340 0.122 0.139

FOLLOW-UP 2016 H 9 0.1289 0.00457 0.1310 0.120 0.134


DAY 6 120 H 9 0.1312 0.00463 0.1300 0.125 0.139

DAY 8 PREDOSE 9 0.1311 0.00483 0.1310 0.123 0.139

192



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.1312 0.00543 0.1310 0.124 0.140 Distribution Width (1)

DAY 22 PREDOSE 9 0.1317 0.00548 0.1300 0.125 0.141

DAY 31 216 H 9 0.1329 0.00537 0.1330 0.126 0.142

DAY 50 672 H 8 0.1336 0.00434 0.1335 0.129 0.141

DAY 78 1344 H 8 0.1343 0.00406 0.1335 0.130 0.143

FOLLOW-UP 2016 H 8 0.1328 0.00480 0.1320 0.127 0.142

IM_200mg 9 DAY 1 PREDOSE 9 0.1307 0.00548 0.1310 0.124 0.141

DAY 5 96 H 9 0.1306 0.00561 0.1300 0.122 0.142

DAY 15 336 H 9 0.1308 0.00648 0.1300 0.123 0.144

DAY 29 672 H 9 0.1321 0.00779 0.1310 0.124 0.150

DAY 57 1344 H 8 0.1306 0.00780 0.1285 0.123 0.147

FOLLOW-UP 2016 H 8 0.1316 0.00924 0.1290 0.119 0.146

Reticulocyte IV_200mg 9 DAY 1 PREDOSE 9 104.53 62.221 86.70 64.7 266.7 s (10^9/L)

193



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte IV_200mg 9 DAY 5 96 H 9 93.41 12.979 92.00 73.6 114.6 s (10^9/L)

DAY 15 336 H 9 94.46 17.289 87.10 74.0 127.2

DAY 29 672 H 9 89.58 16.994 85.60 66.9 126.5

DAY 57 1344 H 9 89.16 17.141 93.80 64.0 110.3

FOLLOW-UP 2016 H 9 81.76 9.753 81.30 66.9 96.7

SQ_200mg 9 DAY 1 PREDOSE 9 87.99 25.247 83.10 59.7 142.1

DAY 5 96 H 9 88.00 30.477 79.20 51.3 138.6

DAY 15 336 H 9 86.01 28.025 77.20 44.2 133.9

DAY 29 672 H 9 85.54 21.980 77.20 55.6 125.9

DAY 57 1344 H 9 90.63 19.448 97.10 59.5 122.1

FOLLOW-UP 2016 H 9 74.67 23.212 75.30 39.3 118.9


DAY 6 120 H 9 77.03 17.084 71.00 52.5 107.7

DAY 8 PREDOSE 9 78.16 19.926 72.50 55.3 107.7

DAY 15 PREDOSE 9 75.78 11.978 77.20 55.4 98.7

194



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte SQ_50mg x 4 9 DAY 22 PREDOSE 9 77.00 14.431 84.50 44.7 91.8 s (10^9/L)

DAY 31 216 H 9 86.59 17.444 86.30 64.9 121.6

DAY 50 672 H 8 81.06 15.632 79.90 51.1 98.8

DAY 78 1344 H 8 79.84 25.869 72.05 62.3 141.6

FOLLOW-UP 2016 H 8 89.84 31.863 86.40 46.4 152.6

IM_200mg 9 DAY 1 PREDOSE 9 76.81 18.176 77.80 43.9 101.7

DAY 5 96 H 9 72.99 21.806 65.60 56.2 119.6

DAY 15 336 H 9 83.37 20.142 86.10 57.1 114.2

DAY 29 672 H 9 80.52 14.741 80.90 54.9 98.4

DAY 57 1344 H 8 69.41 13.186 67.50 54.2 98.2

FOLLOW-UP 2016 H 8 75.51 13.524 72.05 60.2 96.7

Reticulocyte IV_200mg 9 DAY 1 PREDOSE 9 0.0210 0.01285 0.0170 0.012 0.054 s/Erythrocyt es (1)

DAY 5 96 H 9 0.0189 0.00302 0.0190 0.014 0.024

195



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte IV_200mg 9 DAY 15 336 H 9 0.0191 0.00318 0.0190 0.015 0.026 s/Erythrocyt es (1)

DAY 29 672 H 9 0.0180 0.00371 0.0180 0.013 0.025

DAY 57 1344 H 9 0.0174 0.00332 0.0190 0.012 0.022

FOLLOW-UP 2016 H 9 0.0163 0.00158 0.0170 0.013 0.018

SQ_200mg 9 DAY 1 PREDOSE 9 0.0186 0.00568 0.0180 0.012 0.030

DAY 5 96 H 9 0.0179 0.00609 0.0150 0.011 0.028

DAY 15 336 H 9 0.0179 0.00607 0.0160 0.010 0.029

DAY 29 672 H 9 0.0177 0.00485 0.0160 0.011 0.026

DAY 57 1344 H 9 0.0186 0.00400 0.0200 0.013 0.023

FOLLOW-UP 2016 H 9 0.0157 0.00520 0.0150 0.008 0.025


DAY 6 120 H 9 0.0149 0.00310 0.0140 0.010 0.020

DAY 8 PREDOSE 9 0.0153 0.00391 0.0150 0.010 0.021

DAY 15 PREDOSE 9 0.0152 0.00217 0.0160 0.011 0.019

196



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte SQ_50mg x 4 9 DAY 22 PREDOSE 9 0.0158 0.00259 0.0170 0.011 0.019 s/Erythrocyt es (1)

DAY 31 216 H 9 0.0170 0.00287 0.0160 0.012 0.022

DAY 50 672 H 8 0.0158 0.00287 0.0160 0.012 0.020

DAY 78 1344 H 8 0.0154 0.00487 0.0140 0.011 0.027

FOLLOW-UP 2016 H 8 0.0176 0.00566 0.0175 0.010 0.028

IM_200mg 9 DAY 1 PREDOSE 9 0.0156 0.00347 0.0160 0.009 0.020

DAY 5 96 H 9 0.0147 0.00308 0.0140 0.012 0.021

DAY 15 336 H 9 0.0169 0.00408 0.0180 0.011 0.022

DAY 29 672 H 9 0.0164 0.00292 0.0150 0.012 0.021

DAY 57 1344 H 8 0.0139 0.00210 0.0140 0.011 0.018

FOLLOW-UP 2016 H 8 0.0156 0.00226 0.0155 0.013 0.019

Leukocytes IV_200mg 9 DAY 1 PREDOSE 9 5.44 1.093 4.90 4.1 7.4 (10^9/L)

DAY 5 96 H 9 5.48 1.006 5.30 3.8 6.9

197



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Leukocytes IV_200mg 9 DAY 15 336 H 9 6.29 0.925 6.40 4.7 7.9 (10^9/L)

DAY 29 672 H 9 4.96 0.977 4.70 3.7 6.4

DAY 57 1344 H 9 5.30 1.501 4.40 3.7 7.8

FOLLOW-UP 2016 H 9 6.04 1.868 5.70 4.2 9.4

SQ_200mg 9 DAY 1 PREDOSE 9 6.62 1.595 6.50 3.9 8.8

DAY 5 96 H 9 6.03 1.503 5.80 3.3 9.1

DAY 15 336 H 9 5.89 1.563 6.40 2.9 7.8

DAY 29 672 H 9 5.72 1.324 5.60 2.9 7.1

DAY 57 1344 H 9 6.50 2.257 6.50 2.9 9.7

FOLLOW-UP 2016 H 9 6.47 2.171 6.50 2.5 9.6


DAY 6 120 H 9 5.11 1.379 5.00 3.5 7.4

DAY 8 PREDOSE 9 5.80 1.494 5.40 4.2 8.1

DAY 15 PREDOSE 9 6.08 1.823 6.10 3.9 8.2

DAY 22 PREDOSE 9 6.36 1.094 6.60 4.3 7.7

198



Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Leukocytes SQ_50mg x 4 9 DAY 31 216 H 9 5.14 0.800 5.00 4.0 6.6 (10^9/L)

DAY 50 672 H 8 5.36 0.865 5.25 4.3 7.1

DAY 78 1344 H 8 5.76 1.143 5.50 4.1 7.4

FOLLOW-UP 2016 H 8 5.48 1.651 5.20 3.3 7.8

IM_200mg 9 DAY 1 PREDOSE 9 5.80 1.161 5.90 4.2 7.6

DAY 5 96 H 9 5.11 0.821 4.80 4.1 6.8

DAY 15 336 H 9 5.12 0.646 5.20 3.8 5.8

DAY 29 672 H 9 4.84 0.806 4.90 3.9 6.0

DAY 57 1344 H 8 4.96 0.930 5.10 3.6 6.5

FOLLOW-UP 2016 H 8 5.08 1.155 4.90 3.4 6.8

199


Protocol: BA1116891 Page 1 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results

Lab Test: Alanine Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

200



Lab Test: Alanine Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 0 0 0

201



Lab Test: Albumin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 1 (11%) Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

202



Lab Test: Albumin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0

203



Lab Test: Alkaline Phosphatase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 2 (22%) 3 (33%) 2 (22%)

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 1 (11%)

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 3 (33%) 2 (22%)

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 2 (22%)

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0

204



Lab Test: Alkaline Phosphatase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 3 (38%) 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 4 (44%) 0 1 (13%)

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 3 (38%) 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 3 (33%) 3 (38%) 1 (13%)

205



Lab Test: Aspartate Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

206



Lab Test: Aspartate Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 1 (11%) 0 1 (13%) Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


207



Lab Test: Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 0 0 1 (11%) Low 0 0 0 0

DAY 5 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

208



Lab Test: Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0

209



Lab Test: Blood Urea Nitrogen (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 1 (11%) Low 1 (11%) 1 (11%) 0 1 (11%)

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 2 (22%) 0 0

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 3 (33%) 3 (33%) 0 0

DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 1 (11%) 0

DAY 29 n 9 9 0 9 High 0 0 0 1 (11%) Low 1 (11%) 3 (33%) 0 1 (11%)

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

210



Lab Test: Blood Urea Nitrogen (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 2 (22%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 2 (22%) 0 0

211



Lab Test: Calcium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 1 (11%)

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

212



Lab Test: Calcium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 2 (22%) 0 0 0

213



Lab Test: Carbon Dioxide (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 5 (56%) 3 (33%) 1 (11%) 4 (44%) Low 0 0 0 0

DAY 5 n 9 9 0 9 High 3 (33%) 4 (44%) 0 4 (44%) Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 3 (33%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 2 (22%) 4 (44%) 2 (22%) 3 (33%) Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 3 (33%) 3 (33%) 0 3 (33%) Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0

214



Lab Test: Carbon Dioxide (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 1 (11%) 1 (11%) 0 1 (13%) Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 3 (33%) 3 (33%) 1 (13%) 2 (25%) Low 0 0 0 0

215



Lab Test: Chloride (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

216



Lab Test: Chloride (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


217



Lab Test: Creatine Kinase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 0 0 0 1 High 0 0 0 1 (100%) Low 0 0 0 0

218



Lab Test: Creatine Kinase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP High 0 0 0 0 Low 0 0 0 0

219



Lab Test: Creatine Kinase BB (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 1 0 High 0 0 1 (100%) 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 0 1 0 0 High 0 1 (100%) 0 0 Low 0 0 0 0

220



Lab Test: Creatine Kinase BB (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


221



Lab Test: Creatine Kinase MB (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 1 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 0 1 0 0 High 0 1 (100%) 0 0 Low 0 0 0 0

222



Lab Test: Creatine Kinase MB (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


223



Lab Test: Creatinine (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 3 (33%) 0 1 (11%)

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

224



Lab Test: Creatinine (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 2 (22%) 4 (44%) 3 (38%) 1 (13%)

225



Lab Test: Direct Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 1 (11%) Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

226



Lab Test: Direct Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 0 0 0

227



Lab Test: Gamma Glutamyl Transferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 2 (22%) 0 1 (11%)

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 4 (44%) 2 (22%) 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 2 (22%) 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

228



Lab Test: Gamma Glutamyl Transferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 3 (33%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 2 (22%) 2 (25%) 0

229



Lab Test: Glucose (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 1 (11%) Low 0 0 0 1 (11%)

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

230



Lab Test: Glucose (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 0 0 Low 0 0 0 0

231



Lab Test: Potassium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

232



Lab Test: Potassium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


233



Lab Test: Protein (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

234



Lab Test: Protein (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


235



Lab Test: Sodium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

236



Lab Test: Sodium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


237



Lab Test: Thyrotropin (mIU/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 High 0 0 0 0 Low 0 0 0 0

238



Lab Test: Thyrotropin (mIU/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


239



Lab Test: Thyroxine, Free (pmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 High 0 0 0 0 Low 0 0 0 0

240



Lab Test: Thyroxine, Free (pmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


241



Lab Test: Triiodothyronine, Free (nmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 High 0 0 0 0 Low 0 0 0 0

242



Lab Test: Triiodothyronine, Free (nmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


243



Lab Test: Troponin I (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0

244



Lab Test: Troponin I (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


245



Lab Test: Urate (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

246



Lab Test: Urate (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 0 0 0

247


Protocol: BA1116891 Page 1 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results

Lab Test: Basophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

248



Lab Test: Basophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


249



Lab Test: Basophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

250



Lab Test: Basophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


251



Lab Test: Eosinophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 1 (11%) 1 (11%) 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 1 (11%) 0 1 (11%) Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 1 (11%) 1 (11%) 1 (11%) Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

252



Lab Test: Eosinophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 1 (11%) 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 2 (22%) 0 0 Low 0 0 0 0

253



Lab Test: Eosinophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 3 (33%) 5 (56%) 4 (44%) 4 (44%) Low 0 0 0 0

DAY 5 n 9 9 0 9 High 2 (22%) 5 (56%) 0 3 (33%) Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 5 (56%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 5 (56%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 3 (33%) 3 (33%) 6 (67%) 3 (33%) Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 6 (67%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 3 (33%) 3 (33%) 0 3 (33%) Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0

254



Lab Test: Eosinophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 2 (25%) 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 3 (33%) 3 (33%) 0 4 (50%) Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 4 (50%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 3 (33%) 4 (44%) 3 (38%) 4 (50%) Low 0 0 0 0

255



Lab Test: Ery. Mean Corpuscular HGB Concentration (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

256



Lab Test: Ery. Mean Corpuscular HGB Concentration (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


257



Lab Test: Ery. Mean Corpuscular Hemoglobin (pg) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

258



Lab Test: Ery. Mean Corpuscular Hemoglobin (pg) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


259



Lab Test: Ery. Mean Corpuscular Volume (fL) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

260



Lab Test: Ery. Mean Corpuscular Volume (fL) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


261



Lab Test: Erythrocytes (10^12/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 1 (11%) 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 31 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 2 (22%) 0

262



Lab Test: Erythrocytes (10^12/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 1 (11%) 2 (22%) 1 (13%) 0

263



Lab Test: Erythrocytes Distribution Width (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 0 0 1 (11%) Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

264



Lab Test: Erythrocytes Distribution Width (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0

265



Lab Test: Hematocrit (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 3 (33%) 2 (22%) 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 2 (22%)

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 3 (33%) 1 (11%) 1 (11%)

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

266



Lab Test: Hematocrit (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 1 (11%) 1 (11%) 1 (13%) 0

267



Lab Test: Hemoglobin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 2 (22%) 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 1 (11%)

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 0 1 (11%) 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 1 (11%)

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

268



Lab Test: Hemoglobin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


269



Lab Test: Leukocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 1 (11%) 1 (11%)

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 3 (33%)

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

270



Lab Test: Leukocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 1 (13%)

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 1 (11%) 2 (25%) 2 (25%)

271



Lab Test: Lymphocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

272



Lab Test: Lymphocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 1 (11%) 0 0

273



Lab Test: Lymphocytes Atypical (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 0 0 0 Low 0 0 0 0 n 0 1 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 High 0 0 0 0 Low 0 0 0 0

274



Lab Test: Lymphocytes Atypical (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


275



Lab Test: Lymphocytes Atypical/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0

DAY 8 High 0 0 0 0 Low 0 0 0 0

DAY 15 High 0 1 (100%) 0 0 Low 0 0 0 0 n 0 1 0 0

DAY 22 High 0 0 0 0 Low 0 0 0 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

DAY 57 High 0 0 0 0 Low 0 0 0 0

276



Lab Test: Lymphocytes Atypical/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0


277



Lab Test: Lymphocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 2 (22%) 1 (11%) 3 (33%) 2 (22%) Low 0 0 0 1 (11%)

DAY 5 n 9 9 0 9 High 1 (11%) 0 0 1 (11%) Low 0 1 (11%) 0 1 (11%)

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 1 (11%) 0

DAY 8 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 2 (22%) 3 (33%) 2 (22%) Low 2 (22%) 2 (22%) 0 1 (11%)

DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 2 (22%) Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0

278



Lab Test: Lymphocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 1 (11%) 0 0 2 (25%) Low 1 (11%) 3 (33%) 0 1 (13%)

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 2 (25%) 2 (25%) Low 1 (11%) 2 (22%) 0 1 (13%)

279



Lab Test: Monocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

280



Lab Test: Monocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


281



Lab Test: Monocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 3 (33%) 1 (11%) 1 (11%) Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 1 (11%) Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

282



Lab Test: Monocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 1 (11%) 3 (33%) 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 3 (33%) 0 2 (25%) 1 (13%) Low 0 0 0 0

283



Lab Test: Neutrophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 2 (22%) 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

284



Lab Test: Neutrophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 1 (13%) 0

285



Lab Test: Neutrophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 1 (11%) 2 (22%) 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

286



Lab Test: Neutrophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 1 (11%) 0 0 Low 1 (11%) 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 0 0 Low 0 0 1 (13%) 0

287



Lab Test: Platelet Count (Lt Blue) (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0

DAY 5 High 0 0 0 0 Low 0 0 0 0

DAY 6 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0

DAY 8 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0

DAY 15 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0

DAY 22 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0

DAY 29 High 0 0 0 0 Low 0 0 0 0

DAY 31 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0

DAY 50 High 0 0 0 0 Low 0 0 0 0

288



Lab Test: Platelet Count (Lt Blue) (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 57 High 0 0 0 0 Low 0 0 0 0

DAY 78 High 0 0 0 0 Low 0 0 0 0


289



Lab Test: Platelets (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 6 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

DAY 15 n 9 9 9 9 High 0 1 (11%) 0 0 Low 0 0 0 0

DAY 22 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0

DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 1 (11%) 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0

290



Lab Test: Platelets (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 7 0 High 0 0 0 0 Low 0 0 1 (14%) 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 0 0 0

DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0


291



Lab Test: Reticulocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 2 (22%) 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

292



Lab Test: Reticulocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0


293



Lab Test: Reticulocytes/Erythrocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 5 n 9 9 0 9 High 0 2 (22%) 0 0 Low 0 0 0 0

DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 15 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0

DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0

294



Lab Test: Reticulocytes/Erythrocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0

DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0

DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0

FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 1 (13%) 0 Low 0 0 0 0

295


Protocol: BA1116891 Page 1 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)

Lab Test: Bacteria IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%) 1 (11%) Rare 1 (11%)

DAY 5 Negative 2 (22%) 2 (22%) 2 (22%)

DAY 6 Negative 2 (22%)


DAY 15 Negative 2 (22%) 3 (33%) 4 (44%) 4 (44%)


DAY 29 Negative 2 (22%) 2 (22%)



DAY 57 Negative 2 (22%) 2 (22%) 2 (22%)


FOLLOW-UP Negative 2 (22%) 1 (11%) 1 (11%) 4 (44%) Rare 1 (11%)

Note:Data available only for Subjects who took this test.

296



Lab Test: Calcium Oxalate Crystals IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 29 Rare 1 (11%)


297



Lab Test: Casts IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 2 (22%) 1 (11%)

DAY 5 Negative 2 (22%) 2 (22%) 2 (22%)



DAY 15 Negative 1 (11%) 2 (22%) 4 (44%) 4 (44%)


DAY 29 Negative 2 (22%) 2 (22%)



DAY 57 Negative 1 (11%) 2 (22%) 2 (22%)


FOLLOW-UP Negative 3 (33%) 1 (11%) 1 (11%) 4 (44%)


298



Lab Test: Crystals IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%)

DAY 5 Negative 2 (22%) 1 (11%) 2 (22%)


DAY 15 Negative 2 (22%) 3 (33%) 4 (44%) 2 (22%)


DAY 29 Negative 2 (22%) 1 (11%)


DAY 57 Negative 1 (11%) 2 (22%) 2 (22%)




299



Lab Test: Epithelial Cells IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%) 1 (11%)

DAY 5 Negative 1 (11%) 1 (11%)



DAY 15 Negative 1 (11%) 1 (11%) 2 (22%) 3 (33%)


DAY 29 Negative 1 (11%) 1 (11%)



DAY 57 Negative 2 (22%) 2 (22%)

FOLLOW-UP Negative 2 (22%) 1 (11%) 2 (22%)


300



Lab Test: Glucose IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 9 (100%) 9 (100%) 9 (100%)

DAY 5 Negative 9 (100%) 9 (100%) 9 (100%)



DAY 15 Negative 9 (100%) 9 (100%) 8 (89%) 9 (100%)


DAY 29 Negative 9 (100%) 9 (100%) 9 (100%)



DAY 57 Negative 8 (89%) 9 (100%) 8 (89%)




301



Lab Test: Ketones IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 8 (89%) 9 (100%) 9 (100%)

DAY 5 Negative 9 (100%) 9 (100%) 9 (100%)



DAY 15 Negative 7 (78%) 8 (89%) 8 (89%) 9 (100%)


DAY 29 Negative 9 (100%) 8 (89%) 9 (100%)



DAY 57 Negative 8 (89%) 6 (67%) 8 (89%)




302



Lab Test: Mucous Threads IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Rare 1 (11%)

DAY 5 Rare 1 (11%) 1 (11%) 1 (11%)

DAY 6 Rare 1 (11%)

DAY 15 Negative 1 (11%) 1 (11%) Rare 1 (11%) 1 (11%) 2 (22%)

DAY 29 Rare 1 (11%) 1 (11%)

DAY 31 Rare 1 (11%)

DAY 50 Rare 1 (11%)

DAY 57 Rare 2 (22%) 1 (11%)

DAY 78 Rare 1 (11%)

FOLLOW-UP Rare 2 (22%) 1 (11%) 2 (22%)


303



Lab Test: Nitrite IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%)



304



Lab Test: Occult Blood IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 9 (100%) 9 (100%) 9 (100%)

DAY 5 Negative 9 (100%) 9 (100%) 8 (89%)



DAY 15 Negative 9 (100%) 9 (100%) 9 (100%) 7 (78%)


DAY 29 Negative 9 (100%) 9 (100%) 9 (100%)



DAY 57 Negative 8 (89%) 8 (89%) 8 (89%)




305



Lab Test: Protein IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 8 (89%) 9 (100%) 7 (78%) 8 (89%)

DAY 5 Negative 7 (78%) 7 (78%) 7 (78%)



DAY 15 Negative 7 (78%) 6 (67%) 5 (56%) 5 (56%)


DAY 29 Negative 7 (78%) 7 (78%) 9 (100%)



DAY 57 Negative 6 (67%) 7 (78%) 6 (67%)




306



Lab Test: Spermatozoa IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 6 Rare 2 (22%)

DAY 29 Rare 1 (11%)

DAY 57 Rare 1 (11%)

DAY 78 Rare 1 (11%)


307


Protocol: BA1116891 Page 1 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)

LABTEST: Erythrocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 1 0.000 0.000 0.00 0.00

DAY 5 96 H 2 0.000 0.0000 0.000 0.00 0.00

DAY 15 336 H 2 0.000 0.0000 0.000 0.00 0.00

DAY 29 672 H 1 0.000 0.000 0.00 0.00

DAY 57 1344 H 1 0.000 0.000 0.00 0.00

FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00

SQ_200mg 9 DAY 15 336 H 2 0.500 0.7071 0.500 0.00 1.00

DAY 29 672 H 2 3.500 3.5355 3.500 1.00 6.00

DAY 57 1344 H 2 6.000 8.4853 6.000 0.00 12.00

FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00


DAY 6 120 H 2 1.000 0.0000 1.000 1.00 1.00

DAY 15 PREDOSE 3 1.000 1.0000 1.000 0.00 2.00

DAY 22 PREDOSE 1 1.000 1.000 1.00 1.00

DAY 50 672 H 2 0.500 0.7071 0.500 0.00 1.00

308



LABTEST: Erythrocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 78 1344 H 1 0.000 0.000 0.00 0.00

FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00

IM_200mg 9 DAY 5 96 H 2 90.000 125.8650 90.000 1.00 179.00

DAY 15 336 H 3 14.667 25.4034 0.000 0.00 44.00

DAY 57 1344 H 1 0.000 0.000 0.00 0.00

FOLLOW-UP 2016 H 4 1.500 1.0000 1.000 1.00 3.00

309



LABTEST: Granular Casts (/LPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 57 1344 H 1 2.0 2.0 2 2

310



LABTEST: Hyaline Casts (/LPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 15 336 H 1 12.0 12.0 12 12

SQ_200mg 9 DAY 15 336 H 1 1.0 1.0 1 1

311



LABTEST: Leukocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 5 96 H 1 0.00 0.00 0.0 0.0

DAY 15 336 H 1 2.00 2.00 2.0 2.0

DAY 57 1344 H 2 1.50 0.707 1.50 1.0 2.0

FOLLOW-UP 2016 H 1 2.00 2.00 2.0 2.0

SQ_200mg 9 DAY 5 96 H 1 1.00 1.00 1.0 1.0

DAY 15 336 H 2 1.00 0.000 1.00 1.0 1.0

DAY 29 672 H 2 40.50 55.861 40.50 1.0 80.0

DAY 57 1344 H 1 2.00 2.00 2.0 2.0


DAY 6 120 H 2 2.00 1.414 2.00 1.0 3.0

DAY 8 PREDOSE 1 1.00 1.00 1.0 1.0

DAY 15 PREDOSE 3 5.00 4.583 4.00 1.0 10.0

DAY 22 PREDOSE 1 1.00 1.00 1.0 1.0

DAY 31 216 H 1 1.00 1.00 1.0 1.0

DAY 78 1344 H 1 3.00 3.00 3.0 3.0

312



LABTEST: Leukocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 FOLLOW-UP 2016 H 1 1.00 1.00 1.0 1.0

IM_200mg 9 DAY 5 96 H 2 1.00 1.414 1.00 0.0 2.0

DAY 15 336 H 1 0.00 0.00 0.0 0.0

DAY 57 1344 H 1 1.00 1.00 1.0 1.0

FOLLOW-UP 2016 H 3 2.67 2.082 2.00 1.0 5.0

313



LABTEST: Specific Gravity Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 9 1.0178 0.00455 1.0200 1.009 1.023

DAY 5 96 H 9 1.0179 0.00501 1.0190 1.010 1.025

DAY 15 336 H 9 1.0168 0.00795 1.0180 1.001 1.027

DAY 29 672 H 9 1.0137 0.00610 1.0130 1.001 1.023

DAY 57 1344 H 8 1.0173 0.00658 1.0175 1.008 1.025

FOLLOW-UP 2016 H 9 1.0170 0.00819 1.0200 1.002 1.027

SQ_200mg 9 DAY 1 PREDOSE 9 1.0111 0.00805 1.0130 1.002 1.021

DAY 5 96 H 9 1.0129 0.01022 1.0120 1.002 1.028

DAY 15 336 H 9 1.0157 0.00522 1.0160 1.009 1.023

DAY 29 672 H 9 1.0180 0.00444 1.0180 1.010 1.026

DAY 57 1344 H 9 1.0181 0.00639 1.0190 1.007 1.026

FOLLOW-UP 2016 H 9 1.0136 0.00844 1.0160 1.003 1.026


DAY 6 120 H 9 1.0172 0.00356 1.0180 1.011 1.021

DAY 8 PREDOSE 9 1.0172 0.00716 1.0160 1.010 1.032

314



LABTEST: Specific Gravity Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 15 PREDOSE 9 1.0220 0.00638 1.0230 1.008 1.030

DAY 22 PREDOSE 9 1.0189 0.00675 1.0180 1.009 1.027

DAY 31 216 H 9 1.0169 0.00623 1.0190 1.006 1.023

DAY 50 672 H 8 1.0136 0.00802 1.0130 1.004 1.024

DAY 78 1344 H 8 1.0155 0.00431 1.0160 1.009 1.022

FOLLOW-UP 2016 H 8 1.0128 0.00688 1.0115 1.004 1.027

IM_200mg 9 DAY 1 PREDOSE 9 1.0201 0.00754 1.0200 1.005 1.028

DAY 5 96 H 9 1.0188 0.00476 1.0200 1.011 1.026

DAY 15 336 H 9 1.0167 0.00723 1.0190 1.007 1.026

DAY 29 672 H 9 1.0163 0.00577 1.0160 1.007 1.025

DAY 57 1344 H 8 1.0184 0.00600 1.0205 1.006 1.025

FOLLOW-UP 2016 H 8 1.0228 0.00565 1.0235 1.015 1.031

315



LABTEST: Squamous Epithelial Cells (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 29 672 H 1 1.0 1.0 1 1

FOLLOW-UP 2016 H 1 1.0 1.0 1 1

SQ_200mg 9 DAY 5 96 H 1 1.0 1.0 1 1

SQ_50mg x 4 9 FOLLOW-UP 2016 H 1 1.0 1.0 1 1

IM_200mg 9 DAY 5 96 H 1 1.0 1.0 1 1

FOLLOW-UP 2016 H 1 1.0 1.0 1 1

316



LABTEST: pH Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 9 5.67 0.559 6.00 5.0 6.5

DAY 5 96 H 9 6.44 0.950 6.50 5.0 8.0

DAY 15 336 H 9 6.17 0.750 6.00 5.5 7.5

DAY 29 672 H 9 6.33 0.829 6.50 5.0 7.5

DAY 57 1344 H 8 6.44 0.729 6.50 5.5 7.5

FOLLOW-UP 2016 H 9 5.94 0.527 6.00 5.5 7.0

SQ_200mg 9 DAY 1 PREDOSE 9 6.22 0.712 6.50 5.0 7.5

DAY 5 96 H 9 6.28 0.755 6.00 5.0 7.0

DAY 15 336 H 9 6.28 0.667 6.50 5.0 7.0

DAY 29 672 H 9 6.44 1.014 6.50 5.0 8.0

DAY 57 1344 H 9 6.06 0.391 6.00 5.5 6.5

FOLLOW-UP 2016 H 9 5.89 0.741 5.50 5.0 7.0


DAY 6 120 H 9 5.94 0.527 5.50 5.5 6.5

DAY 8 PREDOSE 9 5.61 0.333 5.50 5.0 6.0

317



LABTEST: pH Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 15 PREDOSE 9 5.83 0.354 6.00 5.5 6.5

DAY 22 PREDOSE 9 5.89 0.417 6.00 5.5 6.5

DAY 31 216 H 9 6.11 0.601 6.00 5.5 7.0

DAY 50 672 H 8 5.88 0.791 5.75 5.0 7.0

DAY 78 1344 H 8 5.75 0.535 5.50 5.0 6.5

FOLLOW-UP 2016 H 8 6.06 0.729 6.00 5.0 7.0

IM_200mg 9 DAY 1 PREDOSE 9 5.67 0.500 5.50 5.0 6.5

DAY 5 96 H 9 6.06 0.527 6.00 5.5 7.0

DAY 15 336 H 9 6.00 0.791 6.00 5.0 7.5

DAY 29 672 H 9 6.17 0.707 6.00 5.5 7.5

DAY 57 1344 H 8 6.00 0.886 5.50 5.5 8.0

FOLLOW-UP 2016 H 8 6.06 0.496 6.00 5.5 7.0

318


Analysis Value

-999

-998

Cumulative Planned Relative Time

-999 -998

GS

K93

3776

Con

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L)

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Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacokinetic Concentration

Figure 11.1Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Note: LLQ=100 ng/mL

Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O

Protocol: BA1116891Population: Pharmacokinetic Concentration

Figure 11.1Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Note: LLQ=100 ng/mL

Linear Scale

O

O

OOO

OO

O

O

O

O

O

Semi-Logarithmic Scale

O

O

OOOOO

O

O

O

O

O

319


Analysis Value

-999

-998


-999 -998

GS

K93

3776

Con

cent

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L)

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0 200 400 600 800

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3776

Con

cent

ratio

n (n

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0 200 400 600 800


Figure 11.2Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Note: LLQ=100 ng/mL



Figure 11.2Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Note: LLQ=100 ng/mL

Linear Scale

O

O

O O O

OO

O

O

O

O


O

O

O O OO O

O

O

O

O

320


Analysis Value

-999

-998


-999 -998

GS

K93

3776

Con

cent

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0 520 1040 1560 2080 2600


Figure 11.3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Note: LLQ=100 ng/mL



Figure 11.3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Note: LLQ=100 ng/mL

Linear Scale

OO

OOO

OO

O

O

O

O

O


O

O

OOO

OOO

O

O

O

O

321


Analysis Value

-999

-998


-999 -998

GS

K93

3776

Con

cent

ratio

n (n

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L)

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K93

3776

Con

cent

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n (n

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0 200 400 600 800


Figure 11.4Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Note: LLQ=100 ng/mL



Figure 11.4Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Note: LLQ=100 ng/mL

Linear Scale

OO

O OO

OO

O

O

O

O


O

O

O O O

O OO

O

O

O

322


GS

K93

3776

Con

cent

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Actual Relative Time (Hrs)

0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

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L)

100

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0 520 1040 1560 2080 2600


Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Note: LLQ=100 ng/mL

Subject ID: Treatment:SQ_200mg

Linear Scale

OO

O

OO

OO

O

O

O

O

O


O

O

O

OO

OOO

O

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O

O

323


GS

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0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL

Subject ID: Treatment:SQ_50mg x 4

Linear Scale

OOOOO O

OOOO

OOOO

O

OO

OOOO

O

OO

OO

O

O

OO

O


O

OO

OO OOOOO

OOOOOOO

OOOOO

OO

OOO

O

O

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O

324


GS

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Note: LLQ=100 ng/mL

Subject ID: Treatment:IM_200mg

Linear Scale

O

O

OOO

OO

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GS

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Note: LLQ=100 ng/mL

Subject ID: Treatment:IV_200mg

Linear Scale

OOO

O

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OO

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OOOOOOOO

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Note: LLQ=100 ng/mL


Linear Scale

OOO

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OOOOOOOO

OOOO

O

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Note: LLQ=100 ng/mL


Linear Scale

O

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Note: LLQ=100 ng/mL


Linear Scale

O

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OOOOO

O

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Note: LLQ=100 ng/mL


Linear Scale

O

OOOOO OOOO

OOO

OOOOOOO

OO

OOO

OO

OO

OO


O

OOO

OO OOOOO

OOOOOOOOO

OO

OOO

OOO

O

O

O

330


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOO

OOO

O

O

O

OO

O

O

OO

O


OOOOOOOO

OOOO

OO

O

O

O

331


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OOOO

O

OO

O

O


O

O

OOOO

O

O

O

O

O

332


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

O

O

OOO

O

O

OO

O


O

O

OOOOO

O

O

O

O

O

333


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

OOOOO O

OOOOOO OO

OOOOO

OOOOO

OOO

O

OO


O

OOO

OOOOOOO

OO OOOOOOO OOOOO

OOO

O

O

O

334


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

OOO

O

OOOO

O

O

OO


OOOOOOOO

OOOO

O

O

O

O

335


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OOOOO

O

O

OO

O


O

O

OOOOO

OO

O

O

O

336


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOOO O

OOOOOO

OOOOO

OOO

O

OOO

OOO

OO

O


OOO

OO OOOOO

OOOOOOO

OOOO

OOO

OOO

OO

O

337


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OOO

OO

O

O

OO

O


O

O

OOO

OOO

O

OO

O

338


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO O

O

O

O

O


O

O

OO OO

O

O

O

339


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

OOO

OO

O

O

OO

OO

O

O

O

O

O


OOOOOOOO

OOOO

OO

O

O

O

340


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

O

O O

O

O

O


O

O

OO

OO O

O

O

O

341


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

OOOO O

O

OOOOO

OOOOO

OO OO

O

OO

OO

O

O

OO

O


O

OOOO O

O

OOOOO OO

OOOOO O

OOOOOO

O

O

O

O

O

342


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOOOO

OO

OO

O

O

O

O

OO


OOOOOOOO

OOOO

O

O

O

O

343


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

OOO

OO

O

O

OO

O


O

O

OOO

OOO

O

O

O

O

344


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOO

OO OOOOO

OO OOOOO

OO OO

OOO

OO

O

O

OO


O

OOO

OO OOOOO

OO OOOOO

OO OOOOO

OO O

O

O

O

345


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

OOO

O

O

O

O


O

O

OO

OO O

O

O

O

O

346


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

OOO

O

O

O

O


O

O

OO

OOO

O

O

O

O

347


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

OOO

OO O

OO

O

O


O

O

OO

OO OO

O

O

O

348


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

O

OOO

O

O

O

O

O

O

O

OO

O


OOOOOOO

OO

OO

OO

O

O

O

349


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOOO OOOOO

OO OOOOO

OO OOOOOOO

O OO O


OOO

OO OOOOO

OO OO

OOO

OO OOOOO

OO

OO

OO

350


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOO

OO

O

O

OOOO

O

O

OO

O


OOOOOOOO

OOOO

O

O

O

O

O

351


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

O

O

O

O

OO

O


O

OOO

OO

OO

O

O

O

352


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

O

OOOOO OO

OOO

OO O

OOOOOOO

O

OOO

O

OO

O

OO

O


O

OOOOO OO

OOO

OO O

OOOOOO O

OOOO

O

OO

O

O

O

O

353


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

O

OO

OO

O

O

O

O

O


O

O

O

OO

OOO

O

O

O

O

354


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOOO O

OOOOOO OOO

OOOO

OOOOO

OO

O

OO


OOO

OO OOOOOOO O

OOOOOO

OOOOO

OOO

O

O

355


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OOOOOOO

O

OO

O

O

O

O

O

O

O


OOOOOOOO

OO

OO

OO

O

O

O

356


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

O

OO

OO

O

OO

O


O

O

O

OO

OO O

O

O

O

357


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 520 1040 1560 2080 2600

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 520 1040 1560 2080 2600



Note: LLQ=100 ng/mL


Linear Scale

OO

OOO

OO

O

O

OO

O


O

O

OOO

OOO

O

O

O

O

358


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000


Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Note: LLQ=100 ng/mL


Linear Scale

OO

O

O O

O O

O

O

O

O


O

O

O

O O

O OO

O

O

O

359


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

OO O

O O OOO O O

O OOO

O

O O

O OOO

O

O O

OO

O


O

OO

O O OOO O O

O OOOO

O O

O OOO

O

O O

O OO

360


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

O

O O

O

O

OO


O

O

O O OO O

O

O

O

O

361


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

OOO

O

O

OO

O

O

OO

O

O

O

O

O


OOOOOOOO

O

O OO

OO

O

O

362


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

OOO

O

OOO

O

O

OO

O

O

O

O

O


OOOOOOOO

OO O

O

O

O

O

O

363


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O

O

OO

O

O

O

O

OO


O

O

OO O

OO

O

O

O

O

364


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO O O

O

O

OO

O


O

O

O O O O O

O

OO

O

365


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O O OO

O OO O O O

O OOOO

O OO O

OO

OO

O

O O

O


O

O O O

OO O

OO O O

O OOOO

O OO O

OO

OO

O

O OO

366


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

OOOO

OOO

O

O

O

OO

O

O

OO


OOOOOOOO

O OO O

OO

O

O

367


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O

O O OO

O

OO

O


O

O

O O OO

O

O

O

O

368


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

OO

O

O

OO O

O

O

OO


O

O

OO

O O O

O

O

O

O

369


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O O OO O O

O O O OO O OO

OO O

O OOO O O O

O OO


O

O O O

O OOO O O O

O O OOO

O OO O

OO O O OO O

O

370


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

100

1000

10000

100000


0 200 400 600 800 1000



Note: LLQ=100 ng/mL


Linear Scale

O

O

OO

OOO

O

OO

OO

O

O

OO


OOOOOOOO

OO O O

O

O

O

O

371


GS

K93

3776

Con

cent

ratio

n (n

g/m

L)

0

20000

40000

60000

80000


0 200 400 600 800 1000

GS

K93

3776

Con

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Protocol: BA1116891 Page 1 of 4Population: PK Concentration Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]

No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 8 8 NQ NQ NQ NQ 0.25 H 9 0 59553.9 (53117.0, 65990.7) 8374.04 59298.0 48466 71858 0.5 H 9 0 60036.7 (53782.8, 66290.5) 8135.94 61059.0 46293 72412 0.75 H 9 0 60308.3 (54220.7, 66396.0) 7919.72 60505.0 45858 72690 1 H 9 0 61534.1 (54242.0, 68826.2) 9486.70 61624.0 47684 79060 2 H 9 0 57057.1 (51346.4, 62767.8) 7429.38 56904.0 47076 71858 4 H 8 0 57206.5 (50903.4, 63509.6) 7539.40 57129.5 44813 68162 6 H 9 0 55827.6 (50276.2, 61378.9) 7222.05 53904.0 47076 70103 DAY 2 24 H 9 0 47895.1 (43154.0, 52636.2) 6167.95 50158.0 38239 58690 DAY 3 48 H 9 0 32207.4 (28490.9, 35924.0) 4835.07 31443.0 25778 42170 DAY 4 72 H 9 0 28468.9 (25954.1, 30983.7) 3271.66 29227.0 22995 32520 DAY 5 96 H 9 0 31205.1 (27946.9, 34463.4) 4238.82 32547.0 23759 38187 DAY 6 120 H 9 0 27108.0 (24801.6, 29414.4) 3000.48 28313.0 21285 30676 DAY 10 216 H 9 0 19899.1 (18369.1, 21429.1) 1990.45 20196.0 16073 22657 DAY 15 336 H 9 0 14879.6 (13013.9, 16745.2) 2427.17 15646.0 11477 18340 DAY 22 504 H 9 0 10104.4 (8470.3, 11738.6) 2125.97 10260.0 6462 13116 DAY 29 672 H 9 0 6716.6 (5490.2, 7942.9) 1595.37 7296.0 3705 8735 DAY 57 1344 H 8 1 1450.0 (833.1, 2066.9) 737.84 1491.0 0 2418 FOLLOW-UP 2016 H 6 6 NQ NQ NQ NQ

Note: LLQ=100 ng/mL

395



No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_200mg 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ 2 H 6 1 1936.5 (490.0, 3383.0) 1378.38 1722.0 0 3581 6 H 9 0 3981.8 (1769.0, 6194.6) 2878.76 2530.0 1264 10391 DAY 2 24 H 9 0 11418.7 (6800.8, 16036.5) 6007.64 10668.0 5689 24415 DAY 3 48 H 8 0 15861.9 (10940.6, 20783.2) 5886.59 15265.5 9242 27231 DAY 4 72 H 8 0 16696.0 (12240.9, 21151.1) 5328.92 16667.0 10125 26340 DAY 5 96 H 9 0 22142.3 (19102.6, 25182.0) 3954.51 22151.0 16235 27386 DAY 6 120 H 9 0 21977.6 (19087.2, 24867.9) 3760.15 22463.0 14297 26489 DAY 10 216 H 9 0 18750.7 (16509.6, 20991.8) 2915.57 18308.0 12921 22725 DAY 15 336 H 9 0 14552.8 (12495.1, 16610.5) 2676.96 14744.0 9285 18216 DAY 22 504 H 9 0 10597.2 (9120.4, 12074.0) 1921.23 10583.0 6746 13021 DAY 29 672 H 9 0 6920.4 (5672.5, 8168.4) 1623.56 7185.0 3646 8894 DAY 57 1344 H 8 0 1682.5 (1384.8, 1980.2) 356.09 1734.0 1015 2068 FOLLOW-UP 2016 H 6 6 NQ NQ NQ NQ

Note: LLQ=100 ng/mL

396



No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_50mg x 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ4 6 H 4 0 2090.8 (588.1, 3593.4) 944.32 2127.5 1150 2958 DAY 2 24 H 9 0 4258.9 (2818.9, 5698.8) 1873.31 3920.0 2113 6773 DAY 3 48 H 9 0 4787.2 (3702.2, 5872.2) 1411.56 4749.0 2392 6336 DAY 4 72 H 9 0 5347.6 (4357.9, 6337.2) 1287.54 5469.0 3108 6971 DAY 5 96 H 9 0 7264.4 (6320.8, 8208.1) 1227.65 7575.0 4945 8546 DAY 6 120 H 9 0 7283.2 (6485.6, 8080.8) 1037.64 7545.0 5486 8405 DAY 8 PREDOSE 9 0 6786.1 (6145.4, 7426.8) 833.52 6795.0 5274 8093 6 H 9 0 7642.3 (6657.7, 8627.0) 1280.99 8196.0 5274 8927 DAY 9 24 H 9 0 8932.6 (6834.9, 11030.2) 2728.98 7754.0 4797 13988 DAY 10 48 H 9 0 9152.4 (7284.3, 11020.6) 2430.38 8456.0 4917 12488 DAY 11 72 H 9 0 9172.6 (7467.5, 10877.6) 2218.21 8384.0 5235 12260 DAY 12 96 H 9 0 12359.4 (10282.9, 14436.0) 2701.47 11749.0 8074 16505 DAY 13 120 H 9 0 11743.2 (9786.6, 13699.8) 2545.42 11537.0 7455 15614 DAY 15 PREDOSE 9 0 10580.3 (9105.2, 12055.4) 1919.01 10069.0 7550 13153 6 H 9 0 11786.4 (9927.8, 13645.1) 2417.96 11408.0 7550 15245 DAY 16 24 H 9 0 12225.3 (9304.7, 15145.9) 3799.58 11397.0 5699 18034 DAY 17 48 H 9 0 11182.2 (9372.0, 12992.4) 2354.98 11633.0 6036 13721 DAY 18 72 H 9 0 11218.8 (9294.3, 13143.2) 2503.61 10809.0 6160 14055 DAY 19 96 H 9 0 14582.6 (12323.1, 16842.0) 2939.39 13691.0 9282 19715 DAY 20 120 H 9 0 14694.6 (12450.7, 16938.4) 2919.12 14156.0 9346 19144 DAY 22 PREDOSE 9 0 13184.1 (11220.7, 15147.6) 2554.37 13529.0 8931 16802 6 H 9 0 14945.6 (12320.6, 17570.5) 3414.92 16031.0 9091 18521 DAY 23 24 H 9 0 14525.1 (10732.0, 18318.2) 4934.63 12475.0 7806 22497 DAY 24 48 H 9 0 13227.0 (10989.0, 15465.0) 2911.52 12582.0 7959 17770 DAY 25 72 H 9 0 12777.0 (10541.4, 15012.6) 2908.40 12011.0 8138 17798 DAY 26 96 H 9 0 18093.4 (14416.9, 21769.9) 4782.95 17576.0 10412 26572 DAY 27 120 H 9 0 16643.4 (13765.7, 19521.2) 3743.81 16188.0 9278 22078 DAY 31 216 H 9 0 13612.4 (11215.2, 16009.7) 3118.76 14096.0 7373 17205 DAY 36 336 H 9 0 10318.1 (8600.1, 12036.2) 2235.11 9899.0 6423 13084

Note: LLQ=100 ng/mL

397



No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_50mg x 9 DAY 43 504 H 9 0 7325.3 (6019.6, 8631.0) 1698.66 6708.0 4492 97194 DAY 50 672 H 8 0 5207.1 (4284.6, 6129.7) 1103.50 4982.0 3755 7052 DAY 78 1344 H 3 0 1720.0 (1659.8, 1780.2) 24.25 1716.0 1698 1746 FOLLOW-UP 2016 H 7 7 NQ NQ NQ NQ

IM_200mg 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ 2 H 6 0 2026.8 (1530.1, 2523.6) 473.32 2242.5 1236 2418 6 H 9 0 5879.6 (2533.0, 9226.1) 4353.67 4637.0 1968 15609 DAY 2 24 H 9 0 19661.1 (11805.4, 27516.8) 10219.84 16522.0 7056 37535 DAY 3 48 H 9 0 20577.1 (14544.2, 26610.0) 7848.49 17621.0 10090 34413 DAY 4 72 H 9 0 20901.9 (15274.5, 26529.3) 7320.99 19075.0 10834 35732 DAY 5 96 H 9 0 26883.0 (23070.0, 30696.0) 4960.52 28265.0 16077 31901 DAY 6 120 H 9 0 25089.6 (21521.0, 28658.1) 4642.47 25674.0 16768 31631 DAY 10 216 H 9 0 20255.6 (17279.4, 23231.7) 3871.79 20875.0 13814 24536 DAY 15 336 H 9 0 15227.1 (12691.3, 17763.0) 3299.01 15600.0 8829 19141 DAY 22 504 H 9 0 9940.0 (8244.5, 11635.5) 2205.81 10355.0 5072 12381 DAY 29 672 H 9 0 7044.4 (5477.3, 8611.6) 2038.77 7295.0 2599 9356 DAY 57 1344 H 8 1 1294.0 (767.0, 1821.0) 630.37 1305.5 0 2054 FOLLOW-UP 2016 H 8 8 NQ NQ NQ NQ

Note: LLQ=100 ng/mL

398


Protocol: BA1116891 Page 1 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters

PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-168) N 9 9(h*ng/mL) n 9 9 Geom. Mean 5521998 934531 95% CI (5144565, 5927122) (805702, 1083959) SD Logs 0.0921 0.1930 %CVb 9.23 19.48 Arith. Mean 5542684 949221 95% CI (5154514, 5930855) (819983, 1078458) SD 504991.1 168131.6 Median 5613730 939194 Min. 4664059 628562 Max. 6425054 1135689

AUC(0-168)/D N 9 9(h*ng/mL/mg) n 9 9 Geom. Mean 27610 18691 95% CI (25723, 29636) (16114, 21679) SD Logs 0.0921 0.1930 %CVb 9.23 19.48 Arith. Mean 27713 18984 95% CI (25773, 29654) (16400, 21569) SD 2525.0 3362.6 Median 28069 18784 Min. 23320 12571 Max. 32125 22714

399



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-672) N 9 9(h*ng/mL) n 9 9 Geom. Mean 12049256 7220426 95% CI (11103817, 13075196) (6086594, 8565472) SD Logs 0.1063 0.2222 %CVb 10.66 22.50 Arith. Mean 12109306 7370781 95% CI (11132141, 13086471) (6215333, 8526229) SD 1271244.2 1503181.8 Median 12196400 7064426 Min. 9806847 4476404 Max. 14474115 9204480

AUC(0-inf) N 9 9 9 9(h*ng/mL) n 9 9 9 9 Geom. Mean 14899413 12371299 14196870 12911085 95% CI (13299729, 16691506) (10580158, 14465667) (12082673, 16681004) (10868391, 15337700) SD Logs 0.1478 0.2035 0.2098 0.2241 %CVb 14.86 20.56 21.21 22.69 Arith. Mean 15043184 12579102 14470250 13184376 95% CI (13356409, 16729959) (10871823, 14286381) (12212286, 16728214) (11113835, 15254917) SD 2194412.8 2221087.6 2937502.1 2693673.6 Median 15601969 12685813 13400594 13245585 Min. 11845428 7583941 9584860 8336900 Max. 18985826 15576684 18540300 16018887

400



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-t) N 9 9 9 9(h*ng/mL) n 9 9 9 9 Geom. Mean 13912995 11471735 12210968 11865187 95% CI (12105207, 15990758) (9481356, 13879946) (9756147, 15283465) (9991370, 14090426) SD Logs 0.1811 0.2479 0.2920 0.2236 %CVb 18.26 25.18 29.83 22.64 Arith. Mean 14107679 11746683 12671887 12118002 95% CI (12272912, 15942447) (9924909, 13568457) (9902696, 15441077) (10182547, 14053457) SD 2386943.9 2370039.7 3602583.3 2517933.7 Median 14931389 12270968 11456806 12309600 Min. 9811001 6189117 7287154 7610470 Max. 17786417 14629803 17712773 15535571

%AUCex (%) N 9 9 9 9 n 9 9 9 9 Geom. Mean 5.60 6.31 11.38 6.03 95% CI (3.66, 8.57) (4.27, 9.32) (6.65, 19.46) (3.63, 10.02) SD Logs 0.5534 0.5088 0.6985 0.6601 %CVb 59.87 54.36 79.30 73.90 Arith. Mean 6.52 7.17 13.69 7.77 95% CI (3.13, 9.92) (3.71, 10.62) (7.88, 19.51) (1.82, 13.72) SD 4.414 4.495 7.566 7.745 Median 5.26 6.08 14.51 5.30 Min. 2.84 2.76 4.46 3.02 Max. 17.17 18.39 23.97 27.89

401



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Cmax (ng/mL) N 9 9 9 9 n 9 9 9 9 Geom. Mean 62496 22387 17755 28743 95% CI (56129, 69585) (19721, 25412) (14382, 21920) (24220, 34111) SD Logs 0.1398 0.1649 0.2741 0.2228 %CVb 14.05 16.61 27.94 22.56 Arith. Mean 63037 22651 18335 29317 95% CI (56312, 69762) (19890, 25412) (14642, 22028) (25013, 33621) SD 8749.1 3592.3 4804.8 5599.2 Median 62538 22463 17576 29665 Min. 48466 16235 10412 16768 Max. 79060 27386 26572 37535

CL/F (mL/h) N 9 9 9 9 n 9 9 9 9 Geom. Mean 13.42 16.15 3.53 15.48 95% CI (11.98, 15.04) (13.84, 18.85) (3.00, 4.15) (13.03, 18.39) SD Logs 0.1478 0.2010 0.2116 0.2239 %CVb 14.86 20.30 21.40 22.67 Arith. Mean 13.56 16.48 3.60 15.85 95% CI (11.99, 15.12) (13.51, 19.44) (2.99, 4.21) (12.88, 18.82) SD 2.032 3.857 0.792 3.864 Median 12.82 15.77 3.74 15.09 Min. 10.53 12.84 2.70 12.47 Max. 16.88 26.16 5.25 23.94

402



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Vz/F (mL) N 9 9 9 9 n 9 9 9 9 Geom. Mean 5618 7013 1683 6425 95% CI (5170, 6106) (6036, 8148) (1368, 2071) (5743, 7187) SD Logs 0.1082 0.1952 0.2699 0.1458 %CVb 10.86 19.70 27.49 14.66 Arith. Mean 5648 7137 1746 6484 95% CI (5169, 6128) (6013, 8260) (1302, 2191) (5786, 7181) SD 623.7 1461.7 578.3 907.2 Median 5646 6786 1692 6445 Min. 4795 5438 1300 4792 Max. 6760 10006 3211 7812

t1/2 (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 294 303 333 292 95% CI (258, 329) (273, 333) (301, 364) (255, 329) SD 45.9 38.8 40.5 48.1 Median 286 313 320 286 Min. 203 239 289 194 Max. 357 367 424 344

tmax (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 2 109 583 79 95% CI (1, 2) (99, 118) (559, 608) (50, 109) SD 0.6 12.2 31.8 37.9 Median 2 117 599 96 Min. 1 96 527 24 Max. 3 120 601 120

403



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------tlast (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 1195 1272 1376 1195 95% CI (967, 1422) (1106, 1437) (1114, 1639) (967, 1422) SD 295.9 215.5 341.5 296.1 Median 1344 1343 1176 1344 Min. 673 697 1010 671 Max. 1345 1346 1849 1344

#pts N 9 9 9 9 n 9 9 9 9 Arith. Mean 4.6 3.1 4.8 4.6 95% CI (3.5, 5.6) (2.9, 3.4) (3.9, 5.7) (3.2, 5.9) SD 1.30 0.30 1.20 1.80 Median 5.0 3.0 5.0 4.0 Min. 3.0 3.0 3.0 3.0 Max. 6.0 4.0 6.0 8.0

Lambda_z N 9 9 9 9(/h) n 9 9 9 9 Arith. Mean 0.0024 0.0023 0.0021 0.0024 95% CI (0.0021, 0.0028) (0.0021, 0.0026) (0.0019, 0.0023) (0.0021, 0.0028) SD 0.000 0.000 0.000 0.000 Median 0.0024 0.0022 0.0022 0.0024 Min. 0.0019 0.0019 0.0016 0.0020 Max. 0.0034 0.0029 0.0024 0.0036

404



PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Lambda_z_low N 9 9 9 9er (h) n 9 9 9 9 Arith. Mean 261 480 687 291 95% CI (143, 380) (402, 558) (580, 795) (148, 433) SD 153.8 101.5 140.3 185.3 Median 215 504 624 336 Min. 120 216 598 72 Max. 504 575 1007 504

Lambda_z_upp N 9 9 9 9er (h) n 9 9 9 9 Arith. Mean 1195 1272 1376 1195 95% CI (967, 1422) (1106, 1437) (1114, 1639) (967, 1422) SD 295.9 215.5 341.5 296.1 Median 1344 1343 1176 1344 Min. 673 697 1010 671 Max. 1345 1346 1849 1344

Rsq_adj N 9 9 9 9 n 9 9 9 9 Arith. Mean 0.9987 0.9981 0.9941 0.9982 95% CI (0.9977, 0.9997) (0.9947, 1.0015) (0.9893, 0.9988) (0.9972, 0.9992) SD 0.001 0.004 0.006 0.001 Median 0.9990 0.9996 0.9972 0.9987 Min. 0.9957 0.9865 0.9831 0.9954 Max. 0.9999 1.0000 0.9997 0.9995

405


Protocol: BA1116891 Page 1 of 1Population: PK parameter Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters

Comparison __GeoMetric LS Mean__ Ratio (%) 90% Confidence Parameter Test Vs Reference n Test n Ref (Test/Ref) Interval for Ratio ------------------------------------------------------------------------------------------------------ AUC(0-168)/D (h*ng/mL/mg) SQ_50mg*4 VS IV_200mg 9 18690.62 9 27609.99 67.70 (59.77, 76.67)

AUC(0-672) (h*ng/mL) SQ_50mg*4 VS IV_200mg 9 7220426 9 12049256 59.92 (51.92, 69.16)

AUC(0-inf) (h*ng/mL) IM_200mg VS IV_200mg 9 12911085 9 14899413 86.65 (73.96, 101.53) SQ_200mg VS IV_200mg 9 12371299 9 14899413 83.03 (70.87, 97.29) SQ_50mg*4 VS IV_200mg 9 14196870 9 14899413 95.28 (81.32, 111.64)

AUC(0-t) (h*ng/mL) IM_200mg VS IV_200mg 9 11865187 9 13912995 85.28 (70.43, 103.26) SQ_200mg VS IV_200mg 9 11471735 9 13912995 82.45 (68.10, 99.83) SQ_50mg*4 VS IV_200mg 9 12210968 9 13912995 87.77 (72.49, 106.27)

%AUCex (%) IM_200mg VS IV_200mg 9 6.033362 9 5.598382 107.77 (66.21, 175.41) SQ_200mg VS IV_200mg 9 6.306422 9 5.598382 112.65 (69.21, 183.35) SQ_50mg*4 VS IV_200mg 9 11.37599 9 5.598382 203.20 (124.84, 330.74)

Cmax (ng/mL) IM_200mg VS IV_200mg 9 28743.29 9 62495.91 45.99 (38.98, 54.26) SQ_200mg VS IV_200mg 9 22386.53 9 62495.91 35.82 (30.36, 42.26) SQ_50mg*4 VS IV_200mg 9 17755.24 9 62495.91 28.41 (24.08, 33.52)

CL/F (mL/h) IM_200mg VS IV_200mg 9 15.47911 9 13.42335 115.31 (98.44, 135.09) SQ_200mg VS IV_200mg 9 16.1524 9 13.42335 120.33 (102.72, 140.96) SQ_50mg*4 VS IV_200mg 9 3.52867 9 13.42335 26.29 (22.44, 30.80)

Vz/F (mL) IM_200mg VS IV_200mg 9 6424.608 9 5618.401 114.35 (98.28, 133.05) SQ_200mg VS IV_200mg 9 7013.106 9 5618.401 124.82 (107.28, 145.24) SQ_50mg*4 VS IV_200mg 9 1683.06 9 5618.401 29.96 (25.75, 34.85)

406


Protocol: BA1116891 Page 1 of 1Population: PK Parameter Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters

90% Confidence Comparison ----------Median---------- Difference Interval for Parameter Test vs Reference n Test n Ref. (Test-Ref) Difference -------------------------------------------------------------------------------------------------- t1/2 (h) SQ_200mg vs IV_200mg 9 313.20 9 286.19 7.96 (-28.99, 45.7) SQ_50mg x 4 vs IV_200mg 9 320.00 9 286.19 31.3 (-2.46, 71.89) IM_200mg vs IV_200mg 9 285.89 9 286.19 -3.25 (-40.27, 32.72)

tmax (h) SQ_200mg vs IV_200mg 9 116.92 9 1.50 115.42 (94.42, 117.85) SQ_50mg x 4 vs IV_200mg 9 598.73 9 1.50 596.8 (594.97, 598.07) IM_200mg vs IV_200mg 9 95.63 9 1.50 93.7 (45.37, 94.42)

407


Analysis Value

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Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacodynamic

Figure 7.1Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear and Semi-Log)


Protocol: BA1116891Population: Pharmacodynamic

Figure 7.1Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear and Semi-Log)

Linear Scale

O

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Figure 7.2Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear and Semi-Log)



Figure 7.2Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear and Semi-Log)

Linear Scale

O

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Analysis Value

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Figure 7.3Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear and Semi-Log)



Figure 7.3Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear and Semi-Log)

Linear Scale

O

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Analysis Value

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Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)




Parameter:Abeta1-22

Linear Scale

OOOO O O O O O


O

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411


Analysis Value

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Parameter:Abeta18-35

Linear Scale

O

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Analysis Value

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Parameter:Abeta42

Linear Scale

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413


Change from Baseline

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Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)

Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.





Parameter:Abeta1-22

Linear Scale

OOOO O O O O O


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Analysis Value

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Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)




Parameter:Abeta1-22

Linear Scale

OO O O O O O


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Analysis Value

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Analysis Value

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Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)






Parameter:Abeta1-22

Linear Scale

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Analysis Value

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Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)




Parameter:Abeta1-22

Linear Scale

OOOO O O O O O


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Analysis Value

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Analysis Value

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Parameter:Abeta42

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Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)






Parameter:Abeta1-22

Linear Scale

OOOO O O O O O


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Parameter:Abeta42

Linear Scale

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Analysis Value

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Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)




Parameter:Abeta1-22

Linear Scale

OO O O O O O


OO O O

O OO

429


Analysis Value

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Analysis Value

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Parameter:Abeta42

Linear Scale

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Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)






Parameter:Abeta1-22

Linear Scale

OO O O O O O


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Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)

Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg

Linear Scale

OOOO O O O O O


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O

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Con

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g/m

L)

0

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cent

ratio

n (p

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L)

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Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4

Linear Scale

OOOO O OOOO O OOOO O OOOO O O O O O O


O

OOOO O

OOO O OOOO

OOOOO

OO

OO O

O

436


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

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Con

cent

ratio

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L)

10

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0 520 1040 1560 2080 2600



Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg

Linear Scale

OOOO O O O O O


O

OOO O

OO O

O

437


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

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60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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1000

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0 520 1040 1560 2080 2600



Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg

Linear Scale

OOOOOOO O O O O O


O

OOOOOO

O

OO

O

O

438


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

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60000


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Con

cent

ratio

n (p

g/m

L)

10

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100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOOOO O

O O

O

O

439


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

OOO O O O

O

O

440


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO

OO O O

O

441


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

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100000


0 520 1040 1560 2080 2600



Linear Scale

OOOO O OOOO O OOOO O OOOO O O O O O O O


OOOO O OOOO O OOOO O OOOO O O O O

OO

O

442


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOOOO

O OO O O

443


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O

O O O O

444


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O O

O O O

445


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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100000


0 520 1040 1560 2080 2600



Linear Scale



O

O

OOO OOOO

O

OOOO O O

OO

OO

OO O

OO

446


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOOOO O O

O O

O

447


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

OOO

O

O OO

O

448


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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10000

100000


0 520 1040 1560 2080 2600



Linear Scale



O

OOO O O

OOOO O

O

OO OOOOO O O

O O

O O

449


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

OOO O O

O

O

O

450


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOO O O O O O


O

OO O O O O

O

451


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOO

O

OO O

OO

O

452


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O


OOOO

O OO

453


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 520 1040 1560 2080 2600



Linear Scale



OOOOO OO

OO O OOOO O OOOO O O O O

O O

454


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOO

O

O

OO O

OO

455


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO

O OO

OO

456


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale



OOOO O OOOO O OOOO O OOOOO O O O

O O

457


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O

OO

OO

458


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O

O OO

O

459


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO

O OO

OO

460


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOO O O O O O


O

OO

O

O

OO

OO

O O

461


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale



OOOO O OOOO O OOOO O OOOO O O O

O OO

462


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOO

O

O

OO

OO

OO

463


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

OOO

O OO

OO

464


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale



OOOO O O

OOO O OOOO

O OOOO O OO

O OO

465


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O

O O

OO

466


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale



OOOO

O OOOO O OOOO O OOOO OO

O

467


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOO

O

O

O O OO

O O

468


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O O

O OO

469


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


OOOO O

O O OO

470


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

O

O


O

O

O

O OO

O

O

O

471


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

OO

O

O

OOO

O

OO OO

OO

O OOOO

O

O

O

O

OO


O

O

O

O

O OO

OO O OO

OO O OOOO O O

O

O

O

O

472


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO

O

O

O

O

O

473


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

O

O

O

O

O

O


O

OOOO

OO O

O

O

O

O

474


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

O

O

O

O

OO


O

OOOO

OO O

O

O

O

O

475


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O O

O

O

O O


O

O

OO O

O

O

OO

476


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO O

O

O

O

O

477


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

O

O

O

O

OOO

OO

O

O

O

OO O OO

O

O

O

O

O

O

OO

O


O

O

OO O OO

OO OOOOO O OOO

O O

O

O

O

O

O

O

478


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

O

O

O

O

OO


O

OO

OO

OO OO

O

O

O

479


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

O

OO

O

O

O

O

480


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O O

O

O

OO


O

O

OO O

O

O

O

O

481


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

O

O

OO O OO

OOO OO

OO O

OOOO O

O

O

O

OO


O

O

OO O OOOO O OO

OO O OOOO OO

OO

O

O

482


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

O

O

O

O

O

O


OOOOO

OO O

O

OO

O

483


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO O

O

O

O

O

484


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

OO

O

O

O OO

O

O O

OO

OO OOOOO

O

O

O

O

OO


O

O

O

OO OO

OO O

OOOO O OOO

O O O

OO

O

O

485


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O O

O

O

O

O


O

O

OO O

O

O

O

O

486


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

O


O

O

O

O O

O

O

O

487


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

OO

O

O O

O

O

OO


O

OOOO

OO O

O

O

O

O

488


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O


O

O

OO O

O

O

489


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

OO

O

O

OOO

O

O O

OOOO O O

O

OOO

O

O

O

O

O


O

O

O

OO OO

OOOOOOO O OO

OO OO

O

O

O

O

490


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

O

O

O

O O


O

OOOO

OO O

O

O

O

O

491


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OOO

O

O

O

O

492


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

O

O

O

O O OO

OO

O OO

O

O O

OO

OO O

O

O

O

OO


O

O

OO O OO

OO O OOOO O OO

OO OO

OO

O

O

493


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO

OO

O

O

O

494


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

O

OO

O

O

O

O

495


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO

OO

O

O

O

496


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

O

O

OO


O

OO

O

OOO

O

O

O

O

497


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

OO

O

O

O OOOO O OO

OO O

OO

O

OO

O

O

O

OO


O

O

O

OO OOO

O O OOOO O OO

OO O O

O

O

O

O

498


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

O O

O

O

O

O


O

OO

OOOO O O

O

O

O

499


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

OO

O

O

O

O

O


O

O

OO OO

O

O

O

500


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

O

O

OO

OOO

O

O

O

OOOO

O

O

O

O

O

O

O

O

O

O

O


O

O

OOO OO

OO O OOOO

O OOO

OO O

OO

O

O

501


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO O

O

O

O

O

502


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Linear Scale

OO

O

O

O OO

OO O OO

OO

O

OO

OOO

O

O


O

O

O

OO OO

OO O OOOO O OO

OO O O

O

503


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

OO

O

O

O

OO

O

O

OO


O

OOOO

OO O

O

O

O

O

504


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

OO


O

O

OO

O

O

O

OO

505


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

O

O

O

O

O

O

O

O

O


O

O

OO O O

O

O

O

506


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Parameter:Abeta42, Subject ID: Treatment:SQ_200mg

Linear Scale

OOOO O O O O O


O

O

OO

OO

O

OO

507


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4

Linear Scale



O

O

O

O

O OOOO O OO

OOO OOOO O O

OO

O

O

508


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Parameter:Abeta42, Subject ID: Treatment:IM_200mg

Linear Scale

OOOO O O O O O


O

O

OO O

O

O

O

O

509


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600



Parameter:Abeta42, Subject ID: Treatment:IV_200mg

Linear Scale

OOOOOOO O O O O O


O

OOOOOO O O

OO

O

510


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OO

OO

OO OO

O

O

O

511


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OOO

O

O

O

O

512


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O

O O O


OOOO O O

O OO

513


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O OOOO O OOOO O OOOO O O O O O O O


O

O

OO

O OOOO O OO

OO

O OOOO O O

O

O

O

O

O

514


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOO

OO OO

O

O

O

515


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO O O

O

O

O

516


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OOO

O

O

O

O

517


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale



O

O

OO O OOOO O OOO

O O OOOO O O

OO

O

O

518


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOO

O O

OO

O

O


OOOOOO

O O

OO

O

O

519


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO O

O

O

O

O

520


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOO OOOO O OOOO O OOOO O O O O O O


O

O

OO

O OOOO O OOO

O O OOOO O O

OO

O

O

521


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO O

OO

O

O

522


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOO O O O O O


O

O

O

O O

O

O

O

523


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OO

OO

OOO

O

O

O

O

524


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O


O

O

OO O O

O

525


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOO OOOO O OOOO O OOOO O O O O O O


O

O

O

OO OO

OO O OOOO O OO

OO O OO

O

O

O

526


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OO

OO

OO O

O

O

OO

527


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OOO

O

O

O

O

528


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale



O

O

OO O OO

OO O OOOO O O

OOO O O

OO

O

O

529


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO O

O

O

O

O

530


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO

OO

O

O

O

531


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOO

O O

O O O

O


OOO

O O

OO O

O

532


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOO O O O O O


O

OO

O

OO O

O

O

O

O

533


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale



O

O

O

OO OOO

O O OOOO O OO

OO O OO

O

O

O

534


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOO

OO O

O

O

O

O

535


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OOO

O

O

O

O

536


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O OOO

O O OOOO O OOOO O OO O O O


O

O

OO O OO

OO O OOOO

O OOOO O

O

O

O

O

O

537


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O O O O


O

O

OO O

O

O

O

O

538


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

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40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

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1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale



O

O

OO

OOOOO O OO

OO O OOOO O O

O

539


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

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10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOOOOO O O O O O


O

OOOO

OO

OO

O

O

O

540


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

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10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO

OO

O O O


O

OOO

OO

O OO

541


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 520 1040 1560 2080 2600

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 520 1040 1560 2080 2600




Linear Scale

OOOO O O

O

O

O


OOOO O O

O

O

O

542


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

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L)

10

100

1000

10000

100000


0 200 400 600 800 1000


Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)


Linear Scale

OO O O O O O


OO O O O O O

543


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


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Con

cent

ratio

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L)

10

100

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10000

100000


0 200 400 600 800 1000



Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4

Linear Scale

OO O O O OO O O O OO O O O OO O O O O


O

O O O O OOO

O O OO O OO

OO O OO

O

544


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


O

O O O O

OO

545


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOO O O

O

OO

546


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

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L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOO O O O

O O

547


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


O

O O O O O O

548


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O

OO O

549


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

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L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale




550


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

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40000

50000

60000


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Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOOO O O O

O

551


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

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10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O OO O

552


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OOO

O O OO

553


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



O

O

O O O OOO

OO

OO O O O O

O O

OO

O

554


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOOO

O O OO

555


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


O

O O O

O

O O

556


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



O

OO

O O OO O O

O O

O

O O OOOO

O O O

557


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


O

O O O O O

O

558


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O


O

OO O O O

559


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOO

O

OO O

O

560


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OOO O

O OO

561


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



OO O OO OO

O O O OOO O O OO O O O O

562


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOOO

O

O

OO O

563


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O

O OO

564


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



OO O O O OO O O O OO O O O OO O OO O

565


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O O

OO

566


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O OO O

567


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OOO

OO O

O

568


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOO O O O O O


O

OO

O

O

OO

OO

569


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale




570


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOO

O

O

OO

OO

571


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


O

OO O O O

O

572


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



OO O O O OO O O O OO

O O O OO O O O O

573


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O O

O O

574


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale



OOO O O OO O O O OO O O O OO O O O

O

575


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OOOOO O O O O O


O

OOO

O

O

O O OO

576


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OOO O O O

O

577


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO O O O O O


OO O O O

O O

578


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O

O


O

O

O

O OO

O

579


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO

O

O

OOO

O

OO O

O

O O

O OO O

OO

O


O

O

O

O

O OO

OO O OO

O O O OO O O O O

580


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O

O


O

O

OO

O

O

O

581


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

OO

O

O

O

O

O

O

O


O

OOOO

OO O

O

O

582


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

OO

O

O

O

O

O

O

O


O

OOOO

O O O

O

O

583


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O O

O

O


O

O

OO O

O

O

584


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O

O


O

O

OO O

O

O

585


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

OOO

OO

O

O

O

O O O OO

O

O

O

O


O

O

OO O OO

O O OOOO O O OO O

O O

O

586


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

OO

O

O

O

O

O

O

O


O

OO

OO

O O OO

O

587


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O

O


O

O

O

OO

O

O

588


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O O

O

O


O

O

O O O

O

O

589


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

OO O OO

O OO OO

OO O

OOO O O

O


O

O

O O O OOO O O OO

O O O OO O O OO

590


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

OO

O

O

O

O

O

O

O


OOOOO

OO O

O

O

591


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O

O


O

O

OO O

O

O

592


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

OO

O

O

O OO

O

O O

OO

O OO

OOO

O

O

O


O

O

O

OO OO

OO O

OOO O O OO O O O O

593


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O O

O

O


O

O

OO O

O

O

594


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

cent

ratio

n (p

g/m

L)

10

100

1000

10000

100000


0 200 400 600 800 1000




Linear Scale

O

O

O

O

O

O


O

O

O

O O

O

595


Con

cent

ratio

n (p

g/m

L)

0

10000

20000

30000

40000

50000

60000


0 200 400 600 800 1000

Con

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OO

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598


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O

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O

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O O OO

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O

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O OOO

O O OO

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606


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O

O

OO

OOO

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O

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609


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OO

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O OO

O O O OO

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O O O OOO O O OO

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611


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613


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OO O O O O O


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616


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OOO O O OO O O O OO O O O OO O O O O


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626


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O O

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629


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O O

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O


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Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]

Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 632.6 (471.4, 793.8) 209.75 559.5 42 101 1 H 9 6 111.4 31.3 3 51 2 H 9 6 113.7 31.3 3 56 4 H 8 6 115.4 31.3 3 53 6 H 9 4 136.3 72.3 3 54 DAY 2 24 H 9 2 252.9 (100.4, 405.4) 198.42 204.8 3 69 DAY 3 48 H 9 2 361.0 (172.9, 549.1) 244.71 334.3 3 78 DAY 6 120 H 9 1 457.9 (232.6, 683.2) 293.10 487.6 3 90 DAY 15 336 H 9 0 545.2 (303.9, 786.5) 313.92 599.9 8 99 DAY 29 672 H 9 0 647.6 (354.7, 940.4) 381.02 726.9 8 118 DAY 57 1344 H 9 0 811.2 (470.5, 1151.9) 443.20 944.8 22 160 FOLLOW-UP 2016 H 9 0 964.0 (803.8, 1124.2) 208.42 930.0 73 135

SQ_200mg 9 DAY 1 PREDOSE 9 0 676.0 (516.7, 835.3) 207.26 562.7 49 109 6 H 9 1 544.5 (342.4, 746.5) 262.88 590.9 3 97 DAY 2 24 H 9 1 589.3 (366.0, 812.7) 290.56 645.2 3 102 DAY 3 48 H 8 1 614.9 (338.8, 890.9) 330.19 640.5 3 103 DAY 6 120 H 9 0 672.3 (516.8, 827.8) 202.27 673.8 43 99 DAY 15 336 H 9 0 698.6 (479.7, 917.5) 284.79 681.9 12 107 DAY 29 672 H 9 0 774.8 (529.3, 1020.4) 319.41 775.9 11 126 DAY 57 1344 H 9 0 882.9 (632.8, 1133.0) 325.38 933.3 15 131 FOLLOW-UP 2016 H 9 0 916.6 (815.5, 1017.7) 131.57 927.1 75 114

SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 765.7 (368.1, 1163.4) 517.36 579.9 33 210 6 H 9 0 677.9 (257.5, 1098.4) 546.95 731.3 11 195 DAY 2 24 H 9 0 647.0 (241.6, 1052.4) 527.42 632.9 17 190 DAY 3 48 H 9 0 677.2 (272.0, 1082.4) 527.18 644.4 20 191 DAY 6 120 H 9 0 691.3 (319.7, 1062.9) 483.39 756.8 22 177

[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.

651



Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 743.5 (321.6, 1165.4) 548.88 823.3 21 200 6 H 9 0 664.0 (253.3, 1074.8) 534.34 714.0 15 190 DAY 9 24 H 9 0 627.7 (222.7, 1032.6) 526.85 653.9 16 189 DAY 10 48 H 9 0 631.7 (227.7, 1035.8) 525.66 652.3 16 189 DAY 13 120 H 9 0 633.2 (270.0, 996.5) 472.59 679.0 16 170 DAY 15 PREDOSE 9 0 674.2 (275.6, 1072.9) 518.61 704.2 23 190 6 H 9 0 642.8 (224.7, 1060.9) 543.91 663.9 15 193 DAY 16 24 H 9 0 611.2 (205.7, 1016.7) 527.52 563.0 19 191 DAY 17 48 H 9 0 613.1 (200.5, 1025.7) 536.76 639.6 18 193 DAY 20 120 H 9 0 646.3 (256.6, 1036.0) 506.96 632.5 18 185 DAY 22 PREDOSE 9 0 657.4 (259.3, 1055.5) 517.91 702.2 20 188 6 H 9 0 626.4 (224.6, 1028.3) 522.81 701.1 11 183 DAY 23 24 H 9 0 588.9 (229.0, 948.7) 468.19 637.5 10 167 DAY 24 48 H 9 0 605.3 (214.1, 996.4) 508.86 629.1 17 183 DAY 27 120 H 9 0 622.6 (238.4, 1006.8) 499.82 648.5 19 180 DAY 31 216 H 9 0 667.9 (257.4, 1078.4) 534.08 685.4 19 191 DAY 43 504 H 9 0 721.9 (341.8, 1102.0) 494.49 658.5 25 179 DAY 50 672 H 8 0 816.0 (300.6, 1331.4) 616.54 559.7 26 194 DAY 78 1344 H 8 0 966.6 (685.0, 1248.2) 336.80 1034.0 36 146 FOLLOW-UP 2016 H 9 0 867.9 (748.9, 987.0) 154.85 868.0 58 112

IM_200mg 9 DAY 1 PREDOSE 9 0 545.9 (404.6, 687.2) 183.84 549.0 31 93 6 H 9 3 360.5 (148.7, 572.3) 275.55 402.3 3 80 DAY 2 24 H 9 3 376.4 (146.7, 606.0) 298.77 413.0 3 90 DAY 3 48 H 9 3 421.8 (168.0, 675.6) 330.17 475.4 3 92 DAY 6 120 H 9 3 440.9 (187.9, 693.9) 329.15 571.7 3 92 DAY 15 336 H 9 2 545.8 (285.4, 806.2) 338.79 600.1 3 112 DAY 29 672 H 9 1 738.1 (499.0, 977.2) 311.07 775.8 3 123


652



Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 794.9 (465.0, 1124.9) 394.67 980.8 14 111 FOLLOW-UP 2016 H 8 0 824.8 (741.9, 907.6) 99.14 841.8 62 92


653



Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 2087.8 (-259.3, 4434.9) 3053.49 1028.0 57 1013 1 H 9 0 9555.8 (7394.2, 11717.4) 2812.15 8706.5 704 1505 2 H 9 0 11523.3 (9366.1, 13680.5) 2806.38 10815.1 871 1718 4 H 8 0 16057.6 (12254.3, 19861.0) 4549.35 14861.8 1214 2643 6 H 9 0 20278.6 (17026.6, 23530.6) 4230.71 20458.7 1487 2918 DAY 2 24 H 9 0 39008.4 (35743.2, 42273.7) 4247.93 39138.1 2975 4403 DAY 3 48 H 9 0 44999.6 (41100.0, 48899.2) 5073.19 48071.9 3557 5025 DAY 6 120 H 9 0 43699.4 (39758.3, 47640.4) 5127.11 43941.5 3517 5053 DAY 15 336 H 9 0 29084.2 (23310.1, 34858.4) 7511.92 27927.1 2217 4719 DAY 29 672 H 9 0 15268.2 (11270.9, 19265.5) 5200.35 15389.6 697 2616 DAY 57 1344 H 9 0 4963.2 (2739.8, 7186.6) 2892.49 3974.8 155 1152 FOLLOW-UP 2016 H 9 0 2640.3 (892.5, 4388.0) 2273.78 1874.2 97 857

SQ_200mg 9 DAY 1 PREDOSE 9 0 1331.3 (354.0, 2308.5) 1271.34 1113.5 43 463 6 H 9 0 7860.2 (6490.1, 9230.3) 1782.44 7343.2 483 1040 DAY 2 24 H 9 0 20097.4 (17593.9, 22601.0) 3257.01 19321.8 1474 2557 DAY 3 48 H 8 0 28603.4 (25415.4, 31791.3) 3813.28 29175.1 2302 3410 DAY 6 120 H 9 0 34359.3 (31040.7, 37677.9) 4317.31 34521.5 2839 4207 DAY 15 336 H 9 0 26299.5 (23153.4, 29445.6) 4092.90 24917.9 2209 3305 DAY 29 672 H 9 0 13241.6 (11160.7, 15322.5) 2707.14 13686.7 870 1804 DAY 57 1344 H 9 0 4128.0 (3397.1, 4859.0) 950.94 4002.0 265 578 FOLLOW-UP 2016 H 9 0 2107.2 (1296.5, 2917.8) 1054.65 1965.6 105 469



654



Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 15771.5 (13928.7, 17614.2) 2397.37 15660.9 1254 1964 6 H 9 0 15895.7 (13953.5, 17837.9) 2526.69 16186.5 1213 1938 DAY 9 24 H 9 0 20727.1 (17935.9, 23518.3) 3631.21 19286.4 1644 2687 DAY 10 48 H 9 0 23616.1 (19771.5, 27460.7) 5001.65 23012.9 1707 3408 DAY 13 120 H 9 0 22284.0 (18972.6, 25595.4) 4307.94 21826.4 1631 3036 DAY 15 PREDOSE 9 0 20081.7 (17786.5, 22376.8) 2985.90 19318.7 1568 2667 6 H 9 0 20932.7 (18549.4, 23316.0) 3100.54 20174.0 1759 2809 DAY 16 24 H 9 0 24506.8 (22460.3, 26553.4) 2662.47 23622.7 2054 2896 DAY 17 48 H 9 0 25508.1 (24054.9, 26961.2) 1890.54 25636.5 2232 2872 DAY 20 120 H 9 0 25652.0 (22673.0, 28631.1) 3875.56 25504.7 2070 3478 DAY 22 PREDOSE 9 0 23862.4 (21128.7, 26596.0) 3556.34 23117.9 1816 3105 6 H 9 0 24142.2 (22109.2, 26175.2) 2644.85 24640.1 1975 2841 DAY 23 24 H 9 0 26221.4 (24691.4, 27751.4) 1990.40 25962.3 2347 3002 DAY 24 48 H 9 0 29280.2 (25803.1, 32757.3) 4523.51 28586.5 2403 3833 DAY 27 120 H 9 0 28985.3 (25727.3, 32243.2) 4238.42 27761.3 2399 3829 DAY 31 216 H 9 0 25422.6 (22204.4, 28640.8) 4186.74 23969.5 2040 3537 DAY 43 504 H 9 0 14266.8 (12341.1, 16192.5) 2505.24 14748.8 1113 1938 DAY 50 672 H 8 0 10047.1 (7833.2, 12261.0) 2648.13 8932.4 818 1627 DAY 78 1344 H 8 0 3522.4 (2538.5, 4506.3) 1176.91 3096.0 261 608 FOLLOW-UP 2016 H 9 0 1596.1 (1139.7, 2052.4) 593.70 1390.4 79 266

IM_200mg 9 DAY 1 PREDOSE 9 0 1244.1 (352.4, 2135.8) 1160.07 1040.0 35 411 6 H 9 0 8809.3 (7284.0, 10334.7) 1984.41 8576.7 556 1250 DAY 2 24 H 9 0 27278.8 (25326.6, 29231.0) 2539.73 26578.2 2398 3232 DAY 3 48 H 9 0 33188.4 (30964.5, 35412.3) 2893.16 33275.4 2954 3900 DAY 6 120 H 9 0 36438.5 (33076.1, 39800.8) 4374.30 35470.8 2991 4299 DAY 15 336 H 9 0 26288.5 (21776.4, 30800.6) 5870.06 26445.1 1793 3909 DAY 29 672 H 9 0 13522.1 (10576.8, 16467.4) 3831.66 13462.4 612 1852


655



Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 3969.2 (2360.0, 5578.4) 1924.80 3885.5 128 797 FOLLOW-UP 2016 H 8 0 1961.1 (878.1, 3044.0) 1295.37 1681.7 86 497


656



Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 495.3 (-271.7, 1262.2) 997.82 101.8 5 310 1 H 9 0 796.5 (255.7, 1337.4) 703.58 551.0 36 260 2 H 9 0 923.1 (327.5, 1518.8) 774.92 651.2 46 293 4 H 8 0 1239.4 (463.3, 2015.5) 928.34 1004.7 66 348 6 H 9 0 1367.1 (743.8, 1990.4) 810.89 1169.1 72 345 DAY 2 24 H 9 0 2290.8 (1621.9, 2959.7) 870.21 2180.3 146 444 DAY 3 48 H 9 0 2969.5 (1581.1, 4357.9) 1806.24 2448.0 166 768 DAY 6 120 H 9 0 2868.7 (1355.4, 4382.1) 1968.78 2343.7 165 802 DAY 15 336 H 9 0 2018.7 (1236.6, 2800.8) 1017.47 1846.7 116 457 DAY 29 672 H 9 0 1282.0 (660.3, 1903.7) 808.78 1172.0 55 319 DAY 57 1344 H 9 0 1015.5 (-389.6, 2420.5) 1827.88 373.5 8 580 FOLLOW-UP 2016 H 9 0 449.3 (-62.1, 960.8) 665.40 142.6 5 200

SQ_200mg 9 DAY 1 PREDOSE 9 0 1066.4 (-539.8, 2672.7) 2089.63 76.6 5 618 6 H 9 0 1212.6 (155.8, 2269.3) 1374.75 599.4 38 411 DAY 2 24 H 9 0 2026.3 (853.3, 3199.4) 1526.07 1352.4 111 507 DAY 3 48 H 8 0 2362.9 (1273.8, 3452.0) 1302.72 1703.1 150 497 DAY 6 120 H 9 0 2633.9 (1564.3, 3703.4) 1391.40 1996.6 173 578 DAY 15 336 H 9 0 2595.2 (984.2, 4206.2) 2095.78 1667.7 143 780 DAY 29 672 H 9 0 1565.1 (645.3, 2484.9) 1196.61 1062.6 61 426 DAY 57 1344 H 9 0 1010.3 (-97.7, 2118.2) 1441.40 306.6 19 424 FOLLOW-UP 2016 H 9 0 723.8 (-196.0, 1643.6) 1196.60 113.0 8 347



657



Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 1133.6 (956.8, 1310.5) 230.11 1084.7 83 156 6 H 9 0 1173.0 (974.4, 1371.7) 258.43 1162.2 77 154 DAY 9 24 H 9 0 1474.2 (1208.5, 1739.9) 345.63 1392.1 102 200 DAY 10 48 H 9 0 1570.1 (1273.0, 1867.1) 386.45 1485.9 126 251 DAY 13 120 H 9 0 1522.7 (1279.1, 1766.4) 316.95 1573.9 117 219 DAY 15 PREDOSE 9 0 1431.4 (1214.6, 1648.2) 282.01 1370.5 114 207 6 H 9 0 1453.0 (1223.7, 1682.3) 298.29 1355.9 111 202 DAY 16 24 H 9 0 1634.9 (1395.6, 1874.1) 311.29 1537.4 123 230 DAY 17 48 H 9 0 1767.8 (1500.5, 2035.1) 347.71 1652.5 138 230 DAY 20 120 H 9 0 1677.5 (1374.5, 1980.5) 394.18 1572.5 115 249 DAY 22 PREDOSE 9 0 1615.7 (1355.3, 1876.0) 338.68 1571.5 124 232 6 H 9 0 1657.7 (1412.8, 1902.6) 318.59 1687.7 119 223 DAY 23 24 H 9 0 1847.4 (1521.9, 2173.0) 423.51 1711.3 136 258 DAY 24 48 H 9 0 1905.4 (1537.6, 2273.3) 478.60 1681.9 141 269 DAY 27 120 H 9 0 1739.2 (1474.1, 2004.3) 344.85 1662.3 134 239 DAY 31 216 H 9 0 1710.3 (1322.7, 2097.9) 504.30 1474.8 124 286 DAY 43 504 H 9 0 1105.7 (868.8, 1342.5) 308.16 938.8 77 170 DAY 50 672 H 8 0 740.4 (601.8, 879.0) 165.80 662.2 57 96 DAY 78 1344 H 8 0 232.5 (162.9, 302.1) 83.29 217.6 14 41 FOLLOW-UP 2016 H 9 0 118.9 (80.4, 157.3) 49.99 99.5 4 20

IM_200mg 9 DAY 1 PREDOSE 9 0 698.4 (-263.8, 1660.6) 1251.78 98.8 3 348 6 H 9 0 1232.9 (211.6, 2254.1) 1328.62 654.4 44 411 DAY 2 24 H 9 0 2137.9 (1194.7, 3081.2) 1227.13 1775.0 121 489 DAY 3 48 H 9 0 3129.5 (599.2, 5659.8) 3291.81 1863.0 145 1171 DAY 6 120 H 9 0 3360.2 (702.8, 6017.6) 3457.18 2081.6 167 1237 DAY 15 336 H 9 0 2159.7 (1198.5, 3120.9) 1250.47 1569.5 129 478 DAY 29 672 H 9 0 1461.7 (591.2, 2332.1) 1132.44 1062.8 48 392


658



Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 1488.0 (-554.8, 3530.8) 2443.50 296.2 11 674 FOLLOW-UP 2016 H 8 0 1970.3 (-1430.3, 5370.8) 4067.56 132.1 6 1162


659


Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]

Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 606.4 (482.4, 762.2) 0.297584 30.4 1 H 9 6 59.6 2 H 9 6 59.0 4 H 8 6 56.2 6 H 9 4 79.0 DAY 2 24 H 9 2 174.5 (77.7, 392.2) 1.053401 142.6 DAY 3 48 H 9 2 238.5 (94.8, 600.1) 1.200622 179.6 DAY 6 120 H 9 1 319.8 (136.1, 751.6) 1.111469 156.2 DAY 15 336 H 9 0 435.7 (234.1, 811.0) 0.808287 96.0 DAY 29 672 H 9 0 508.3 (263.1, 981.9) 0.856724 104.1 DAY 57 1344 H 9 0 688.6 (418.4, 1133.2) 0.648146 72.3 FOLLOW-UP 2016 H 9 0 944.8 (803.6, 1110.9) 0.210632 21.3

SQ_200mg 9 DAY 1 PREDOSE 9 0 651.1 (523.5, 809.7) 0.283713 29.0 6 H 9 1 421.3 (192.6, 921.8) 1.018486 135.0 DAY 2 24 H 9 1 450.2 (201.2, 1007.5) 1.047941 141.4 DAY 3 48 H 8 1 451.1 (175.5, 1159.8) 1.129439 160.7 DAY 6 120 H 9 0 647.3 (518.9, 807.6) 0.287816 29.4 DAY 15 336 H 9 0 614.3 (375.7, 1004.2) 0.639423 71.1 DAY 29 672 H 9 0 670.3 (391.8, 1146.6) 0.698431 79.3 DAY 57 1344 H 9 0 783.9 (484.4, 1268.5) 0.626187 69.3 FOLLOW-UP 2016 H 9 0 908.3 (814.2, 1013.4) 0.142421 14.3

SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 672.3 (461.1, 980.2) 0.490556 52.2 6 H 9 0 510.8 (269.4, 968.6) 0.832386 100.0 DAY 2 24 H 9 0 503.2 (283.6, 892.7) 0.745916 86.3 DAY 3 48 H 9 0 538.5 (312.7, 927.2) 0.707044 80.5 DAY 6 120 H 9 0 562.4 (332.1, 952.6) 0.685549 77.5

[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.

660



Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 594.8 (344.2, 1028.0) 0.711787 81.2 6 H 9 0 506.1 (274.6, 932.7) 0.795287 93.9 DAY 9 24 H 9 0 483.0 (270.0, 863.8) 0.756381 87.9 DAY 10 48 H 9 0 485.0 (268.8, 875.0) 0.767773 89.6 DAY 13 120 H 9 0 500.3 (283.5, 882.7) 0.738828 85.2 DAY 15 PREDOSE 9 0 540.5 (317.6, 919.9) 0.69169 78.3 6 H 9 0 486.7 (265.1, 893.6) 0.790377 93.1 DAY 16 24 H 9 0 476.6 (274.9, 826.1) 0.715644 81.8 DAY 17 48 H 9 0 468.8 (262.3, 837.7) 0.755165 87.7 DAY 20 120 H 9 0 510.2 (292.2, 891.1) 0.725321 83.2 DAY 22 PREDOSE 9 0 518.4 (297.7, 902.8) 0.721649 82.7 6 H 9 0 459.4 (235.3, 896.8) 0.870358 106.4 DAY 23 24 H 9 0 447.1 (238.4, 838.6) 0.81818 97.6 DAY 24 48 H 9 0 466.3 (261.3, 832.3) 0.753662 87.4 DAY 27 120 H 9 0 485.4 (274.3, 859.0) 0.742572 85.8 DAY 31 216 H 9 0 521.2 (295.3, 920.1) 0.73932 85.3 DAY 43 504 H 9 0 595.4 (360.4, 983.5) 0.652977 72.9 DAY 50 672 H 8 0 639.7 (344.3, 1188.6) 0.740918 85.5 DAY 78 1344 H 8 0 900.9 (626.4, 1295.7) 0.434723 45.6 FOLLOW-UP 2016 H 9 0 855.0 (740.4, 987.3) 0.187196 18.9

IM_200mg 9 DAY 1 PREDOSE 9 0 520.4 (404.9, 668.7) 0.326325 33.5 6 H 9 3 200.5 (67.8, 593.4) 1.411281 251.6 DAY 2 24 H 9 3 205.4 (68.3, 617.6) 1.432466 260.4 DAY 3 48 H 9 3 222.6 (70.7, 700.2) 1.491166 287.1 DAY 6 120 H 9 3 232.2 (72.5, 743.4) 1.513647 298.1 DAY 15 336 H 9 2 340.4 (118.7, 975.9) 1.370194 235.3 DAY 29 672 H 9 1 566.0 (243.0, 1318.6) 1.100123 153.4


661



Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 649.8 (334.8, 1261.3) 0.793289 93.6 FOLLOW-UP 2016 H 8 0 819.0 (735.1, 912.6) 0.129376 13.0


662



Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 1290.9 (662.8, 2514.1) 0.867233 105.9 1 H 9 0 9235.1 (7509.7, 11356.9) 0.269055 27.4 2 H 9 0 11249.5 (9444.2, 13400.0) 0.227576 23.1 4 H 8 0 15603.1 (12723.2, 19135.0) 0.244069 24.8 6 H 9 0 19915.8 (17095.6, 23201.2) 0.198646 20.1 DAY 2 24 H 9 0 38785.3 (35472.3, 42407.8) 0.116162 11.7 DAY 3 48 H 9 0 44729.8 (40844.7, 48984.4) 0.118207 11.9 DAY 6 120 H 9 0 43425.8 (39608.3, 47611.4) 0.119709 12.0 DAY 15 336 H 9 0 28372.7 (23839.9, 33767.4) 0.226452 22.9 DAY 29 672 H 9 0 14472.6 (11004.4, 19034.0) 0.35642 36.8 DAY 57 1344 H 9 0 4343.0 (2850.6, 6616.8) 0.547759 59.2 FOLLOW-UP 2016 H 9 0 2173.9 (1384.7, 3412.9) 0.586765 64.1




663



Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 15608.7 (13874.1, 17560.1) 0.153254 15.4 6 H 9 0 15714.9 (13882.9, 17788.6) 0.161251 16.2 DAY 9 24 H 9 0 20466.5 (18019.1, 23246.3) 0.165685 16.7 DAY 10 48 H 9 0 23184.0 (19872.0, 27048.1) 0.200545 20.3 DAY 13 120 H 9 0 21922.7 (18923.3, 25397.4) 0.191403 19.3 DAY 15 PREDOSE 9 0 19896.5 (17830.1, 22202.3) 0.142656 14.3 6 H 9 0 20749.7 (18674.7, 23055.4) 0.137074 13.8 DAY 16 24 H 9 0 24379.1 (22430.6, 26496.8) 0.108366 10.9 DAY 17 48 H 9 0 25445.5 (24029.9, 26944.5) 0.074466 7.5 DAY 20 120 H 9 0 25417.4 (22814.3, 28317.6) 0.140567 14.1 DAY 22 PREDOSE 9 0 23633.4 (21111.4, 26456.7) 0.146811 14.8 6 H 9 0 24011.3 (22044.6, 26153.5) 0.111177 11.2 DAY 23 24 H 9 0 26155.4 (24689.6, 27708.3) 0.075032 7.5 DAY 24 48 H 9 0 28986.4 (25850.9, 32502.3) 0.148937 15.0 DAY 27 120 H 9 0 28731.3 (25835.3, 31951.9) 0.13822 13.9 DAY 31 216 H 9 0 25151.4 (22392.3, 28250.5) 0.151167 15.2 DAY 43 504 H 9 0 14079.4 (12342.3, 16061.0) 0.171307 17.3 DAY 50 672 H 8 0 9806.3 (8140.8, 11812.6) 0.222648 22.5 DAY 78 1344 H 8 0 3383.8 (2658.3, 4307.4) 0.28866 29.5 FOLLOW-UP 2016 H 9 0 1503.7 (1134.7, 1992.7) 0.36632 37.9



664



Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 3560.7 (2302.8, 5505.7) 0.521316 55.9 FOLLOW-UP 2016 H 8 0 1701.4 (1084.9, 2668.3) 0.538258 58.0


665



Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 171.4 (63.5, 462.5) 1.291285 207.3 1 H 9 0 645.4 (403.7, 1031.8) 0.610447 67.2 2 H 9 0 767.2 (496.0, 1186.5) 0.56727 61.6 4 H 8 0 1061.9 (681.6, 1654.5) 0.530348 57.0 6 H 9 0 1232.8 (880.1, 1726.8) 0.438421 46.0 DAY 2 24 H 9 0 2179.8 (1710.0, 2778.7) 0.315814 32.4 DAY 3 48 H 9 0 2679.6 (1927.6, 3725.1) 0.428546 44.9 DAY 6 120 H 9 0 2531.1 (1767.6, 3624.4) 0.467069 49.4 DAY 15 336 H 9 0 1859.8 (1367.1, 2530.0) 0.400395 41.7 DAY 29 672 H 9 0 1113.9 (736.2, 1685.4) 0.538744 58.0 DAY 57 1344 H 9 0 445.6 (178.2, 1114.5) 1.192692 177.4 FOLLOW-UP 2016 H 9 0 216.2 (88.1, 530.9) 1.168409 170.8




666



Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 1113.2 (952.9, 1300.5) 0.202284 20.4 6 H 9 0 1147.0 (963.6, 1365.5) 0.226773 23.0 DAY 9 24 H 9 0 1438.9 (1202.5, 1721.7) 0.233452 23.7 DAY 10 48 H 9 0 1535.8 (1304.2, 1808.5) 0.212683 21.5 DAY 13 120 H 9 0 1495.5 (1283.6, 1742.4) 0.198816 20.1 DAY 15 PREDOSE 9 0 1409.7 (1227.2, 1619.3) 0.18036 18.2 6 H 9 0 1427.3 (1225.7, 1662.2) 0.198131 20.0 DAY 16 24 H 9 0 1610.8 (1403.3, 1848.9) 0.179391 18.1 DAY 17 48 H 9 0 1738.8 (1501.0, 2014.3) 0.191338 19.3 DAY 20 120 H 9 0 1639.2 (1378.2, 1949.5) 0.225587 22.8 DAY 22 PREDOSE 9 0 1586.7 (1362.2, 1848.2) 0.198471 20.0 6 H 9 0 1630.6 (1405.5, 1891.7) 0.19322 19.5 DAY 23 24 H 9 0 1806.4 (1521.9, 2144.1) 0.222944 22.6 DAY 24 48 H 9 0 1855.9 (1543.5, 2231.5) 0.239747 24.3 DAY 27 120 H 9 0 1710.9 (1478.9, 1979.2) 0.189569 19.1 DAY 31 216 H 9 0 1655.7 (1356.4, 2020.9) 0.259337 26.4 DAY 43 504 H 9 0 1071.2 (876.0, 1309.8) 0.261661 26.6 DAY 50 672 H 8 0 724.9 (604.4, 869.4) 0.217411 22.0 DAY 78 1344 H 8 0 221.5 (169.0, 290.2) 0.323359 33.2 FOLLOW-UP 2016 H 9 0 109.1 (76.8, 155.0) 0.456906 48.2



667



Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 497.2 (145.2, 1702.2) 1.472044 278.1 FOLLOW-UP 2016 H 8 0 316.2 (64.8, 1542.4) 1.895685 594.7


668


Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data

Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 6 0.15 0.063 0.03 0.5 2 H 9 6 0.15 0.063 0.03 0.56 4 H 8 6 0.151 0.062 0.03 0.53 6 H 9 4 0.186 0.09 0.06 0.54 DAY 2 24 H 9 2 0.367 (0.208, 0.526) 0.2072 0.341 0.06 0.68 DAY 3 48 H 9 2 0.533 (0.306, 0.76) 0.2953 0.579 0.06 0.87 DAY 6 120 H 9 1 0.681 (0.409, 0.954) 0.3544 0.825 0.07 0.98 DAY 15 336 H 9 0 0.826 (0.536, 1.115) 0.3765 0.967 0.2 1.31 DAY 29 672 H 9 0 0.974 (0.634, 1.315) 0.4429 1.166 0.19 1.46 DAY 57 1344 H 9 0 1.249 (0.843, 1.654) 0.5273 1.23 0.53 1.93 FOLLOW-UP 2016 H 9 0 1.59 (1.326, 1.854) 0.3434 1.476 1.13 2.21

SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 1 0.794 (0.544, 1.045) 0.3258 0.848 0.06 1.13 DAY 2 24 H 9 1 0.851 (0.591, 1.111) 0.3386 0.876 0.06 1.22 DAY 3 48 H 8 1 0.909 (0.567, 1.25) 0.4086 0.892 0.06 1.4 DAY 6 120 H 9 0 1.02 (0.834, 1.206) 0.242 0.913 0.65 1.37 DAY 15 336 H 9 0 1.041 (0.75, 1.333) 0.3795 1.096 0.25 1.48 DAY 29 672 H 9 0 1.165 (0.807, 1.523) 0.4653 1.275 0.23 1.74 DAY 57 1344 H 9 0 1.357 (0.924, 1.79) 0.5636 1.534 0.31 2 FOLLOW-UP 2016 H 9 0 1.433 (1.182, 1.684) 0.3265 1.503 0.9 1.83

SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 0.86 (0.575, 1.145) 0.3708 1.006 0.23 1.39 DAY 2 24 H 9 0 0.816 (0.581, 1.051) 0.3058 0.907 0.3 1.13 DAY 3 48 H 9 0 0.865 (0.616, 1.114) 0.3242 0.911 0.36 1.29

[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value

669



Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 0.899 (0.643, 1.155) 0.3331 0.894 0.39 1.42 DAY 8 PREDOSE 9 0 0.954 (0.686, 1.222) 0.3488 0.954 0.37 1.47 6 H 9 0 0.834 (0.573, 1.094) 0.3387 0.905 0.27 1.27 DAY 9 24 H 9 0 0.782 (0.553, 1.01) 0.2971 0.9 0.28 1.19 DAY 10 48 H 9 0 0.79 (0.553, 1.027) 0.3081 0.888 0.28 1.23 DAY 13 120 H 9 0 0.815 (0.566, 1.063) 0.3239 0.904 0.31 1.27 DAY 15 PREDOSE 9 0 0.86 (0.626, 1.094) 0.3045 0.953 0.4 1.31 6 H 9 0 0.798 (0.554, 1.041) 0.3169 0.92 0.26 1.18 DAY 16 24 H 9 0 0.76 (0.55, 0.97) 0.273 0.87 0.37 1.18 DAY 17 48 H 9 0 0.759 (0.537, 0.981) 0.2891 0.893 0.33 1.14 DAY 20 120 H 9 0 0.824 (0.583, 1.066) 0.3141 0.888 0.36 1.32 DAY 22 PREDOSE 9 0 0.835 (0.586, 1.083) 0.3231 0.902 0.38 1.37 6 H 9 0 0.783 (0.508, 1.058) 0.3576 0.872 0.21 1.29 DAY 23 24 H 9 0 0.746 (0.508, 0.984) 0.3099 0.861 0.2 1.14 DAY 24 48 H 9 0 0.758 (0.531, 0.985) 0.295 0.883 0.33 1.13 DAY 27 120 H 9 0 0.799 (0.54, 1.057) 0.3365 0.883 0.34 1.21 DAY 31 216 H 9 0 0.854 (0.567, 1.141) 0.3734 0.934 0.34 1.55 DAY 43 504 H 9 0 0.963 (0.641, 1.285) 0.4189 0.896 0.45 1.8 DAY 50 672 H 8 0 1.027 (0.614, 1.44) 0.4941 0.956 0.46 1.99 DAY 78 1344 H 8 0 1.461 (0.968, 1.954) 0.59 1.625 0.48 2.01 FOLLOW-UP 2016 H 9 0 1.236 (0.852, 1.621) 0.5003 1.456 0.37 1.71

IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 3 0.578 (0.289, 0.867) 0.3757 0.784 0.08 0.89 DAY 2 24 H 9 3 0.601 (0.292, 0.911) 0.4024 0.751 0.08 1.05 DAY 3 48 H 9 3 0.68 (0.31, 1.05) 0.4816 0.87 0.08 1.42 DAY 6 120 H 9 3 0.711 (0.348, 1.074) 0.4722 0.994 0.08 1.12


670



Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 2 0.92 (0.549, 1.291) 0.4828 1.138 0.08 1.36 DAY 29 672 H 9 1 1.337 (0.916, 1.757) 0.5471 1.375 0.1 2.04 DAY 57 1344 H 8 0 1.448 (0.91, 1.986) 0.643 1.599 0.39 2.32 FOLLOW-UP 2016 H 8 0 1.666 (1.298, 2.034) 0.4406 1.745 0.99 2.18


671



Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 0 8.287 (5.605, 10.968) 3.4889 8.663 1.3 12.33 2 H 9 0 10.267 (6.776, 13.758) 4.5417 10.852 1.41 16.06 4 H 8 0 14.548 (8.837, 20.258) 6.8305 15.029 1.77 23.03 6 H 9 0 18.809 (11.869, 25.749) 9.028 19.728 2.07 30.23 DAY 2 24 H 9 0 37.726 (22.247, 53.204) 20.136 37.515 3.87 68.48 DAY 3 48 H 9 0 43.674 (24.61, 62.738) 24.801 40.205 4.76 84.12 DAY 6 120 H 9 0 41.889 (24.861, 58.917) 22.152 41.503 4.4 76.89 DAY 15 336 H 9 0 26.88 (16.512, 37.248) 13.488 26.38 2.81 52.37 DAY 29 672 H 9 0 13.63 (8.278, 18.982) 6.9626 13.607 1.57 26.93 DAY 57 1344 H 9 0 3.814 (2.197, 5.43) 2.103 3.458 1.14 8.74 FOLLOW-UP 2016 H 9 0 1.852 (1.115, 2.589) 0.9587 1.565 0.85 4.16

SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 8.233 (5.538, 10.929) 3.5066 7.728 2.12 12.78 DAY 2 24 H 9 0 21.437 (14.694, 28.179) 8.7719 21.553 4.55 33.9 DAY 3 48 H 8 0 31.797 (20.262, 43.331) 13.796 31.361 6.15 52.93 DAY 6 120 H 9 0 37.22 (24.526, 49.913) 16.513 36.084 7.45 66.11 DAY 15 336 H 9 0 28.93 (18.749, 39.111) 13.245 28.343 4.77 53.36 DAY 29 672 H 9 0 14.575 (8.728, 20.423) 7.6071 14.644 2.48 31.46 DAY 57 1344 H 9 0 4.245 (2.877, 5.613) 1.78 4.125 1.25 7.79 FOLLOW-UP 2016 H 9 0 1.996 (1.287, 2.704) 0.9219 1.817 1.01 4.25



672



Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 19.279 (15.034, 23.523) 5.5223 19.373 11.35 26.95 DAY 8 PREDOSE 9 0 18.486 (14.225, 22.747) 5.5431 18.313 11.13 28.23 6 H 9 0 18.622 (14.093, 23.151) 5.8923 18.072 11.52 31.13 DAY 9 24 H 9 0 24.643 (17.677, 31.61) 9.0634 24.226 12.69 43.3 DAY 10 48 H 9 0 28.317 (19.698, 36.935) 11.212 27.592 14.13 47.13 DAY 13 120 H 9 0 26.648 (18.921, 34.375) 10.052 28.3 13.84 41.05 DAY 15 PREDOSE 9 0 24.384 (16.719, 32.048) 9.9713 22.637 12.22 41.05 6 H 9 0 25.13 (17.89, 32.37) 9.4188 25.217 13.27 42.13 DAY 16 24 H 9 0 29.972 (20.214, 39.73) 12.695 26.997 15.07 51.79 DAY 17 48 H 9 0 31.305 (20.874, 41.735) 13.569 26.778 16.21 57.76 DAY 20 120 H 9 0 31.195 (20.99, 41.4) 13.276 30.185 16.34 58.47 DAY 22 PREDOSE 9 0 28.803 (19.982, 37.624) 11.475 28.946 15.21 50.4 6 H 9 0 29.819 (19.515, 40.123) 13.405 26.489 14.36 55.46 DAY 23 24 H 9 0 32.297 (21.263, 43.331) 14.354 26.995 16.75 61.14 DAY 24 48 H 9 0 35.276 (24.513, 46.039) 14.002 35.734 18.87 61.94 DAY 27 120 H 9 0 34.922 (24.126, 45.717) 14.044 29.205 18.1 62.48 DAY 31 216 H 9 0 30.808 (21.292, 40.324) 12.379 31.585 15.75 52.08 DAY 43 504 H 9 0 16.966 (12.366, 21.566) 5.9844 18.072 9.72 25.5 DAY 50 672 H 8 0 12.212 (8.012, 16.413) 5.0246 13.132 5.53 18.42 DAY 78 1344 H 8 0 4.268 (2.772, 5.764) 1.7892 4.94 1.71 6.03 FOLLOW-UP 2016 H 9 0 1.732 (1.225, 2.238) 0.6591 1.793 0.79 2.81

IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 11.434 (4.869, 18) 8.5418 8.631 3.04 29.81 DAY 2 24 H 9 0 35.951 (18.222, 53.681) 23.065 31.078 7.11 78.44 DAY 3 48 H 9 0 42.899 (22.277, 63.52) 26.827 32.165 9.48 94.34 DAY 6 120 H 9 0 46.285 (25.26, 67.309) 27.351 33.698 10.42 91.65


673



Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 0 31.136 (19.094, 43.177) 15.665 25.3 9.5 56.05 DAY 29 672 H 9 0 15.39 (10.013, 20.767) 6.9953 14.79 4.5 27.99 DAY 57 1344 H 8 0 4.211 (2.566, 5.857) 1.9685 3.653 1.94 8.36 FOLLOW-UP 2016 H 8 0 2.066 (1.223, 2.91) 1.0088 2.006 0.83 3.76


674



Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 0 4.495 (2.855, 6.134) 2.1328 5.265 0.84 6.8 2 H 9 0 5.447 (3.382, 7.512) 2.6864 6.024 0.94 8.63 4 H 8 0 7.428 (3.929, 10.926) 4.1851 8.074 1.12 12.07 6 H 9 0 9.34 (5.437, 13.243) 5.0781 11.1 1.11 16.37 DAY 2 24 H 9 0 17.606 (10.013, 25.199) 9.8784 20.129 1.43 30.19 DAY 3 48 H 9 0 20.821 (11.8, 29.842) 11.736 23.836 2.48 37.33 DAY 6 120 H 9 0 19.362 (11.488, 27.236) 10.243 23.238 2.58 30.12 DAY 15 336 H 9 0 14.218 (8.548, 19.887) 7.3761 15.332 1.47 21.72 DAY 29 672 H 9 0 8.18 (4.863, 11.496) 4.3145 9.531 1.03 13.19 DAY 57 1344 H 9 0 2.862 (1.942, 3.781) 1.1959 2.98 0.96 4.57 FOLLOW-UP 2016 H 9 0 1.396 (0.893, 1.898) 0.6535 1.362 0.65 2.61

SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 5.025 (2.461, 7.589) 3.3354 6.509 0.66 9.73 DAY 2 24 H 9 0 12.016 (5.594, 18.437) 8.3544 17.477 0.82 21.2 DAY 3 48 H 8 0 17.23 (6.864, 27.596) 12.399 24.04 0.8 28.79 DAY 6 120 H 9 0 18.776 (8.279, 29.274) 13.657 25.584 0.94 33.52 DAY 15 336 H 9 0 15.796 (7.171, 24.42) 11.220 20.742 1.26 28 DAY 29 672 H 9 0 9.223 (4.18, 14.266) 6.5608 9.44 0.69 17.34 DAY 57 1344 H 9 0 2.719 (1.609, 3.828) 1.4433 2.811 0.69 5.2 FOLLOW-UP 2016 H 9 0 1.239 (0.901, 1.577) 0.4396 1.258 0.56 1.92



675



Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 12.719 (9.148, 16.289) 4.6456 12.931 4.07 19.48 DAY 8 PREDOSE 9 0 12.063 (8.786, 15.34) 4.2635 12.585 3.86 18.08 6 H 9 0 12.279 (9.172, 15.386) 4.0418 13.538 4.53 17.87 DAY 9 24 H 9 0 15.555 (11.176, 19.935) 5.6971 15.71 6.03 23.26 DAY 10 48 H 9 0 17.016 (11.399, 22.634) 7.3082 17.308 5.39 29.13 DAY 13 120 H 9 0 16.453 (11.4, 21.505) 6.5729 17.738 5.28 25.42 DAY 15 PREDOSE 9 0 15.508 (10.694, 20.321) 6.2621 15.466 5.01 24.01 6 H 9 0 15.509 (11.051, 19.967) 5.7996 15.58 5.42 23.4 DAY 16 24 H 9 0 17.8 (12.047, 23.552) 7.4834 17.333 5.82 28.81 DAY 17 48 H 9 0 18.725 (13.556, 23.894) 6.7247 18.311 7.21 27.5 DAY 20 120 H 9 0 17.813 (12.653, 22.974) 6.7134 18.068 6.17 28.84 DAY 22 PREDOSE 9 0 17.33 (12.22, 22.439) 6.6474 18.057 5.75 26.94 6 H 9 0 17.99 (12.361, 23.62) 7.324 19.392 6.03 26.54 DAY 23 24 H 9 0 19.608 (13.878, 25.338) 7.4545 18.997 7.43 29.96 DAY 24 48 H 9 0 19.999 (14.305, 25.693) 7.4078 19.117 8.11 31.18 DAY 27 120 H 9 0 18.659 (13.091, 24.226) 7.2431 19.1 6.67 28.27 DAY 31 216 H 9 0 18.305 (12.054, 24.556) 8.1325 17.178 6.57 33.15 DAY 43 504 H 9 0 11.664 (7.969, 15.359) 4.8067 10.936 4.51 19.77 DAY 50 672 H 8 0 8.251 (5.617, 10.885) 3.1505 8.489 3 12.63 DAY 78 1344 H 8 0 2.676 (1.566, 3.785) 1.3271 2.393 0.61 4.79 FOLLOW-UP 2016 H 9 0 1.182 (0.683, 1.682) 0.6497 1.123 0.3 2.16

IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 6.45 (3.015, 9.885) 4.469 6.251 1.18 13.59 DAY 2 24 H 9 0 16.758 (7.158, 26.358) 12.488 15.408 1.4 36.86 DAY 3 48 H 9 0 19.487 (9.017, 29.958) 13.621 19.45 1.72 40.29 DAY 6 120 H 9 0 21.657 (9.543, 33.772) 15.760 21.237 1.81 46.22


676



Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 0 16.373 (7.599, 25.147) 11.414 17.401 1.37 35.82 DAY 29 672 H 9 0 9.356 (4.614, 14.098) 6.1691 10.147 1.13 21.33 DAY 57 1344 H 8 0 2.944 (1.933, 3.956) 1.2101 2.963 1.06 5.29 FOLLOW-UP 2016 H 8 0 1.869 (1.156, 2.582) 0.8529 1.503 0.93 3.33


677


Protocol: BA1116891 Page 1 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data

ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 1 Screening n 9 9 9 9 Positive 0 1 (11%) 2 (22%) 0 Negative 9 (100%) 8 (89%) 7 (78%) 9 (100%) Not reportable 0 0 0 0 Not applicable 0 0 0 0

Confirming n 9 9 9 9 Positive 0 1 (11%) 1 (11%) 0 Negative 0 0 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 7 (78%) 9 (100%)

Titer n 9 9 9 9 Positive 0 1 (11%) 1 (11%) 0 Negative 0 0 0 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)

DAY 22 Screening n 9 Positive 2 (22%) Negative 7 (78%) Not reportable 0 Not applicable 0

Confirming n 9 Positive 1 (11%) Negative 1 (11%) Not reportable 0 Not applicable 7 (78%)

678



ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 22 Titer n 9 Positive 1 (11%) Negative 0 Not reportable 0 Not applicable 8 (89%)



Titer n 9 Positive 1 (11%) Negative 0 Not reportable 0 Not applicable 8 (89%)

DAY 29 Screening n 9 9 9 Positive 0 0 0 Negative 9 (100%) 9 (100%) 9 (100%) Not reportable 0 0 0 Not applicable 0 0 0

679



ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 29 Confirming n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)

Titer n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)



Titer n 8 Positive 1 (13%) Negative 0 Not reportable 0 Not applicable 7 (88%)

680



ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 57 Screening n 9 9 8 Positive 0 0 0 Negative 9 (100%) 9 (100%) 8 (100%) Not reportable 0 0 0 Not applicable 0 0 0

Confirming n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)




681



ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 78 Titer n 8 Positive 1 (13%) Negative 0 Not reportable 0 Not applicable 7 (88%)

FOLLOW-UP Screening n 9 9 8 8 Positive 0 0 2 (25%) 0 Negative 9 (100%) 9 (100%) 6 (75%) 8 (100%) Not reportable 0 0 0 0 Not applicable 0 0 0 0

Confirming n 9 9 8 8 Positive 0 0 1 (13%) 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 6 (75%) 8 (100%)

Titer n 9 9 8 8 Positive 0 0 1 (13%) 0 Negative 0 0 0 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)

682



ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 1 Screening n 9 9 9 9 Positive 0 0 0 0 Negative 0 0 0 0 Not reportable 0 1 (11%) 1 (11%) 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)

Confirming n 9 9 9 9 Positive 0 0 0 0 Negative 0 1 (11%) 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)

Titer n 9 9 9 9 Positive 0 0 0 0 Negative 0 1 (11%) 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)

DAY 22 Screening n 9 Positive 0 Negative 0 Not reportable 1 (11%) Not applicable 8 (89%)

Confirming n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)

683



ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 22 Titer n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)



Titer n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)

DAY 29 Screening n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)

684



ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 29 Confirming n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)




Titer n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)

685



ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 57 Screening n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)

Confirming n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)




686



ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 78 Titer n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)

FOLLOW-UP Screening n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 0 0 Not reportable 0 0 1 (13%) 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)

Confirming n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)

Titer n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)

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Page 1 of 4Page 1 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic

Figure 13.1Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time

by Treatment

688




by Treatment

689




by Treatment

690




by Treatment

691



Figure 13.2Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus

Nominal Time by Treatment

692





693





694





695




by Treatment (Truncated)

696





697





698





699




Nominal Time by Treatment (Truncated)

700





701





702





703



1

Synopsis

Study Number: BA1116891


Investigator(s):

Leese Philip, MD

Study Center(s):

Quintiles, 6700 W. 115th Street, Overland Park, Kansas, 66211, United States

Publication(s):

None at the time of this report

Study Period: 22-Jan-2014 - 15-Jul-2014

Phase of development: I

Objectives and Endpoints (criteria for evaluation):


Primary


The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion

Secondary




2





Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22


Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status)

Methodology:

This study was conducted to evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administration. An intravenous (IV) infusion arm was included in this study to allow estimation of relative bioavailability following SQ and IM administration. This study was conducted in healthy adult volunteers. Subjects were assigned 1 of 4 possible treatment arms in a 1:1:1:1 ratio and received either a single administration of GSK933776 200 milligram (mg) by IV infusion (reference arm), 200 mg SQ, 200 mg IM or GSK933776 50 mg SQ once every week for 4 weeks (total dose of 200 mg). Subjects were followed for approximately 84 days after drug administration.

Diagnosis and Main Criteria for Inclusion:

Healthy male/ female subjects aged 18 – 50 years of age, body weight ≥ 55 kg [121 lbs (pounds)] and ≤ 85 kg (187 lbs) with a body mass index (BMI) between 18.5 and 29 (inclusively) were included in the study.

Number of Subjects:

36 subjects were enrolled in this study


3

Treatment Administration:

PRODUCT NAME:








50 mg/ milliliter (mL) (1 mL nominal volume) in a 3 mL glass vial







The dose was administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site was either the abdomen or the upper thigh. Injection site was documented and rotated

The dose was administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed)

The dose was administered through an IV catheter over approximately 1 hour


GSK933776 was drawn into a sterile disposable syringe.Study drug was then administered through a sterile needle (27GA).

GSK933776 was drawn into a sterile disposable syringe. Study drug was then administered through a sterile needle (23GA).

GSK933776 was prepared in 0.9% Sodium Chloride in infusion bags. Study drug was then administered using an IV delivery pump and a catheter.

Batch Numbers PK Lot ID: 132379262

Lot No: 091217577

PK Lot ID: 132379262

Lot No: 091217577

PK Lot ID: 132379262

Lot No: 091217577

Statistical Methods:

The sample size for this study was based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776.

This study was designed to estimate the bioavailability of GSK933776 administered by SQ or IM injection relative to GSK933776 administered intravenously. No formal hypothesis was tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals were constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (SQ GSK933776)/( IV GSK933776) and (IM GSK933776)/( IV GSK933776).

Plasma concentration-time data was analyzed by non-compartmental methods with WinNonlin. Pharmacokinetic data was presented in graphical and/or tabular form and


4

was summarized descriptively. Following loge-transformation, AUC (0-inf), AUC (0-t) and Cmax of GSK933776 were separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for regimen.

All subjects enrolled in the study who received at least one dose of study drug were included in the Safety Population. PK Concentration Population consisted of all subjects in the Safety Population who underwent plasma PK sampling and had evaluable PK assay results. The PK Parameter Population consisted of all subjects with valid and evaluable PK parameters. The Pharmacodynamic (PD) Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). The PK/PD Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776.

SUMMARY

Number of Subjects: Treatment A (200mg

IV)

Treatment B (200mg

SQ)


Treatment D (200mg

IM)Number of subjects planned, [N] 6 6 6 6Number of subjects randomized2, [N] 9 9 9 9Number of subjects included in All subjects (safety) population, [n (%)]

9 (100%) 9 (100%) 9 (100%) 9 (100%)

Number of subjects included in PK population, [n (%)]

9 (100%) 9 (100%) 9 (100%) 9 (100%)

Number of subjects completed as planned, [n (%)]

9 (100%) 9 (100%) 8 (89%) 8 (89%)

Number of subjects withdrawn (any reason), [n (%)]

0 0 1 (11%) 1 (11%)

Number of subjects withdrawn for SAE, [n (%)]

0 0 0 0

Number of subjects withdrawn for AE, [n (%)]

0 0 0 0

Reasons for subject withdrawal, [n (%)]Lost to follow-up 0 0 1 (11%) 0Adverse events 0 0 0 0Protocol violation 0 0 0 0Other1 0 0 0 1 (11%)

1. 2. Study overenrolled each arm by 3 to ensure 24 subjects

completed each arm per protocol


5

Demographics Summary:

Demographics: Treatment A (200mg

IV)

Treatment B (200mg

SQ)


Treatment D (200mg

IM)Age in Years [Mean (SD)] 34.7 (8.9) 27.8 (7.7) 26.3 (6.2) 24.8 (6.1)

Sex [n (%)]Female 0 0 1 (11%) 0Male 9 (100%) 9 (100%) 8 (89%) 9 (100%)BMI (kg/m2) [Mean (SD)] 25.2 (2.2) 23.2 (2.1) 23.7 (1.9) 23.1 (2.3)

Height (cm) [Mean (SD)] 176.7 (6.0)) 179.4 (4.7) 171.2 (7.7) 174.2 (4.2)Weight (kg) [Mean (SD)] 78.4 (4.61) 74.4 (5.8) 69.5 (7.1) 70.0 (6.9)

Ethnicity [n (%)]Hispanic or Latino 1 (11%) 0 0 1 (11%)Not Hispanic or Latino 8 (89%) 9 (100%) 9 (100%) 8 (89%)

Race [n (%)]African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%)American Indian or Alaskan Native 0 0 0 1 (11%)Asian – Japanese Heritage 1 (11%) 0 0 0White – Arabic/North African Heritage 1 (11%) 0 0 0White – White/Caucasian/European Heritage

5 (56%) 5 (56%) 3 (33%) 2 (22%)

Adverse Events:

Summary of Adverse EventsTreatment A (200mg IV)

Treatment B (200mg SQ)

Treatment C (50mg SQ x 4)

Treatment D (200mg IM)

Total Number of AEs 5 10* 6 2Number of Subjects Exposed 9 9 9 9

Number of Subjects with AEs 4 6 3 2

*including one (1) Serious Adverse Event

The overall frequency of AEs reported in this study was similar between treatment groups. All AEs were mild or moderate in intensity. There was one serious adverse event (SAE) reported during the study. There were no deaths reported.

There were no clinically significant changes in laboratory parameters, vital signs (heart rate and blood pressure) or 12-lead safety ECG parameters during the study.

Pharmacokinetic Results:

There is a typical plasma PK profile across all arms with a small to moderate between-subject variability (%CVb<30%)


6

The exposure of GSK933776 as measured by AUC(0-inf) following 50 mg repeat-dose SQ administration as compared with 200 mg IV administration were similar. In general, the exposure for the first 672 hours and 168 hours (dose normalized) following the 50 mg repeat-dose SQ administration as compared with 200 mg IV administration showed approximately 40% lower exposure. The Cmax following the 50 mg repeated-dose SQ was approximately 70% lower when compared with the 200 mg IV administered dose.

The exposure of GSK933776 as measured by AUC(0-inf) following 200 mg single-dose IM and SQ administration as compared to 200 mg IV administration showed approximately 15% lower exposure. The Cmax was 55% to 65% lower for the IM and SQ dosing, respectively.

Immunogenicity Results:

No antibodies are generated against GSK933776 in serum samples.

Relationship between PK and PD Results:

There is a decrease of Abeta1-22, increase of Abeta18-35 and Abeta42 after GSK933776 administration.

Conclusions:

Compared to intravenous administration, the relative bioavailability of subcutaneous and intramuscular administrations of GSK933776 were 83% and 87% for AUC(0-inf) and 36% and 46% for Cmax, respectively.

Compared to intravenous administration, the relative bioavailability results indicate that 200 mg subcutaneous and intra-muscular administrations of GSK933776 produce comparable exposure profiles, with the relative bioavailability at approximately 82% and 85%, respectively, compared to IV administration.

Subcutaneous administration of GSK933776 50 mg weekly were 68% for dose normalized exposure over 7 days (i.e., AUC(0-168)/D) and 60% for exposure over 28 days (i.e., AUC(0-672), respectively. Cmax following 50 mg weekly dosing was substantially lower at 28% of that following 200 mg intravenous administration.

The median t½ was comparable across routes of administration.

Intravenous, subcutaneous and intra-muscular GSK933776 were well tolerated in this study. No significant safety findings could be attributed to investigational product. Vital signs, laboratory and electrocardiographic parameters fell within expected ranges

Plasma Abeta1-22 decreased, Abeta18-35 and Abeta42 increased followingGSK933776 dosing by all routes of administration.


7

No antibodies were detected post dose against GSK933776 in serum samples collected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776.

Effective Date: 11-MAY-2015

2012N142727_00 CONFIDENTIALGlaxoSmithKline group of companies BA1116891

1

TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Clinical Protocol



Phase I

Effective Date: 05-NOV-2013

Subject: Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody

Author(s):

(CPSSO); (Clinical Statistics); (CPMS); (PTS); (Clinical Immunology); (MPD); (Ophthalmology).

Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

2014N211143_00

2012N142727_00 CONFIDENTIALBA1116891

2

SYNOPSIS:

GSK933776 is a humanized IgG1 monoclonal antibody directed against amyloid-β (Aβ) being developed for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). GSK933776 has previously been studied in patients with Alzheimer’s disease (AD). To date, all studies with GSK933776 have utilized intravenous (IV) infusion as the route of administration. This study will evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administration. An IV infusion arm is included in this study to allow calculation of estimated relative bioavailability following SQ and IM administration.

This study will be conducted in healthy adult volunteers. Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio; subjects will receive either a single administration of GSK933776 200 mg (milligram) by IV infusion (reference arm), 200 mg SQ, 200 mg IM or GSK933776 50 mg SQ once every week for 4 weeks (total dose of 200 mg). Subjects will be followed for approximately 84 days after drug administration.

The primary endpoints of the study are the estimated relative bioavailability based on area under the concentration-time curve AUC(0-inf) and a characterization of the pharmacokinetic profile of GSK933776 with each route of administration (AUC(0-), Cmax (maximum observed concentration), Tmax (time of occurrence of Cmax), T1/2 (terminal phase half-life), clearance, and volume of distribution (as data permit). Secondary endpoints include routine safety and tolerability assessments, an evaluation of potential immunogenicity as determined by the presence of antibodies to GSK933776 in serum, and characterization of the pharmacodynamic profile as determined by the measurement of plasma concentrations of GSK933776, total Aβ and total Aβ fragmentsas data permit, as well as unbound concentrations of Aβ, if possible.

2014N211143_00

2014N211143_00


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SPONSOR/MEDICAL MONITOR INFORMATION PAGE

Medical Monitor and Sponsor Contact Information:

Role Name Day Time Phone Number

After-hours Phone/Cell/PagerNumber

Fax Number

GSK Address

Primary Medical Monitor

MD, MPH

5 Moore Drive PO Box 13398, RTP, NC 27709-3398

Secondary Medical Monitor

MD,

PhD

2301 Renaissance BlvdKing of Prussia, PA 19406

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.

Regulatory Agency Identifying Number(s): US IND #109501

2014N211143_00


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name:

Investigator Address:

Investigator Phone Number:

Investigator Signature Date

2014N211143_00


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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS.............................................................................................9

1. INTRODUCTION....................................................................................................121.1. Study Rationale ..........................................................................................121.2. Brief Background ........................................................................................12

1.2.1. GSK933776 Preclinical Data........................................................131.2.2. GSK933776 Clinical Experience ..................................................13

2. OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14

3. STUDY DESIGN ....................................................................................................153.1. Study Schematic.........................................................................................153.2. Study Design Detail ....................................................................................153.3. Discussion of Study Design ........................................................................16

3.3.1. Dose Rationale ............................................................................163.4. Risk Management.......................................................................................19

4. STUDY POPULATION ...........................................................................................214.1. Number of Subjects ....................................................................................214.2. Eligibility Criteria .........................................................................................21

4.2.1. Inclusion Criteria ..........................................................................214.2.2. Exclusion Criteria.........................................................................22

4.2.2.1. Criteria Based Upon Medical Histories .......................224.2.2.2. Criteria Based Upon Diagnostic Assessments............234.2.2.3. Other Criteria..............................................................23

4.3. Lifestyle and/or Dietary Restrictions............................................................244.3.1. Contraception Requirements .......................................................24

4.3.1.1. Male Subjects.............................................................244.3.2. Meals and Dietary Restrictions ....................................................244.3.3. Caffeine, Alcohol, and Tobacco ...................................................244.3.4. Activity .........................................................................................244.3.5. Other Restrictions ........................................................................24

4.4. Screen and Baseline Failures .....................................................................244.5. Withdrawal Criteria and Procedures............................................................25

4.5.1. Subject Withdrawal Procedures ...................................................254.5.2. Treatment After the End of the Study...........................................25

4.6. Subject Completion.....................................................................................25

5. STUDY TREATMENT ............................................................................................265.1. Investigational Product and Other Study Treatment....................................265.2. Treatment Assignment................................................................................275.3. Planned Dose Adjustments.........................................................................275.4. Subject Specific Dose Adjustment/Stopping Criteria ...................................27

5.4.1. Liver Chemistry Stopping Criteria ................................................275.4.2. QTc Withdrawal Criteria...............................................................285.4.3. Other Dose Adjustment/Stopping Safety Criteria .........................28

5.4.3.1. Allergic Reaction ........................................................285.5. Masking ......................................................................................................28

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5.6. Packaging and Labelling.............................................................................285.7. Preparation/Handling/Storage/Accountability ..............................................295.8. Assessment of Compliance ........................................................................295.9. Treatment of Study Treatment Overdose....................................................295.10. Treatment After the End of the Study..........................................................305.11. Concomitant Medications and Non-Drug Therapies....................................30

5.11.1. Permitted Medications: ................................................................305.11.2. Prohibited Medications and Non-Drug Therapies.........................305.11.3. Non-Drug Therapies ....................................................................30

6. STUDY ASSESSMENTS AND PROCEDURES .....................................................316.1. Time and Events Table ...............................................................................32

6.1.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection) .........32

6.2. Demographic/Medical History Assessments ...............................................366.3. Safety .........................................................................................................36

6.3.1. Physical Exams ...........................................................................366.3.2. Vital Signs....................................................................................366.3.3. Electrocardiogram (ECG).............................................................366.3.4. Clinical Laboratory Assessments .................................................37

6.4. Pharmacokinetics .......................................................................................396.4.1. Blood Sample Collection..............................................................396.4.2. Sample Analysis ..........................................................................39

6.5. Biomarker(s)/Pharmacodynamic Markers ...................................................406.5.1. Confirmed Biomarkers/Pharmacodynamic Markers .....................40

6.6. Immunogenicity...........................................................................................40

7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND PREGNANCY ..........417.1. Adverse Events (AE) and Serious Adverse Events (SAEs).........................41

7.1.1. Time period for collecting AE and SAE information......................417.1.2. Method of Detecting AEs and SAEs.............................................417.1.3. Definition of Adverse Events........................................................417.1.4. Definition of Serious Adverse Events ...........................................427.1.5. Prompt Reporting of SAEs to GSK...............................................447.1.6. Regulatory Reporting Requirements for SAEs .............................44

7.2. Pregnancy ..................................................................................................447.2.1. Time period for collecting pregnancy information .........................447.2.2. Action to be taken if pregnancy occurs ........................................447.2.3. Action to be taken if pregnancy occurs in a female partner

of a male study subject ................................................................45

8. DATA MANAGEMENT ...........................................................................................46

9. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................469.1. Hypotheses and Treatment Comparisons...................................................469.2. Sample Size Considerations.......................................................................46

9.2.1. Sample Size Assumptions ...........................................................469.2.2. Sample Size Sensitivity................................................................479.2.3. Sample Size Re-estimation..........................................................47

9.3. Data Analysis Considerations .....................................................................479.3.1. Interim Analysis ...........................................................................479.3.2. Final Analyses .............................................................................47

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9.3.2.1. Safety Analyses..........................................................479.3.2.2. Pharmacokinetic Analyses..........................................489.3.2.3. Pharmacokinetic/Pharmacodynamic Analyses ...........489.3.2.4. Pharmacodynamic/Biomarker Analyses .....................48

10. STUDY GOVERNANCE CONSIDERATIONS........................................................4910.1. Posting of Information on Publicly Available Clinical Trial Registers............4910.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................4910.3. Quality Control (Study Monitoring) ..............................................................4910.4. Quality Assurance.......................................................................................5010.5. Study and Site Closure ...............................................................................5010.6. Records Retention ......................................................................................5010.7. Provision of Study Results to Investigators, Posting of Information

on Publically Available Clinical Trials Registers and Publication .................51

11. REFERENCES.......................................................................................................52

12. APPENDICES ........................................................................................................5312.1. Appendix 1: Liver Safety Process ...............................................................5312.2. Appendix 2: Drug Preparation....................................................................5712.3. Appendix 3: STUDY TREATMENT INFORMATION ...................................5912.4. Appendix 4: Assessment of Injection Site Reaction Terms .........................6112.5. Appendix 5: Procedures for Detection, Evaluation, Follow-Up and

Reporting of Adverse Events Recording of AEs and SAEs .........................62

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LIST OF ABBREVIATIONS

Aβ Amyloid betaAD Alzheimer’s diseaseADCC Antibody-dependent cellular cytotoxicityAE Adverse eventALT Alanine aminotransferase (SGPT)AMD Age-related macular degenerationANOVA Analysis of varianceARIA Amyloid related imaging abnormalitiesAPTT/INR activated partial thromboplastin time /international normalized ratioARIA-E ARIA-edema/effusionsARIA-H ARIA-hemosiderin depositsAST Aspartate aminotransferase (SGOT)AUC Area under concentration-time curveAUC(0-inf) Area under the concentration-time curve from time zero (pre-dose)

extrapolated to infinite timeAUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to

last time of quantifiable concentration


BUN Blood urea nitrogenCDC Complement-dependent cytotoxicityCL Systemic clearance of parent drugCmax Maximum observed concentration Ct Last observed quantifiable concentrationCO2 Carbon dioxideCPK Creatine phosphokinaseCPMS Clinical Pharmacology Modelling & SimulationCP-RAP Clinical Pharmacology Reporting and Analysis PlanCPSSO Clinical Pharmacology Science and Study OperationsCRF Case Report FormCSF Cerebrospinal FluidCV Coefficient of variationCVA Cerebrovascular accidentECG ElectrocardiogramECL ElectrochemiluminescentF Absolute bioavailability of drug FDA Food and Drug AdministrationFSH Follicle Stimulating HormoneGA Geographic atrophyGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGGT Gamma glutamyltransferaseGLP Good Laboratory PracticeGSK GlaxoSmithKlineHBsAg Hepatitis B surface antigen

2014N211143_00


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HIV Human immunodeficiency virush/hr Hour(s)IB Investigator’s BrochureICH International Conference on Harmonisation IDSL Integrated Data Standards LibraryIEC International Ethics CommitteeIM IntramuscularINR International Normalized RatioIP Investigational productIRB Institutional Review BoardIUD Intrauterine deviceIUS Intrauterine systemIV IntravenousKg Kilogram


L Literlbs PoundsLDH Lactate dehydrogenaseLFTs Liver function testsmAb Monoclonal antibodymg MilligrammL MillilitermmHg Millimeters of mercuryMRI Magnetic Resonance ImagingMSDS Material Safety Data Sheetmsec MillisecondsNONMEM Nonlinear mixed effects modelling programPD PharmacodynamicPK PharmacokineticPoC Proof of conceptQTcB QT duration corrected for heart rate by Bazett’s formulaQTcF QT duration corrected for heart rate by Fridericia’s formulaRBC Red blood cellsSAE Serious adverse event(s)SGOT Serum glutamic-oxaloacetic transaminaseSGPT Serum glutamic pyruvic transaminaseSOP Standard Operating ProcedureSPM Study Procedures ManualSQ SubcutaneousT½ Terminal phase half-lifeτ Dosing intervalTmax Time of occurrence of CmaxULN Upper limit of normalVE Vasogenic edemaWBC White blood cells

2014N211143_00


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Trademarks not owned by the GlaxoSmithKline group of companies

NONE WinNonlin

2014N211143_00


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1. INTRODUCTION

1.1. Study Rationale

The route of administration in clinical studies of GSK933776 to date has been intravenous (IV) infusion; this includes two completed clinical studies evaluating GSK933776 in subjects with AD, and an ongoing Phase II study in patients with GA. It may be beneficial to have an alternate route of administration as a treatment option, allowing greater flexibility for physicians, patients and caregivers. The present study is intended to enable a possible transition to IM or SQ administration for subsequent studies with GSK933776 by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicity of GSK933776 following IM and SQ administration in healthy volunteers. Such alternate routes of administration may provide more options in the selection of an efficacious dose for subsequent development in patients with geographic atrophy.

Although previous studies have been conducted in older patient populations, this study will be conducted in healthy adult volunteers, between ages 18-50. The total dose of 200mg selected for this study equates approximately to the 3 mg/kg regimen administered by intravenous infusion. Since patients have received treatment over 3 months or longer with the 3 mg/kg IV regimen, the accrued safety profile of GSK933776 in these populations, suggest that the administration of GSK933776 as a single dose of 200mg or four repeat doses of 50mg will be well tolerated. Appropriate monitoring is defined in this protocol to insure subject safety.

1.2. Brief Background

GSK933776 is a humanised, Fc-disabled IgG1 monoclonal antibody (mAb) directed against the N-terminal amino acid residues 1-5 of amyloid beta (A). GSK933776 is currently being evaluated as a potential treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD); it has also previously been studied in patients with Alzheimer’s disease (AD).

To date, all studies with GSK933776 have administered the dose by intravenous (IV) infusion. This study will evaluate other potential routes of administration by establishing bioavailability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, tolerability and safety assessments for GSK933776 following IM and SQ administration. An IV infusion arm is included to estimate the relative bioavailability following IM and SQ administration.

Utilizing data from previous studies in AD patients, development of a PK-PD model describing the relationship between GSK933776 concentrations and reductions in unbound serum A is ongoing. The present study will provide additional information on serum A concentrations following GSK933776 administration in healthy volunteers. This data may be used to explore the PK-PD relationship following IM and SQ administration and may provide additional data for refinement of the PK-PD model for GSK933776.

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1.2.1. GSK933776 Preclinical Data

Details of all the preclinical investigations with GSK933776 and GSK719556A (the murine parent antibody of GSK933776) can be found in the current Clinical Investigators Brochure (CIB) and any subsequent revisions [ GlaxoSmithKline Document NumberSC2009/00016/01].

1.2.2. GSK933776 Clinical Experience

Studies in Patients with Alzheimer’s Disease

Two clinical studies with GSK933776, Study BA1106006 and Study BA1113043, in subjects with AD have been completed. BA1106006 was a two-part, single-masked, placebo-controlled, ascending-dose study in subjects with mild to moderate AD. This study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicity following single doses (0.001, 0.01 and 0.1 mg/kg) and 3 repeat doses (0.1, 1, 3, and 6 mg/kg) of GSK933776 administered by intravenous infusion at 1-month intervals. BA1113043 was an open-label, parallel-group study in subjects with mild AD or mild cognitive impairment. The study was designed to assess the pharmacodynamic profile of GSK933776 in plasma and cerebrospinal fluid (CSF) following administration of single doses of 1, 3 and 6 mg/kg intravenously.

In these studies, 48 individuals were administered GSK933776; 19 received a single dose and 29 received multiple infusions. The safety profile of GSK933776 in patients withAD suggests that doses up to 6 mg/kg administered intravenously for up to 3 monthlyintervals have been well tolerated with no apparent significant adverse effects. The adverse events (AEs) reported were mild to moderate in nature and mostly characterised by the Investigators as not related to the study drug. No magnetic resonance imaging (MRI) findings associated with drug administration were noted; there were no reported cases of vasogenic edema. Prior studies in the literature with monoclonal antibodies of this class directed against amyloid beta included reports of vasogenic edema in as many as 10% of patients. In Study BA1106006, a dose-dependent increase in total amyloid beta (A) and a reduction of free A was observed. Similarly, in Study BA1113043, there was an observed increase in both totals A18–35 and A28–42 concentrations in plasma after the administration of GSK933776. After administration of GSK933776 1 mg/kg, 3 mg/kg and 6 mg/kg intravenously, average decreases from baseline in CSF A1–42 (0–12 h) of 22.8 pg/mL (6.2%), 43.5 pg/mL (pg/mL) (9.2%) and 60.5 pg/mL (12.5%), respectively, were observed.

These apparent dose-dependent increases in total A28–42 and A18–35 in plasma and decreases of A1–42 in CSF support the theory of the pharmacologic activity and target engagement of GSK933776 in both plasma and CSF and may be considered initial steps of the postulated ‘peripheral sink’ mechanism. Such increases would be expected if GSK933776 is forming a complex with A in plasma, which in turn results in a shift from brain to plasma as reflected in the lowered levels in CSF.

Details of the two completed clinical studies investigating the use of GSK933776 in subjects with (AD) can be found in the current Clinical Investigators Brochure and any subsequent revisions [GlaxoSmithKline Document Number SC2009/00016/01].

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Study in Patients with Geographic Atrophy

There is currently an ongoing Phase II Study, BAM114341, which is a multi-center, randomised, double-masked, placebo-controlled, parallel-group study investigating the safety, tolerability, efficacy, PK and PD of GSK933776 in adult patients with geographic atrophy due to AMD. Following an observation period of four months, the treatment regimens being evaluated are placebo, 3mg/kg, 6 mg/kg and 15 mg/kg administered by IV infusion once-monthly for a period of 18 months.

2. OBJECTIVE(S) AND ENDPOINT(S)


Primary


The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion (reference arm)

Secondary





Pharmacokinetic parameters including area under the concentration-time curve over the dosing interval (AUC(0-)), Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit


Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22, as data permit

Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status), as data permit

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3. STUDY DESIGN

3.1. Study Schematic

Figure 1:

• Duration: Approximately 85 days for subjects in Treatment Arms A, B and D; approximately 106 days for subjects in Treatment Arm C

• Follow up: 84 days following last dose administration

• Sample size: Planned evaluable subjects = 24. Enrolment will account for dropouts or non-evaluable subjects via replacement

Screening 1:1:1:1

Randomization

A: Single 200 mg IV infusion of GSK933776 (n=6)

B: Single 200 mg SQ dose of GSK933776 (n=6)

C: 4 weekly 50 mg SQ doses of GSK933776 (n=6)

D: Single 200 mg IM dose of GSK933776 (n=6)

Treatment Arms

3.2. Study Design Detail

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table (Section 6.1) are essential and required for study conduct. Deviations to the protocol will be noted in the electronic case report form and the final study report.

This is a randomised, open label study to investigate the relative bioavailability, pharmacokinetic profile, pharmacodynamic profile, safety and tolerability, and immunogenicity profile of GSK933776 administered by IV infusion and IM and SQ routes of administration in healthy volunteers. The study will be conducted at a single clinical center. The planned number of evaluable subjects for this study is 24 with 6 subjects completing all critical assessments in each of the four treatment arms.

Having provided informed consent, subjects will undergo screening to determine whether they are eligible to participate in the study. Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio as illustrated in Figure 1. Subjects will remain in the unit for at least 6 hours post-dose to assess safety and tolerability and to obtain samples

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for pharmacokinetic and pharmacodynamic determinations. Subjects receiving GSK933776 by IM and SQ administration will be monitored for injection site tolerability and immediate post-injection reactions for at least 6 hours after injection.

During the treatment period, the assessments defined in the Time and Events Table (Section 6.1) will be performed according to protocol. Subjects will be followed for approximately 84 days after dose administration (for Treatment Arm C, this 84-day period begins after the final [fourth] dose). Subjects will return for periodic visits over the approximate 84-day post dosing period in order to monitor safety, tolerability and immunogenicity and to obtain samples for pharmacokinetic and pharmacodynamic assessments.

With respect to the IV infusion, if an infusion reaction occurs, the infusion rate may be reduced or the infusion may be halted at the discretion of the Investigator and/or medical monitor, depending on the severity of signs and symptoms. If the infusion is halted, the subject will be withdrawn from the study.

For subjects in Treatment Arm C (50 mg SQ weekly for 4 weeks), the Investigator and/or medical monitor may withdraw the subject from the remainder of the study if the subject has experienced a substantial injection site reaction or other safety/tolerability issues with a prior administration of study drug.

The final visit is to occur approximately 84 days after the final dose of study medication is administered. Each subject will have this final clinic visit scheduled, and assessments will be performed based on the Time and Events schedule (Section 6.1). The total duration of subject participation from screening to follow-up for Treatment Arms A, B and D (single dose of GSK933776), will be approximately 113 days. Total duration of subject participation from screening to follow-up for Treatment Arm C (weekly SQ administration for 4 doses), will be approximately 134 days.

3.3. Discussion of Study Design

3.3.1. Dose Rationale

The total dose selected to estimate the relative bioavailability of GSK933776 for this study is 200 mg. The dose regimens in the present study were selected based on: 1) understanding that relative bioavailability will permit final decisions on the optimal route of administration, 2) safety experience with doses utilized in previous and ongoing studies in AD and GA, and 3) feasibility.

The regimens and routes of administration to be evaluated in this study are:

A: single 200 mg dose of GSK933776 administered by IV infusion (reference arm)

B: single 200 mg dose of GSK933776 administered SQ

C: 50 mg dose of GSK933776 administered SQ once weekly for 4 weeks (total dose = 200 mg)

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D: single 200 mg dose of GSK933776 administered IM

GSK933776 is being investigated in an ongoing study in patients with GA (BAM114341). For reference, the dosages in BAM114341 are 3 mg/kg, 6 mg/kg and 15 mg/kg (administered once-monthly by intravenous infusion); these regimens are approximately equal to 200 mg, 400 mg and 1005 mg, respectively, for a subject weighing 67 kg. Therefore, the 200 mg total dose selected for the present study is approximately equal to the lower dose regimen (3 mg/kg) and ~20% of the higher dose regimen (15 mg/kg) in study BAM114341. Additionally, doses of 3 mg/kg and 6 mg/kg were previously evaluated in study BA1106006 in patients with AD. The dose regimen proposed for this study is expected to be pharmacologically relevant based on available pharmacodynamic data, where dose-dependent reductions in free A plasma concentrations have been observed in the dose range of 1 to 6 mg/kg administered monthly for up to 3 consecutive months.

The GSK933776 formulation for use in the present study has a concentration of 50 mg/mL; therefore, a 200 mg dose will require 4 SQ injections of 1 mL each. Due to the number of injections that are required, a total dose higher than 200 mg SQ was not considered feasible at this time. Intramuscular injection has the potential advantage of allowing a larger volume (5.0 mL) to be injected without causing significant discomfort in patients [Nicoll and Hesby, 2002]; thus, the 200 mg dose administered by the intramuscular route will be given as one 4 mL injection either in the dorso- or ventro-gluteal region.

Rationale for the weekly administration arm

If the efficacious dose of GSK933776 for the GA indication is ultimately shown to be 3 mg/kg administered IV once-monthly, weekly SQ administration represents a viable pathway to deliver an equivalent dose while keeping injection volume reasonable. Assuming a 65% bioavailability for GSK933776, the 50 mg/mL formulation when administered SQ once weekly for 4 weeks (0.65 x 1 mL x 50 mg/mL x 4 weekly doses) would provide an approximate 130 mg IV monthly equivalent. While a weekly SQ dosing regimen would produce a lower maximum observed plasma concentration (Cmax) compared to once-monthly IV administration, the area under the plasma drug concentration versus time curve (AUC) should be approximately equivalent under the assumptions provided. Inclusion of the weekly administration arm will allow testing ofthe expectation of AUC equivalence of 200 mg SQ once-monthly as compared to 50 mg SQ once-weekly x 4 weeks. Of note, therapeutic equivalence between these two regimens (200 mg SQ once monthly vs. 50 mg SQ once weekly) would require that AUC rather than Cmax drives efficacy. Although this assumption has not been formally tested, it is a reasonable supposition given the ‘sink-hypothesis’ of potential efficacy for anti-Atherapeutics.

Therefore, the weekly administration arm is included in the present study to provide repeat-dose tolerability information, and to evaluate the PK profile of weekly SQ administration, representing a dosing frequency that may be employed in future studies if efficacious doses of GSK933776 are on the higher end of the anticipated range.

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Rationale for fixed dosing (rather than mg/kg dosing)

Weight-based (mg/kg) administration has been utilized in all previous studies of GSK933776. However, for SQ delivery, fixed dosing schemes (e.g., 200 mg) are often preferable as they enable use of prefilled, fixed-volume syringes, which are simple and could be convenient to employ in later phase clinical studies. For the present study, fixed dosing was selected based on the consideration of the number of injections required to deliver the dose.

Body weight has been shown to influence the volume of distribution and clearance of some marketed monoclonal antibodies (mAbs), but not others (Wang DD, 2009). The influence of body weight on pharmacokinetic parameters of GSK933776 has been evaluated through simulation. Using a pharmacokinetic model developed from data obtained in study BA1106006, simulations were performed with either fixed dosing or body weight-based dosing. Body weight did not significantly affect the 95th percentile of intervals of concentration-time profiles, distribution, or variability of exposure for 1000 subjects after both dosing approaches were examined (data on file at GSK).

Pharmacokinetics:

Single doses (0.001, 0.01 and 0.1 mg/kg) and 3 repeat doses (0.1, 1, 3, and 6 mg/kg) of GSK933776 were administered to patients with AD by IV infusion at 1-month intervals in study BA1106006. Plasma concentrations of GSK933776 were well characterized over the sampling duration of up to 15 weeks at IV doses of 0.1, 1, 3 and 6 mg/kg. Pharmacokinetic profiles for doses lower than 0.1 mg/kg could not be determined. In studies with other monoclonal antibodies, bioavailability for SQ or IM administration has been reported to be between 50% and 100%, of which the majority of values reported are between 60% to 75% [Lobo, 2004]. At the proposed dose of 200 mg SQ or IM, or 50 mg SQ weekly for 4 weeks, even if bioavailability equates to the lower end of the likely range (50%), plasma concentrations of GSK933776 are expected to be quantifiable with the current assay for sufficient duration to estimate absolute bioavailability.

Pharmacodynamics:

PD sampling for Aβ and related fragments (Table 1) is included in this study to enrich the existing PK-PD dataset and allow for specific PK-PD modelling of SQ administration. It is anticipated that these data could be useful for development of a general model characterizing the GSK933776 PK-PD relationship across multiple populations (AD, GA, and healthy volunteers).

It is generally accepted that the A fragment 1-42 is neurotoxic and thus may be a culprit in Alzheimer’s disease, but whether the A fragment is most relevant to geographic atrophy is not clear. Evidence in the literature is consistent with the general conclusion that the Aβ assemblies in drusen are not the ocular equivalent of A in senile plaques in the brains of patients with AD [Anderson DH, 2004; Sperling, 2011; Westlind-Danielsson, 2001]. For the present study, bound and unbound, intact and fragments of A will be measured, if feasible, given the uncertainty regarding which form or fragment of A is most relevant for GA.

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Table 1 Assays for Detection of A and Related Fragments

ASSAY DESIGNATION

CAPTURE ANTIBODY(EPITOPE RECOGNIZED)

DETECTION ANTIBODY (EPITOPE RECOGNIZED)

Ab FRAGMENTS DETETCTED

Total (28-42) 6F6 (aa28-35) 5G5 (aa35-42)All fragments containing an intact C terminus, such as Ab1-42 and Ab3-42

Total (18-35) 6F6 (aa28-35) 4G8 (aa18-22)

All fragments containing the minimal sequence aa18-35, such as Ab 1-38, ABb1-40, and Ab 1-42

Free (1-22) GSK933776 (aa1-5) 4G8 (aa18-22)

Unbound fragments containing the minimal sequence aa1-22, such as Ab1-38, Ab 1-40, and Ab 1-42

From study BA1106006 in patients with mild to moderate AD, plasma samples for total (bound and unbound) Aβ (18-35) and Aβ (28-42) were collected following administration of GSK933776. No effects on plasma A were observed following single doses of 0.001 and 0.01 mg/kg, whereas a single dose of 0.1 mg/kg and repeat doses of 0.1 to 6 mg/kg resulted in appreciable reductions in free A concentrations in plasma. Compared to baseline, total Aβ (18-35) plasma concentrations increased approximately 5- to 30-foldand free Aβ (1-22) decreased between 40% to 90% depending on dose levels.

Circulating A and related fragments are present in subjects without AD at concentrations similar to those in subjects with AD; consequently, the doses utilized in this study are expected to result in quantifiable decreases in free A and increases in total (i.e., bound by drug) A. These data will be used to characterize the PD response in the PK-PD model.

3.4. Risk Management

Table 2 Summary of Key Issues, Their Impact and Strategy to Mitigate Risk

Potential risk Summary of data Impact-eligibility criteria

Strategy-monitoring/stopping criteria

Acute allergic reaction or potential for antibody-mediated toxicity with GSK933776

As with all antibodies, there is a risk of acute allergic reactions occurring. In contrast to antibodies with an active Fc region, amino acid substitutions in the Fc region of GSK933776 substantially reduce complement fixation and Fc receptor binding, which are responsible for immune/cell-mediated tissue damage related to complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Therefore, the potential for antibody-mediated toxicity with GSK933776

Exclusion criteria have been incorporated to ensure the selection of subjects who are not at increased risk for such events.

All subjects will also be monitored for evidence of infusion reactions or acute allergic reactions following administration.

Subjects that have signs and symptoms of an infusion or injection based reactions will be monitored and will be withdrawn and treated

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is anticipated to be more limited as compared to IgG1 mAbs with native Fc regions.

by standard of care

GSK933776 will have a low potential for immunogenicity

This assumption is supported by data from the completed studies with IV administration in patients with AD. In the initial study, none of the 12 subjects who received a single dose developed antibodies to GSK933776. With repeat administration, two of 24 subjects developed anti-GSK933776 antibodies after receiving 2 doses of the study drug. In study BA1113043, one of 18 patients developed neutralising antibodies of low titre on day 56

None Serum samples are taken and will be tested for anti-drug antibodies

All subjects will be monitored for any evidence of an immunogenicity response.

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4. STUDY POPULATION

4.1. Number of Subjects

A sufficient number of subjects will be enrolled so that approximately 24 evaluable subjects complete this study; six subjects are targeted to complete all critical assessmentsfor each of the treatment arms.

If subjects prematurely discontinue the study, additional subjects may be enrolled as replacement subjects at the discretion of the Sponsor in consultation with the Investigatorif recruitment goals are not met.

4.2. Eligibility Criteria

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the IB.

Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

4.2.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female subject 18 – 50 years of age at the time of signing the informed consent

2. In general good health as determined by a physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with the study procedures

3. Body weight ≥ 55 kg (121 lbs) and ≤ 85 kg [187 lbs (pounds)] with a body mass index (BMI) between 18.5 and 29 (inclusively) where

BMI = (weight in kg)(height in meters)2

at the time of signing the informed consent

4. A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous

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follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory

5. Male subjects must agree to use one form of acceptable contraception methods listed in this protocol (Section 4.3.1.1) if their partner is of childbearing potential. This criterion must be followed from the time of the screening visit through the follow up visit (84 days after last dose of study medication)

6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

4.2.2. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

4.2.2.1. Criteria Based Upon Medical Histories

1. Known risk history of:

a. Central nervous system (CNS) disorders:

i. History and/or evidence (CT or MRI scan performed within the past 12 months) of cerebral haemorrhage OR a known risk of cerebral haemorrhage, including uncontrolled hypertension, cerebrovascular malformation, coagulopathy, CNS vasculitis, degenerative or inflammatory/demyelinating CNS conditions or any other condition that the Investigator and/or the medical monitor considers as a relevant risk factor for cerebral haemorrhage

ii. Transient ischemic attack (TIA)/cerebrovascular accident (CVA) in the last year, or other uncontrolled risk factors for stroke

b. History of seizures (except febrile seizures in childhood) or recent unprovoked seizure

c. Uncontrolled type 2 diabetes mellitus (HbA1C >10%), active cardiovascular disease (e.g., moderate-severe angina, unstable angina, myocardial infarction (MI) within the last 2 years, symptomatic congestive heart failure, clinically significant arrhythmia)

d. Current blood clotting or bleeding disorder or conditions that predispose to these (e.g. cancer)

e. Diagnosis of currently active, or, in remission but chronic relapsing, systemic autoimmune disease or condition (e.g. multiple sclerosis, lupus erythematosus etc) that the Investigator and/or the medical monitor considers as a relevant risk factor for concomitant administration of a therapeutic monoclonal antibody

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2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

3. Use of prescription drugs or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety

4. A positive pre-study drug/alcohol screen. Current or recent drug or alcohol abuse or dependence. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 units for males or >7 units for females. One drink is equivalent to 12 g of alcohol: 12 ounces (~360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Use of illegal drugs

5. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation

4.2.2.2. Criteria Based Upon Diagnostic Assessments

6. Seated systolic blood pressure > 140 mmHg or seated diastolic blood pressure of > 90 mmHg

7. QTc > 450 millisecond (msec)

8. AST and ALT ≥ 2xULN; alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

9. Significant abnormalities on hematology screen: clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for females), or platelet counts below 124 GI/L; INR > 2

10. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

11. A positive test for HIV antibody

4.2.2.3. Other Criteria

12. Where participation in the study would result in donation of blood or blood productsin excess of 500 mL within a 56 day period

13. Exposure to more than four new chemical entities within 12 months prior to screening

14. Prior allergic reactions to biological products (vaccines, antibodies) or known hypersensitivity to any of the components of the drug formulation

15. Prior participation in clinical investigations involving therapeutic monoclonal antibodies with a similar mode of action or proteins derived from monoclonal antibodies with any risk of cross- reactivity or any investigations of treatments or use

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of any other investigational medication or device within 2 months prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever is longer.

4.3. Lifestyle and/or Dietary Restrictions

4.3.1. Contraception Requirements

4.3.1.1. Male Subjects

Male subjects with female partners of child-bearing potential must use one of the following contraceptive methods after the first dose of study treatment and until the follow-up visit, 84 days after the last dose of investigational product.

Condom (during non-vaginal intercourse with any partner - male or female) OR

Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)

Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception

4.3.2. Meals and Dietary Restrictions

4.3.3. Caffeine, Alcohol, and Tobacco

During each dosing session, subjects will abstain from alcohol for 24 hours prior to the start of dosing until collection of the final pharmacokinetic and or pharmacodynamic sample during each session. An alcohol test will be given as outlined on the T&E table in Section 6.1

4.3.4. Activity

Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies.

4.3.5. Other Restrictions

Subjects must refrain from all recreational drugs throughout the study (screening to follow-up). Drugs of abuse tests may be performed randomly throughout the study at the Investigator’s discretion. A positive result at any point will lead to exclusion from the study

4.4. Screen and Baseline Failures

Data for screen and baseline failures will be collected in source documentation at the site but will not be transmitted to GSK in the study defined data capture system

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4.5. Withdrawal Criteria and Procedures

A subject may withdraw from study treatment at any time at his/her own request, or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural or administrative reasons.

Should a subject fail to attend the clinic for a required study visit, the site should attempt to contact the subject and re-schedule the missed visit as soon as possible. The site should also counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study based on previous non-compliance. In cases where the subject does not return for the rescheduled visit or cannot be reached to reschedule the missed visit, the site should make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they can appropriately be withdrawn from the study.

These contact attempts should be documented in the subject’s medical record. Should the subject continue to be unreachable, then and only then will he/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation should be recorded in the eCRF.

Refer to Section 5.3 for planned dose adjustment/stopping criteria and Section 5.4 for subject specific dose adaptation/stopping criteria including Liver Chemistry and QTc.

Liver Chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). See Section 5.4.1 for details.

4.5.1. Subject Withdrawal Procedures

A subject who is withdrawn from study medication and participation in this clinical study will complete the assessments specified in the Time and Events table (Section 6.1) for the final follow up visit. Information obtained will be included in assessments of safety and effects following withdrawal from treatment.

Before discontinuing a subject from the study, the Investigator should be in contact with the GSK Medical Monitor to discuss the specific situation. In the event that the Investigator is unable to reach the GSK medical monitor, the Investigator will make a decision at his or her discretion, until the GSK medical monitor can be informed.

4.5.2. Treatment After the End of the Study

Subjects will not receive any additional treatment from GSK after completion of the study because only healthy volunteers are eligible for study participation.

4.6. Subject Completion

A completed subject is one who has completed all phases of the study including the follow-up visit. Subjects who are screened, but are not eligible will be considered “screen failures.”

The end of the study is defined as the last subject’s last visit.

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5. STUDY TREATMENT

5.1. Investigational Product and Other Study Treatment

PRODUCT NAME:















The dose will be administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site is either the abdomen or the upper thigh. Injection site is to be documented and should be rotated. Detailed instructions are included in Appendix 3.

The dose will be administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed). Detailed instructions are included in Appendix 3.

The dose will be administered through an IV catheter over approximately 1 hour


GSK933776 will be drawn into a sterile disposable syringe. Study drug will then be administered through a sterile needle (27GA).

GSK933776 will be drawn into a sterile disposable syringe. Study drug will then be administered through a sterile needle (23GA).

GSK933776 will be prepared in 0.9% Sodium Chloride in infusion bags. Study drug will then be administered using an IV delivery pump and a catheter.

Please see the Time & Events Table (Section 6.1) for further detail on administration and study day assessments. Further information about the administration of investigational product can be found in Appendix 2, and ordering of drug supplies can be found in the Study Procedures Manual (SPM).

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5.2. Treatment Assignment

Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio in accordance with the randomisation schedule generated using RandAll, a web-based clinical trials system, by QSci, Clinical Statistics Department at GlaxoSmithKline (GSK).

A description of each potential study regimen is provided below:

TREATMENT ARM DESCRIPTIONA 200 mg GSK933776 administered by IV infusionB 200 mg GSK933776 administered by SQ injection C 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks D 200 mg GSK933776 administered by IM injection

5.3. Planned Dose Adjustments

This protocol does not allow for alteration from the currently outlined doses for each cohort. The maximum total dose will not exceed 200 mg in any subject or cohort.

5.4. Subject Specific Dose Adjustment/Stopping Criteria

A subject may discontinue treatment and withdraw from the study at any time at his/her own request or may be withdrawn at any time for safety or administrative reasons at the discretion of the Investigator. Additional criteria for withdrawal are provided below.

5.4.1. Liver Chemistry Stopping Criteria

Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).

Study treatment will be stopped for a subject if any of the following liver chemistry stopping criteria is met:

1. ALT 3xULN and bilirubin 2xULN (or ALT 3xULN and INR1 > 1.5) NOTE: serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury)

2. ALT 5xULN

3. ALT 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or

1 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants

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tenderness or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia)

4. ALT 3xULN persists for 4 weeks

5. ALT 3xULN and cannot be monitored weekly for 4 weeks

Subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash, can continue study treatment as long as they can be monitored weekly for 4 weeks.

NOTE: Refer to Appendix 1, for details of the required assessments if a subject meets any of the above criteria.

5.4.2. QTc Withdrawal Criteria

A subject that meets either criterion below will be withdrawn from the study. The same QT correction formula (e.g QTcB, QTcF) should be used to determine inclusion and discontinuation for any individual subject throughout the study.

[QTcB or QTcF] > 500 msec,

Change from baseline: QTc >60 msec

Withdrawal of subjects is to be based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period of time and then use the averaged QTc values of the 3 ECGs to determine whether the subject should be discontinued from the study.

5.4.3. Other Dose Adjustment/Stopping Safety Criteria

5.4.3.1. Allergic Reaction

Although humanisation of the GSK933776 antibody is expected to reduce the risk of acute allergic reactions, all subjects will be monitored carefully for evidence of acute allergic reactions and infusion reactions (for those subjects participation in the IV arm). It is important to recognise early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis.

If an anaphylactic reaction should occur, study medication should be stopped immediately, where possible, and the subject should not be re-challenged. Subjects should be followed up as specified in Section 4.5.1, Subject Withdrawal Procedures.

5.5. Masking

This will be an open-label study.

5.6. Packaging and Labelling

The contents of the label will be in accordance with all applicable regulatory requirements.

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5.7. Preparation/Handling/Storage/Accountability

A description of the methods and materials required for preparation of the GSK933776 IV, IM and SQ solution is provided in Appendix 2.

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product. Only authorised site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to pharmacy staff or designee. Investigational product is to be stored at 2-8C and protected from light. Maintenance of a temperature log is required.

The study pharmacist or designee is responsible for investigational product accountability, reconciliation, and record maintenance. The pharmacist staff or designee must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from GSK and the amount supplied and administered. The required accountability unit for this study will be individual vials. Discrepancies are to be reconciled or resolved. Procedures for final disposition of unused investigational product are listed in the SPM.

Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. In the case of unintentional occupational exposure notify the monitor, medical monitor and/or study manager. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the Investigator, where this is required by local laws, or is available upon request from GSK.

5.8. Assessment of Compliance

When the individual dose for a subject is prepared from a bulk supply, the preparation of the dose will be confirmed by a second member of the study site staff.

When subjects are dosed at the study site, they will receive study treatment directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of study treatment and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.

5.9. Treatment of Study Treatment Overdose

For this study, any dose of GSK933776 > 200mg within a 24 hour time period +/- 1 hour will be considered an overdose.

GSK does not recommend specific treatment for an overdose. The Investigator will use clinical judgment to treat any overdose.

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5.10. Treatment After the End of the Study

Subjects will not receive any additional treatment from GSK after completion of the study because only healthy volunteers are eligible for study participation.

5.11. Concomitant Medications and Non-Drug Therapies

5.11.1. Permitted Medications:

Acetaminophen, at doses of 2 grams/day is permitted for use any time during the study. Other concomitant medication may be considered on a case by case basis by the GSK Medical Monitor.

5.11.2. Prohibited Medications and Non-Drug Therapies

Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study.

5.11.3. Non-Drug Therapies

Subjects must abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study.

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6. STUDY ASSESSMENTS AND PROCEDURES

This section lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table Section 6.1. Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, blood draws. The timing of the assessments should allow the blood draw to occur at the exact nominal time.

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.

The timing and number of planned study assessments, including safety, pharmacokinetic, and pharmacodynamic, and immunogenicity assessments may be altered during the course of the study based on newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. The change in timing or addition of time points for any planned study assessments must be approved and documented by GSK in a note to file and archived in the study sponsor and site study files, but this will not constitute a protocol amendment. The Institutional review Board (IRB)/International Ethics Committee (IEC) will be informed of any safety issues that require alteration of the safety monitoring scheme. No more than 500 mL of blood will be collected over the duration of the study, including any extra assessments that may be required.

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6.1. Time and Events Table

6.1.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection)

Day Screena

Day 1Day

2Day

3Day

4Day

5Day

6Day 10

Day 15

Day 22

Day 29

Day 57

Follow Up Day 85d

AssessmentsPre-dose

0h0.25

h0.5h

0.75h

1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016h

Informed Consent XDemographics X

Physical Examination X X X XMedical history (inc. family cardiovascular history) XConcomitant Medications X X X X X XDose XAE/SAE Review ----------------------------------------------------------------------------------X------------------------------------------------------------------12-lead ECG X XVital Signs X X X X X X X X X X X X XUrine Drug/Alcoholc X Xc

Follicle stimulating hormone (FSH)/estradiol if indicated XHepatitis B, Hepatitis C, HIV (human immunodeficiency virus) X

Hematology, Chemistry, Urinalysis X X X X X X XHbA1c XPK Blood Sample X Xb Xb Xb Xb X Xb X X X X X X X X X X X XPD Blood Sample X Xb Xb Xb X X X X X X X XImmunogenicity Blood Sample X X X Xa. Subjects should be screened a minimum of 7 days, but no more than 30 days, prior to Day 1 b. Samples drawn only for subjects in Arm A (IV infusion).c. Alcohol breathalyzer test may be given instead of urine test post screening visitd. The follow up visit may occur +/- 3 days

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Time and Events Tables for Treatment Arm C (50 mg SQ injection)

Screening through Week 1

Day Screena Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Assessments Pre-dose 0h 0.5h 1h 2h 4h 6h 24h 48 h 72h 96h 120hInformed Consent XDemographics XPhysical Examination X XMedical history (includingfamily cardiovascular history)

X

Concomitant Medications X XDose XAE/SAE Review ------------------------------------------------------------------------------X----------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X XUrine Drug/Alcoholb

X Xb

Hepatitis B, Hepatitis C, HIV XHematology, Chemistry, Urinalysis X X XFSH, estradiol (if indicated) XHbA1c XPK Blood Sample X X X X X X XPD Blood Sample X X X X XImmunogenicity Blood Sample Xa. Subjects should be screened a minimum of 7 days, but no more than 30 days, prior to Day 1b. Alcohol breathalyzer test may be given instead of urine test post screening visit

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Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3

Day Day 8/15 Day 9/16

Day 10/17

Day 11/18

Day 12/19

Day 13/2

0Assessments Predose 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120hConcomitant Medications XDose XAE/SAE Review ------------------------------------------------------------------------------------------X--------------------------------------------------------------------------Vital Signs X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis XPK Blood Sample X X X X X X X

PD Blood SampleX X X X X

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Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up

Day Day 22Day23

Day 24

Day 25

Day 26

Day 27

Day 31

Day 36

Day 43

Day 50

Day 78

Follow Up

Day 106a

Assessments

Pre-dos

e 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016hPhysical Examination XConcomitant Medications X X X X XDose XAE/SAE Review ---------------------------------------------------------------------------------------------X-----------------------------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis X X X X XPK Blood Sample X X X X X X X X X X X X XPD Blood Sample X X X X X X X X X XImmunogenicity Blood Sample X X X X Xa. Follow up may occur +/- 3 days

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6.2. Demographic/Medical History Assessments

The following demographic parameters will be captured: year of birth, gender, race and ethnicity.

Medical/medication/alcohol history will be assessed as related to the eligibility criteria listed in Section 4.2.

6.3. Safety

Planned time points for all safety assessments are listed in the Time and Events Table (Section 6.1). Additional time points for safety tests such as vital signs, physical exams and laboratory safety tests may be added during the course of the study based on newly available data to ensure appropriate safety monitoring.

6.3.1. Physical Exams

A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height (at screening only) and weight will also be measured and recorded.

6.3.2. Vital Signs

Vital sign measurements will include systolic and diastolic blood pressure and pulse rate. Blood pressure, body temperature and pulse rate measurements will be recorded in the seated position at the times indicated in the Time and Events Table (Section 6.1)

Vital sign measurements to be measured in seated/ semi-supine position after 5 minutes rest will include systolic and diastolic blood pressure and pulse rate and respiratory rate.

When a vital sign measurement is scheduled at the same nominal time as a PK sample draw, the vital sign measurement should be completed first

Repeat or unscheduled measurements may be taken at the discretion of the Investigator

6.3.3. Electrocardiogram (ECG)

If the screening ECG is abnormal e.g. QTc>450, 2 additional ECGs are taken within 10 minutes and the QTc of the 3 ECGs are averaged. If the average is within the normal range, the patient can be entered into the study. If the average is abnormal, they are excluded. This same principle applies to discontinuation criteria.

12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals

All ECGs will be recorded after at least 10 minutes rest in a supine position. Where possible, hot or cold drinks and food should be avoided 30 minutes before an ECG

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measurement. Where possible, the same machine should be used at an individual site for all assessments on an individual subject throughout the study

If a measurement deviates substantially from previous readings and the operator can see no technical reason for the deviation the measurement must be repeated immediately by obtaining triplicate readings in the same sitting then averaged. Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc readings that may be necessary

6.3.4. Clinical Laboratory Assessments

Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed below. Details for the preparation and shipment of samples will be provided by the local laboratory. Reference ranges for all safety parameters will be provided to the site by the laboratory.

If additional non-protocol specified laboratory assessments are performed at the site’s local laboratory and result in a change in subject management or are considered clinical significant by the Investigator (for example SAE or AE or dose modification) the results must be captured and sent to GSK along with other study data as defined in Appendix 5.

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HematologyPlatelet Count Red Blood Cell

(RBC) Indices:Automated White Blood Cell (WBC) Differential:

RBC Count MCV NeutrophilsWBC Count (absolute) MCH LymphocytesReticulocyte Count MCHC MonocytesHemoglobin EosinophilsHematocrit BasophilsAPTT/INR (activated partial thromboplastin time/ international normalized ratio)

Clinical ChemistryBUN (blood urea nitrogen)

Potassium AST (SGOT) (Aspartate aminotransferase ) (Serum glutamic-oxaloacetic transaminase)

Total and direct bilirubin

Creatinine Chloride ALT (SGPT) (serum glutamic pyruvic transminase)

Uric Acid

Glucose, fasting Total CO2

(carbon dioxide)

Gamma glutamyltransferase (GGT)

Albumin

Sodium Calcium Alkaline phosphatase Total Protein

NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are given in Section 5.4.1.

Routine Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstickMicroscopic examination (if blood or protein is abnormal)

Other screening testsHIVHepatitis B (HBsAg) Hepatitis B surface antigenHepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, PCR will be performed on the same sample to confirm the result)

FSH and estradiol (as needed in women of non-child bearing potential only)Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines).

Monitoring of Allergic Reactions

Although humanisation of the GSK933776 antibody is known to reduce the risk of acute allergic reactions, all subjects will be monitored carefully for evidence of infusion,

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injection and other allergic reactions. Subjects will remain in the clinic for observation for at least 6 hours after dosing. It is important to recognise early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis.

During dosing, subjects will be closely monitored for early signs of dyspnoea and oedema and dosing will be stopped if clinically indicated. If an infusion and/or injection reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the Investigator and/or medical monitor, depending on severity of signs and symptoms.

A study physician that is certified in Advanced Cardiac Life Support (ACLS) or local equivalent should be available to be at the clinic within 10 minutes for the time period post-dose.

If more severe clinical signs are noted, then the physician should assess the subject. Assessment of the ABC's (airway, breathing, and circulation from Basic Life Support) will be done in all suspected anaphylactic reactions.

6.4. Pharmacokinetics

6.4.1. Blood Sample Collection

Blood samples for pharmacokinetic analysis of GSK933776 will be collected at the time points indicated in Section 6.1, Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.

Blood samples for pharmacokinetic assessment of GSK933776 will be taken from all subjects in this study according to the Time and Events Schedule of the protocol. All blood samples should be taken from the opposite arm to that of drug infusion. Approximately 2mL of whole blood will be collected into 2mL EDTA tubes (lavender cap) and placed on ice. Approximately 1 ml plasma will be collected into storage tube. The storage tubes and labels for the PK samples will be provided by GSK. Specimen labels will include study number, subject number, sample identification number, nominal time and date.

6.4.2. Sample Analysis

Plasma analysis will be performed under the management of Bioanalytical Science and Toxicokinetics, DMPK, GlaxoSmithKline. Concentrations of GSK933776 will be determined in plasma using the currently approved analytical methodology. Raw data will be stored in the good laboratory practice (GLP) Archives, GlaxoSmithKline. The processing procedures, storage and shipping details are described in the SPM.

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6.5. Biomarker(s)/Pharmacodynamic Markers

6.5.1. Confirmed Biomarkers/Pharmacodynamic Markers

The total and free levels of beta amyloid fragments will be measured in plasma for each subject. Free A (1–22), total A (18–35), and total A (28-42) will be evaluated using immuno-electrochemiluminescent (ECL) assays.

Blood samples will be taken from all subjects in this study according to the Time and Events Schedule, Section 6.1 of the protocol.

Approximately 4mL of whole blood will be collected for free and total A assays. Blood will be collected into 4ml EDTA tubes (polypropylene tubes containing EDTA K2 gel, lavender cap) and the tubes placed on ice immediately. Once collected, the blood samples must be processed within 30 minutes. The processing procedures, storage and shipping details are described in the SPM.

6.6. Immunogenicity

Blood samples for determination of anti-GSK933776 antibodies will be taken from all subjects in this study as a safety measurement for GSK933776 at the time-points specified in the Time and Events Table in Section 6.1. Timing of the assessments may be adjusted based on emerging data.

Samples will be analysed for the presence of anti-GSK933776 antibodies by immuno-electrochemiluminescent (ECL) screening and neutralisation assays. If sera contain anti-GSK933776 antibodies as determined by the ECL screening assay, they will be further analysed for specificity, titres of antibodies and the presence of neutralising antibodies. The immunogenicity assessment report will include the incidence and titres of anti-GSK933776 binding and neutralising antibodies.

Approximately 3mL of whole blood will be collected into serum-separator tubes. All blood samples will be maintained at ambient temperature for at least 1 hour, but no more than 4 hours. If clotting stimulator is added, samples should be held no more than 1 hour. This allows for complete clotting prior to centrifugation. Sample processing, storage and shipping procedures are provided in the SPM.

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7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND PREGNANCY

7.1. Adverse Events (AE) and Serious Adverse Events (SAEs)

The Investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

7.1.1. Time period for collecting AE and SAE information

AEs will be collected from the start of Study Treatment and until the follow-up contact. Medical occurrences that begin prior to the start of study treatment but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions CRF.

SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the Investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the study treatment or study participation, the Investigator would promptly notify GSK.

NOTE: The method of, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided inAppendix 5.

7.1.2. Method of Detecting AEs and SAEs

Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?”

7.1.3. Definition of Adverse Events

An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

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NOTE: An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the Investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.).

Events that do not meet the definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

7.1.4. Definition of Serious Adverse Events

If an event is not an AE per Section 7.1.3, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease, etc).

An SAE is any untoward medical occurrence that, at any dose:

a. Results in death

b. Is life-threatening

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NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c. Requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d. Results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect

f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

g. Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.

* Serum bilirubin fractionation should be performed if testing is available; if unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reportedas an SAE.

** INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

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7.1.5. Prompt Reporting of SAEs to GSK

Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE will be reported to GSK within 24 hours. Any follow-up information on a previously reported SAE will also be reported to GSK within 24 hours.

If the Investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the appropriate data collection tool. The Investigator will always provide an assessment of causality at the time of the initial report as described in Appendix 5.

7.1.6. Regulatory Reporting Requirements for SAEs

Prompt notification of SAEs by the Investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to regulatory authorities, IRBs/IECs and Investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to Investigators as necessary. An Investigator who receives an Investigator safety report describing an SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

7.2. Pregnancy

7.2.1. Time period for collecting pregnancy information

All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until 84 days after the last dose per protocol.

7.2.2. Action to be taken if pregnancy occurs

The Investigator will collect pregnancy information on any female subject, who becomes pregnant while participating in this study. The Investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE.

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A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the study treatment by the investigator, will be reported to GSK as described in Section 7.1.6. While the Investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

Any female subject who becomes pregnant while participating will be withdrawn from the study.

7.2.3. Action to be taken if pregnancy occurs in a female partner of a male study subject

The Investigator will attempt to collect pregnancy information on any female partner of a male study subject who becomes pregnant while participating in this study. This applies only to subjects who are randomized to receive study medication. After obtaining the necessary written informed consent from the female partner directly, the Investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

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8. DATA MANAGEMENT

GSK Data Management will identify and implement the most effective data acquisition and management strategy for each clinical trial protocol and deliver datasets, which support the protocol objectives. Subject data will be entered into GSK defined CRFs and combined with data provided from other sources (e.g. diary data, laboratory data) in a validated data system. Subject initials will not be transmitted to GSK for inclusion in the datasets. CRF’s should be completed for all subjects that receive at least one dose of study drug. CRF’s will not be completed for screen or baseline failures. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures with the objective of removing errors and inconsistencies in the data, which would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded using validated dictionaries.

9. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

This study is designed to estimate the relative bioavailability of GSK933776, given as either a single 200 mg SQ dose (Treatment Arm B), four weekly 50 mg SQ doses (Treatment Arm C) or a single 200 mg IM dose (Treatment Arm D), relative to a single 200 mg IV infusion (Treatment Arm A).

No formal hypothesis will be tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals will be constructed for the ratio of the geometric means of B:A, C:A, and D:A.

9.1. Hypotheses and Treatment Comparisons

This study is designed to estimate the bioavailability of GSK933776 administered by subcutaneous or intramuscular injection relative to GSK933776 administered intravenously. No formal hypothesis will be tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals will be constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (subcutaneous GSK933776)/( intravenous GSK933776) and (intramuscular GSK933776)/( intravenous GSK933776).

9.2. Sample Size Considerations

9.2.1. Sample Size Assumptions

The sample size for this study is based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. To assure that acceptable precision of PK parameters is expected with the sample size proposed, calculations have been performed based on variability estimates from previous studies with IV administration of GSK933776. From study BA11006006, the between-subject variability (CVb) of AUC (0-t) and Cmax of 3 mg/kg dose of GSK933776 was estimated to be between 12.7% and 16.0%. Assuming a CV of 16% and a sample size of 6 subjects per arm, the estimated precision of 90% confidence interval (i.e. half-width) is expected to be no more than 20% of the point estimate. That is for a point estimate of 0.75, the 90% confidence interval would be 0.60 to 0.94.

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9.2.2. Sample Size Sensitivity

From study BA11006006, the between-subject variability (CVb) of AUC (0-t) and Cmax of 1 mg/kg dose of GSK933776 was estimated to be between 24.5% and 38.7%. Additionally, the between-subject variability of either a SQ or IM administration may be greater than that of IV administration. The table below provides estimated precision for a range of variability from 16% to 38.7%. Assuming a CV of 38.7% and a sample size of 6 subjects per arm, the estimate precision of the 90% confidence interval is expected to be approximately 31% of the point estimates.

CVHalf-width of 90% CI

16.0% 20%

21.7% 23%

27.4% 26%

33.0% 29%

38.7% 31%

9.2.3. Sample Size Re-estimation

No sample size re-estimation is currently planned for this study. However, if during the course of the study, new information becomes available about clinically meaningful differences or variability estimates, a blinded sample size re-estimation may be conducted. Full details of the procedure used would be specified in the RAP, and any subsequent change to the target sample size would be documented in a protocol amendment.

9.3. Data Analysis Considerations

9.3.1. Interim Analysis

No interim analyses are planned

9.3.2. Final Analyses

9.3.2.1. Safety Analyses

Safety data will be presented in tabular and/or graphical format and summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

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9.3.2.2. Pharmacokinetic Analyses

Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology Modeling & Simulation department within GlaxoSmithKline. Plasma concentration-time data will be analyzed by non-compartmental methods with WinNonlin, as well as compartmental methods with NONMEM (nonlinear mixed effects modeling program). Calculations will be based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters will be determined, as data permit: maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve [AUC(0-t) and AUC(0-∞)], apparent terminal phase half-life (t1/2), systemic clearance of parent drug (CL for IV), apparent clearance (CL/F for SQ and IM), volume of distribution (V for IV) and apparent volume of distribution (V/F for SQ and IM). To estimate the extent of accumulation after repeat dosing in Arm C, the observed accumulation ratio (Ro) may be determined.

Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.

Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Discovery Biometrics GlaxoSmithKline.

Following loge-transformation, AUC (0-t) and Cmax of GSK933776 will be separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for Regimen. Point estimates and their associated 90% confidence intervals will be constructed for the differences, B – A, C – A and D - A. The point estimates and their associated 90% confidence intervals will then be back-transformed to provide point estimates and 90% confidence intervals for the ratios, B:A, C:A and D:A.

Tmax of GSK933776 will be separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B – A, C - A and D - A.

9.3.2.3. Pharmacokinetic/Pharmacodynamic Analyses

The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta will be explored as data permit. If an apparent concentration-effect relationship exists, a population PK/PD model will be attempted using nonlinear mixed effect modelling technique with NONMEM software. Data from the present study may also be combined with previous PK/PD data from studies in patients with AD (BA1106006 and BA1113043) and the ongoing study in patients with GA (BAM114341) to develop a general model of GSK933776 PK-PD following IV, SQ, and IM administration in patients and volunteers.

9.3.2.4. Pharmacodynamic/Biomarker Analyses

Primary and secondary pharmacodynamic/biomarker endpoints (including immunogenicity) will be presented in graphical and/or tabular form, summarized descriptively and listed as data permit.

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10. STUDY GOVERNANCE CONSIDERATIONS

10.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrollment of subjects begins.

10.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

The study will be conducted in accordance with all applicable regulatory requirements.

The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable subject privacy requirements, and, the guiding principles of the 2008Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each subject before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

Written informed consent must be obtained from each subject prior to participation in the study.

10.3. Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRFwill serve as the source document.

GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The Investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

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10.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the Investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

10.5. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the Investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK procedures.

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with theInvestigator or the head of the medical institution (where applicable), including the reasons for taking such action. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.

If the study is suspended or prematurely discontinued for safety reasons, GSK willpromptly inform Investigators or the head of the medical institution (where applicable) and the regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the Investigator or the head of the medical institution (where applicable) must inform the IRB/IEC promptly and provide the reason for the suspension or premature discontinuation.

10.6. Records Retention

Following closure of the study, the Investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The Investigator must assure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the Investigator must ensure there is an

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acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the Investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The Investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the Investigator leaves the site.

10.7. Provision of Study Results to Investigators, Posting of Information on Publically Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an Investigator signatory will be identified for the approval of the clinical study report. The Investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the Investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

The results summary will be posted to the Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.

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11. REFERENCES

Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. Feb 2004;78(2):243-256.

GlaxoSmithKline Document Number SC2009/00016/01. GSK933776 Investigator's Brochure (Version 03, Supplement 1). Effective Date: 23 Feb 2011.

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. Nov 2004;93(11):2645-2668

Nicoll Leslie H. Hesby, Amy. Intramuscular Injection: An Integrative Research Review and Guideline for Evidence-Based Practice. Applied Nursing Research, Vol. 16, No. 2 (August), 2002: pp 149-162.

Sperling RA. Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Brundman M, Siemers ER, Feldman HH, Schindler, RJ.. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia. 2011; 7: 367-385.

Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.

Westlind-Danielsson, A, Arnerup, G. Spontaneous in vitro formation of supramolecular beta-amyloid structures, “Betaamy balls”, by beta amyloid 1-40 peptide. Biochemistry 2001 Dec 11; 40(49): 14736-43.

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12. APPENDICES

12.1. Appendix 1: Liver Safety Process

Scenario 2 Phase II Studies

The procedures listed below are to be followed if a subject meets any of the liver chemistry stopping criteria defined in Section 5.4.1

Immediately withdraw the subject from study treatment

Notify the GSK medical monitor within 24 hours of learning of the abnormality to confirm the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms. If the event also meets the criteria of an SAE (see Section 7.1.4), the SAE data collection tool will be completed separately with the relevant details.

Upon completion of the safety follow-up withdraw the subject from the study unless further safety follow up is required.

Do not re-challenge with study treatment

Safety Follow-Up Procedures for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct); or ALT 3xULN and INR2 > 1.5 [Stopping Criteria #1]:

This event is considered an SAE (see Section 7.1.4). Serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

Make every reasonable attempt to have the subjects return to the clinic (within 24 hours) for repeat liver chemistries, additional testing and to be monitored closely (with specialist or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

Safety Follow-Up Procedures for subjects with ALT 5xULN or ALT 3xULN who have hepatitis symptoms or rash, can’t be monitored for 4 weeks or have elevations that persist 4 weeks [Stopping Criteria #2 - #5]:

Make every reasonable attempt to have the subject return to the clinic within 24-72 hrs for repeat liver chemistries and additional testing.

2 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants.

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Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.

Safety Follow-Up Procedures for subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety.

Subject can continue study treatment if liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) can be monitored weekly for up to 4 weeks.

If at any point these subjects meet the liver chemistry stopping criteria (outlined in Section 5.4.1), immediately withdraw study treatment, perform additional testing and continue safety follow-up until liver chemistries resolve, stabilize or return to baseline values.

After 4 weeks of monitoring, if ALT < 3xULN and bilirubin < 2xULN, subjects must be monitored twice monthly until liver chemistries normalize or return to within baseline values.

Additional Follow-Up Procedures for subjects who meet any of the stopping criteria:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose can not be approximated OR a PK sample can not be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) as relevant on the AE CRF

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Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins on the Concomitant Medications CRF.

Record alcohol use on the Liver Events CRF.

The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests are performed.

Refer to the diagram below for a visual presentation of the procedures listed above

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ALT≥3xULN ?

Bilirubin ≥ 2xULN

(or INR > 1.5 if measured)* ?

No

No

Yes

Yes

Continue investigational product (IP)

Instruct subject to stop IP Notify GSK within 24 hrs Obtain weekly liver chemistries until resolved, stabilized or returned

to baseline values Perform liver event follow up assessments (serology, PK sample, etc

as in protocol) Complete liver event CRF Withdraw subject from study after liver chemistry monitoring

complete + do not re-challenge with IP

Instruct subject to stop IP Notify GSK and arrange clinical followup within 24 hrs Perform liver event follow up assessments (serology, PK sample etc

as in protocol) Report as SAE (excl. hepatic impairment or cirrhosis studies);

complete SAE & liver event CRF + liver imaging and biopsy CRFs (if these tests are performed)

Obtain twice weekly liver chemistries until resolved, stabilized or returned to baseline values

Consultation with hepatologist/specialist recommended Withdraw subject from study after liver chemistry monitoring

complete + do not re-challenge with IP*INR threshold does not apply to subjects receiving anticoagulants.

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12.2. Appendix 2: Drug Preparation

Investigational Product (IP) Infusion:

o IP will be dosed at 120 mL/hour until IV bag is empty

o All intravenous rates and infusion times will be documented in the subject’s source documents for review by the GSK monitor.

o The time of dosing (start of the infusion) will be designated time “0”, and all subsequent time points will be in relation to this time point. Notation of the completion of the infusion as well as the completion of the normal sterile saline for ‘flushing’ the IV pump tubing and filter will also be documented in the subject’s source documents.

Flush IV Tubing

o At the end of the infusion (after approximately 50 minutes when the bag is empty) a new 50 (or 100) mL normal sterile saline bag will be hung to flush the IV tubing and filter of remaining IP. The IV pump will again be set to deliver this new volume of normal sterile saline solution at 120 mL/hour until 10 minutes have transpired (20 mL) to ensure all IP has been administered and the IV tubing and filter have been properly flushed.

Supplies:

IV Infusion Arm

1-empty 100 mL bag (IV bag must be constructed of PVC material as sourced by site personnel)

1-50 or 100 mL IV bag for ‘flushing’ IV pump tubing once IP administration is complete

Syringe(s) and needle(s) as necessary

Intravenous infusion pump

Filter: Low binding polyether sulfone in-line 0.2 micron filter is required. There are two requirements of a filter for use in the infusion:

o The filter pore size is 0.2 micron is required

o The filter membrane material is composed of Polyether Sulfone (PES).

The brand name and order number for the 0.2 micron filter are to be recorded and kept in the site study file for future reference

It is recommended that the site continue to use the same IV infusion pump and hence tubing as well as 0.2 micron filter throughout the study

Any changes to these materials should be noted and recorded in the site’s source documents

SC or IM Arm

Syringe and needle

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Investigational Product Preparation and Administration (IV)

Remove 4 vials of GSK933776 from the temperature monitored/controlled refrigerator

Withdraw 96 mL of normal saline from a normal saline source (IV bag) and inject into a sterile empty 100 mL PVC-constructed IV bag

Withdraw the contents 4 investigation product vials (total of 4 mL of drug) and inject into the IV bag containing 96 mL of normal saline such that the total volume to be delivered is 100 mL

Make sure contents are thoroughly mixed to ensure a uniform concentration by inverting IV bag gently a few times

Store the labeled bag in the pharmacy fridge at 2-8 C and protect from light prior to dosing. Do not freeze. Note: once diluted, the investigational product is stable for 12 hours including the time required for dosing

The total volume of fluid that will be infused over 1 hour will be 100 mL at a rate of 120 mL/hour

The time of dosing (start of the infusion) will be designated time “0”, and all subsequent time points will be in relation to this time point

Administer IP using an IV pump and an administration set fitted with a 0.2 micron filter

o In-line filter to be placed closest to the patient

o In the event of filter clogging, stop IP dosing, replace the filter and resume dosing. THE ENTIRE IP DOSE MUST BE DELIVERED THROUGH THE FILTER

Dose IP at 120 mL/hour until bag is empty

All intravenous rates and infusion times will be documented in the subject’s source documents for review by the GSK monitor

At the end of the infusion (after approximately 50 minutes when the bag is empty) a new 50 (or 100) mL normal sterile saline bag will be hung and the infusion will resume at 120 mL/hour until the IV infusion pump tubing and filter is properly ‘flushed’

Investigational Product Preparation and Administration (SC and IM)

Remove the appropriate number of vials of GSK933776 from the temperature monitored/controlled refrigerator (e.g. for 200 mg SC dose, remove 4 vials and for 50 mg SC dose, remove 1 vial from cold storage)

Withdraw the entire contents of the vial(s) into a syringe fitted with a needle suitable for either SC or IM administration

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12.3. Appendix 3: STUDY TREATMENT INFORMATION

IP dosing instructions

This procedure follows the SOP PI_WI_DP001 Revision 16 from Quintiles.

General Procedures:

Injections shall be performed by Research Nurse 1 OR 2 staff members who are properly trained in injection administration, unless otherwise directed by the protocol

Don proper PPE (gloves)

Palpate site area for tenderness and mass. Do not use areas where scarring, bruising, abrasions, or inflammation are visible

Use a protocol approved needle

Per each protocol directive, prepare back-up injections in case of injection inside a blood vessel

Clean the area of the injection with a protocol approved cleansing agent

Intramuscular Injection:

IM injections should be performed at the dorso or ventrogluteal sites. A description of the procedures follows:

Dorsogluteal- this is the classic site for IM injections. Care must be taken not to damage the major blood vessels, the greater trochanter, and the sciatic nerve. Damage to this nerve can cause partial to complete paralysis of the affected leg. To locate this site, have the subject lie on his/her abdomen or on his/her side with hip and knee flexed. Palpate the top of the iliac crest. This site should NEVER be used while the subject is standing

Ventrogluteal- this site involves the gluteus medius and the gluteus minimus muscle. To locate this site, the subject receiving the injection may lie on his abdomen, side, or supine. Place the palm of one’s hand over the greater trochanter, using the right hand for the subject’s right side and the left hand for the subject’s left side. Point the thumb toward the index finger over the anterior superior iliac crest, and pull the middle finger back along the crest toward the buttocks. The top of the crest and the index middle fingers form a triangle. The center of the triangle is the injection site

Hold the syringe between the thumb and forefinger of the dominant hand, with palm down and needle bevel up

Using the thumb and first two fingers of the nondominant hand, press the tissue down firmly around the injection site, while using caution not to contaminate the injection area. Compression of the subcutaneous tissue helps ensure the needle

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has entered muscle. Moving the tissue downward assists in dispersing the medication and to seal the needle track when the tissue returns to normal position

Add an air bolus of .2-.3cc to the medication in the syringe to ensure themedication remains in the muscle

Quickly thrust the needle into the tissue at a 90 degree angle at the site

As soon as the needle is in place, use the nondominant hand to hold the syringe barrel and slowly pull back on the plunger to determine if the needle rests inside a blood vessel. If blood is observed, pull the needle back slightly and aspirate again. Muscle tissue is vascular

If blood is not present inside the syringe, inject the medication slowly, followed by the air bubble into the needle. The air pocket will force the medication through the shaft of the needle into the muscle tissue and prevent the medication from entering the subcutaneous tissue as the needle is withdrawn

Remove the needle quickly and cap by approved method

Rub the injection site with a cotton ball. Rubbing assists with distribution and absorption of the medication

Dispose of the needle in the closest sharps container. Return the syringe and label to the Pharmacy

Subcutaneous Injection:

Subcutaneous injections involve depositing a substance in the loose connective tissue beneath the dermis. Absorption is slow, as the tissue is not richly supplied with blood. Absorption is complete if the subject has normal circulation. Common sites for injection are the upper arm, abdomen, and thigh

Using the non-dominate hand, grasp the area around the injection site and hold in a cushion fashion, keeping the skin tight

Hold the syringe between the thumb and forefinger of the dominate hand (similar to throwing a dart) with the palm up. Ensure the bevel of the needle is upward

Quickly inject the needle at an angle approximate to 45 degrees

When the needle is inside of the tissue, release the grasped tissue

Hold the lower portion of the syringe barrel with the non-dominant hand, without moving the syringe, pull back on plunger to determine if the needle is inside a blood vessel

If blood is present, remove the needle from the subject

If no blood appears, inject medication slowly

Remove needle and recap using one hand. Dispose of the needle in the nearest sharps container unless the pharmacist requires the capped syringe returned to the pharmacy. Return the label, and other required supplies, back to the pharmacy

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12.4. Appendix 4: Assessment of Injection Site Reaction Terms

Term Description

Edema Swelling, fluid retention

AbscessA tender, easily pressed mass generally surrounded by a colored area from pink to deep red

Erythema Redness

HematomaLocalized collection of blood outside the blood vessels, usually in liquid form within the tissue

Induration Hardening

Necrosis Dark purplish discoloration

Pain Tenderness, discomfort

PapuleSolid, raised spot on the skin with no visible fluid, less than 1 centimeter wide (may be plural: papules)

Pruritus Itching

PustuleSmall, inflamed, pus-filled, blister-like lesion on the skin surface (may be plural: pustules)

RashA change of the skin which affects its color, appearance or texture

Ulceration

The formation of an ulcer, a patch of tissue that is discontinuous with the surrounding tissue because the tissue within the ulcer has decayed or died and been swept away

Vesiculation Blistering, the formation of vesicles (small fluid-filled blisters)

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12.5. Appendix 5: Procedures for Detection, Evaluation, Follow-Up and Reporting of Adverse Events Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The Investigator will then record all relevant information regarding an AE/SAE in the appropriate data collection tool.

It is not acceptable for the Investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the GSK, AE/SAE data collection tool. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.

The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms.

Evaluating AEs and SAEs

Assessment of Intensity

The Investigator will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort andnot interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

An AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.

Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study treatment will be considered and investigated. The Investigator will also consult

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the Investigator Brochure (IB) and/or Product Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the Investigator has minimal information to include in the initial report to GSK. However, it is very important that the Investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK. The Investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up.

The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE. The Investigator is obligated to assist. This may include additional laboratory tests or Investigations, histopathological examinations or consultation with other health care professionals. If a subject dies during participation in the study or during a recognized follow-up period, the Investigator will provide GSK with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded in the originally completed data collection tool. The Investigator will submit any updated SAE data to GSK within the designated reporting time frames.

Reporting of SAEs to GSK

The primary mechanism for reporting SAEs to GSK will be the electronic data collection tool. If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to the GSK Medical Monitor . Then the site will enter the serious adverse event data into the electronic system as soon as it becomes available.

After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data. If a site receives a report of a new SAE from a study participant or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to their GSK protocol contact by telephone.

GSK contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical Monitor Contact Information page.

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CONFIDENTIALGlaxoSmithKline Group of Companies BA1116891

1

Division: Worldwide DevelopmentRetention Category: GRS019Information Type: Clinical Pharmacology Reporting and Analysis Plan

Title: Clinical pharmacology reporting and analysis plan for arandomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers (BA1116891)


Effective Date: 24-JUL-2014

Description: The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol BA1116891. This RAP is intended to describe the bioavailability, pharmacokinetics (PK), safety and tolerability analyses required for the study. This document will be provided to the study team members to convey the content of the Statistical Analysis Complete (SAC) deliverable.

Subject: GSK933776, Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody, healthy volunteers

Author’s Name, Title and Functional Area:

Clinical Statistics, PAREXEL

Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited

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CONFIDENTIALGlaxoSmithKline Group of Companies BA1116891

2

Approved by (approval captured by e-mail):

Technical approvers of the RAP should include at minimum (when applicable) representatives from the following function areas:

Ophthalmology

Clinical Pharmacology Modelling and Simulation

Clinical Pharmacology Science and Study Operations



Ophthalmology

Statistical Resourcing and Programming

Clinical Immunology

Clinical Programming, PAREXEL

Clinical PK/PD, PAREXEL

The Clinical Statistics Director (or designee) will give final approval

Manager, Clinical Statistics 24-Jul-2014

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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS.............................................................................................5

1. INTRODUCTION......................................................................................................8

2. STUDY OBJECTIVES AND ENDPOINTS................................................................82.1. Study Objectives and Endpoints ...................................................................8

3. STUDY DESIGN ......................................................................................................93.1. Study Design ................................................................................................9

4. PLANNED ANALYSES ..........................................................................................104.1. Interim Analyses .........................................................................................104.2. Final Analyses ............................................................................................10

5. SAMPLE SIZE CONSIDERATIONS.......................................................................105.1. Sample Size Assumptions ..........................................................................105.2. Sample Size Sensitivity...............................................................................105.3. Sample Size Re-estimation.........................................................................11

6. ANALYSIS POPULATIONS ...................................................................................116.1. Safety Population (SAF) .............................................................................116.2. Pharmacokinetic Concentration Population.................................................116.3. Pharmacokinetic Parameter Population ......................................................116.4. Pharmacodynamic Population ....................................................................116.5. PK/PD Analysis Population.........................................................................11

7. TREATMENT COMPARISONS..............................................................................127.1. Treatment and Other Subgroup Descriptors for Data Display .....................12

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...........128.1. Reporting Conventions ...............................................................................128.2. Data Management ......................................................................................138.3. Premature Withdrawal and Missing Data ....................................................138.4. Baseline Definition ......................................................................................138.5. Derived and Transformed Data...................................................................14

8.5.1. Change from Baseline .................................................................148.5.2. Pharmacokinetic Parameters.......................................................148.5.3. Multiple Measurements at One Timepoint....................................14

8.6. Values of Potential Clinical Importance.......................................................15

9. STUDY POPULATION ...........................................................................................179.1. Subject Disposition .....................................................................................179.2. Demographic and Baseline Characteristics.................................................179.3. Concomitant Medications............................................................................179.4. Treatment Compliance and Protocol Deviations .........................................17

10. SAFETY ANALYSES .............................................................................................1710.1. Extent of Exposure .....................................................................................1810.2. Adverse Events...........................................................................................18

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10.3. Deaths and Serious Adverse Events...........................................................1810.4. Adverse Events Leading to Discontinuation of Investigational

Product and/or Withdrawal from the Study and Other Significant Adverse Events...........................................................................................18

10.5. Pregnancies (as applicable)........................................................................1810.6. Clinical Laboratory Evaluations...................................................................1810.7. Other Safety Measures ...............................................................................18

11. PHARMACOKINETIC ANALYSES.........................................................................1911.1. Drug Concentration Measures ....................................................................1911.2. Deriving and Summarizing Pharmacokinetic Parameters............................2011.3. Statistical Analyses.....................................................................................21

12. PHARMACODYNAMIC/BIOMARKER ANALYSES ................................................21

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...................................21

14. REFERENCES.......................................................................................................23

15. ATTACHMENTS ....................................................................................................2415.1. Table of Contents for Data Display Specifications.......................................24

15.1.1. Study Population Tables and Listings ..........................................2515.1.2. Safety Tables and Listings...........................................................2615.1.3. Pharmacokinetic Figures, Tables and Listings .............................2915.1.4. Pharmacodynamic Figures, Tables and Listings..........................3115.1.5. Pk/PD Figures .............................................................................35

15.2. Data Display Specifications (Example Shells).............................................37

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Aβ Amyloid beta

AD Alzheimer’s disease

AE Adverse event

ALT Alanine aminotransferase (SGPT)

AMD Age-related macular degeneration

ANOVA Analysis of variance

AST Aspartate aminotransferase (SGOT)

AUC Area under concentration-time curve

AUC(0-inf) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time

AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration


BUN Blood urea nitrogen

CI Confidence Interval

CL Systemic clearance of parent drug

Cmax Maximum observed concentration

Ct Last observed quantifiable concentration

CO2 Carbon dioxide

CPK Creatine phosphokinase

CPMS Clinical Pharmacology Modelling & Simulation

CP-RAP Clinical Pharmacology Reporting and Analysis Plan

CPSR Clinical Pharmacology Study Report

CPSSO Clinical Pharmacology Science and Study Operations

CRF Case Report Form

CV Coefficient of variation

DBR Database Release

DBF Database Freeze

DMPK Drug Metabolism and Pharmacokinetics

ECG Electrocardiogram

F Absolute bioavailability of drug

GA Geographic atrophy

GCP Good Clinical Practice

GCSP Global Clinical Safety and Pharmacovigilence

GGT Gamma glutamyltransferase

GLP Good Laboratory Practice

GSK GlaxoSmithKline

HARP Harmonisation for Analysis and Reporting Program

HBsAg Hepatitis B surface antigen

HIV Human immunodeficiency virus

h/hr Hour(s)

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IB Investigator’s Brochure

ICH International Conference on Harmonisation

IDSL Integrated Data Standards Library

IEC International Ethics Committee

IM Intramuscular

INR International Normalized Ratio

IP Investigational product

IRB Institutional Review Board

IV Intravenous

Kg Kilogram


L Litre

lbs Pounds

LDH Lactate dehydrogenase

LFTs Liver function tests

LLN Lower limit of normal

mAb Monoclonal antibody

MedDRA Medical Dictionary for Regulatory Activities

mg Milligram

mL Millilitre

mmHg Millimetres of mercury

MRI Magnetic Resonance Imaging

MSDS Material Safety Data Sheet

msec Milliseconds

NA Not Available

NONMEM Nonlinear mixed effects modelling program

PCI Potential Clinical Importance

PD Pharmacodynamic

PK Pharmacokinetic

QTcB QT duration corrected for heart rate by Bazett’s formula

QTcF QT duration corrected for heart rate by Fridericia’s formula

RAP Reporting and Analysis Plan

RBC Red blood cells

SAC Statistical Analysis Complete

SAE Serious adverse event(s)

SD Standard Deviation

SDTM Study Data Tabulation Model

SGOT Serum glutamic-oxaloacetic transaminase

SGPT Serum glutamic pyruvic transaminase

SOC System Organ Class

SOP Standard Operating Procedure

SPM Study Procedures Manual

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SQ Subcutaneous

T½ Terminal phase half-life

τ Dosing interval

Tmax Time of occurrence of Cmax

ULN Upper limit of normal

WBC White blood cells



Trademarks not owned by the GlaxoSmithKline group of

companies

NONE Phoenix WinNonlinSAS

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1. INTRODUCTION

The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the Clinical Pharmacology Study Report for Protocol BA1116891:

Revision Chronology:

2012N142727_00 2013-NOV-05 Original

All decisions regarding final analysis, as defined in this RAP document, have been made prior to Database Freeze of the study data.

2. STUDY OBJECTIVES AND ENDPOINTS

2.1. Study Objectives and Endpoints


Primary


The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion

Secondary

To characterize thepharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration




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To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker


Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22

Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status)

3. STUDY DESIGN

3.1. Study Design

This is a single-center, randomized, open-label, parallel-group study in healthy volunteers to evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administrationcompared to GSK933776 following IV infusion.

Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table are essential. Upon successful completion of the Screening Period, a subject will be eligible to enroll in the study. Twenty-four subjects will be enrolled and randomized to one of 4 possible treatment arms in a 1:1:1:1 ratio. The treatment arms are described in Table 1.

Subjects will be followed for approximately 84 days after dose administration (for Treatment Arm C, this 84-day period begins after the final [fourth] dose). The total duration of subject participation from screening to follow-up for Treatment Arms A, B and D (single dose of GSK933776), will be approximately 113 days. Total duration of subject participation from screening to follow-up for Treatment Arm C (weekly SQ administration for 4 doses), will be approximately 134 days. Subjects who prematurely discontinue the study may be replaced.

Table 1 Study Treatments

Study Treatment

Treatment Description

A 200 mg GSK933776 administered by IV infusionB 200 mg GSK933776 administered by SQ injection C 50 mg GSK933776, administered by SQ injection once weekly for 4

weeks D 200 mg GSK933776 administered by IM injection

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4. PLANNED ANALYSES

4.1. Interim Analyses

There is no interim analysis.

4.2. Final Analyses

The final planned analyses will be performed after all subjects have completed the study and after database freeze. See Section 9 to Section 13 for all final planned analyses for this study.

5. SAMPLE SIZE CONSIDERATIONS

5.1. Sample Size Assumptions

The sample size for this study is based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. To assure that acceptable precision of PK parameters is expected with the sample size proposed, calculations have been performed based on variability estimates from previous studies with IV administration of GSK933776. From study BA11006006, the between-subject variability (CVb) of AUC(0-t) and Cmax of 3 mg/kg dose of GSK933776 was estimated to be between 12.7% and 16.0%. Assuming a coefficient of variation (CV) of 16% and a sample size of 6 subjects per arm, the estimated precision of 90% confidence interval (i.e. half-width) is expected to be no more than 20% of the point estimate. That is for a point estimate of 0.75, the 90% confidence interval would be 0.60 to 0.94.

5.2. Sample Size Sensitivity

From study BA11006006, the CVb of AUC(0-t) and Cmax of 1 mg/kg dose of GSK933776 was estimated to be between 24.5% and 38.7%. Additionally, the CVb of either an SQ or IM administration may be greater than that of IV administration. The table below provides estimated precision for range of variability from 16% to 38.7%. Assuming a CV of 38.7% and a sample size of 6 subjects per arm, the estimate precision of the 90% confidence interval (CI) is expected to be approximately 31% of the point estimates.

CVHalf-width of 90% CI

16.0% 20%

21.7% 23%

27.4% 26%

33.0% 29%

38.7% 31%

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5.3. Sample Size Re-estimation

If during the course of the study, new information becomes available about clinically meaningful differences or variability estimates, a blinded sample size re-estimation may be conducted. Based on the observed CV of AUC(0-t) or Cmax from the blinded data review, the sample size will be increased to allow for the corresponding half-width of 90% CI to be within the boundary set by the new clinical difference. Any subsequent change to the target sample size would be documented in a protocol amendment.

6. ANALYSIS POPULATIONS

6.1. Safety Population (SAF)

All patients enrolled in the study who receive at least one dose of study drug will be included in the Safety Population. This population will be used in the assessment of safety, and for listing and summarizing baseline/demographic and subject disposition data.

6.2. Pharmacokinetic Concentration Population

The PK Concentration Population will consist of all subjects in the Safety Population who undergo plasma PK sampling and have evaluable PK assay results. This population will be used for the concentration tables, listings, and figures.

6.3. Pharmacokinetic Parameter Population

The PK Parameter Population will consist of all subjects in the Pharmacokinetic Concentration Population for whom valid and evaluable pharmacokinetic parameters are derived. This population will be used in the assessment and characterization of PK parameters. This population will also be used for listing and statistical analysis of PK parameters.

6.4. Pharmacodynamic Population

The Pharmacodynamic (PD) Analysis Population will consist of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). This population will be used for listing, summarizing and plotting of plasma concentration-time data for biomarkers.

6.5. PK/PD Analysis Population

The PK/PD Analysis Population will consist of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776. This population will be used for explore the PK/PD relationship.

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7. TREATMENT COMPARISONS

The primary comparisons will be made to estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration.

7.1. Treatment and Other Subgroup Descriptors for Data Display

Subjects will be assigned to treatment in accordance with the randomization schedulegenerated by Clinical Statistics, prior to the start of the study, using validated internalsoftware.

Randomisation Final Data Display (i.e. HARP / other)Code Treatment Description Treatment Description Column

Header

A200 mg GSK933776 administered by IV infusion

200 mg GSK933776 administered by IV infusion

IV_200mg

B200 mg GSK933776 administered by SQ injection

200 mg GSK933776 administered by SQ injection

SQ_200mg

C50 mg GSK933776, administered by SQ injection once weekly for 4 weeks

50 mg GSK933776, administered by SQ injection once weekly for 4 weeks

SQ_50mg x 4

D200 mg GSK933776 administered by IM injection

200 mg GSK933776 administered by IM injection

IM_200mg

8. GENERAL CONSIDERATIONS FOR DATA ANALYSESAND HANDLING

8.1. Reporting Conventions

All data will be reported according to the actual regimen the subject received.

Actual sampling times will be used in the derivation of PK parameters and in plotting individual concentration-time profiles. Planned sampling times will be used in the summary tables and in plotting mean/median concentration-time profiles. Concentration-time data will be listed according to actual sampling times relative to dosing time.

Data from unscheduled visits (except PK data) and Screening visits will be excluded from summary tables, summary plots and statistical analyses, unless otherwise stated. However, these data will be included in the appropriate listings.

No formal assessment windows will be defined.

Analyses will be performed using the SAS/STAT module of the SAS system, version 9.1.3 or higher (SAS and SAS/STAT are registered trademarks of the SAS Institute Inc., Cary, NC, USA). Programs will be imported into HARP (Harmonisation for Analysis and Reporting Program) and the final output will be produced by running drivers in HARP.

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Any deviations from the analyses described in this RAP will be stated with justification in Section 8.2.4 of the final clinical pharmacology study report (CPSR).

8.2. Data Management

Data Type Source Format of Data Planned Date of Final File1

Responsibility

Safety Database SDTM DBF CPDS

PK ConcSMS2000 data files

dat file DBF DMPK

ADPC (Winonlin file)

SDTM PC3 CSV file DBF + 2 Days2 DB (Prog)

PK PAR PK HARP CSV file ADPC + 5 days2 CPMS

PD CSV file CSV file DBFClinical Immunology

LAB External SAS DBR CPSSO

1. This is for study teams to determine upfront if there is a possibility of not meeting the completion of the CPSR within 6 months of LSLV (i.e. novel data that may not be available until several months after LSLV).

2. Provided source data is clean.3. PK concentration data is released via SMS2000 by DMPK and the SDTM PC dataset

contains date/times and PK sample ID.

8.3. Premature Withdrawal and Missing Data

All subjects who withdraw prematurely from the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Pharmacology Study Report (CPSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 6.

In the event that the study is prematurely discontinued, all available data will be listed and a review carried out by the study team to assess which statistical analyses are still considered appropriate.

8.4. Baseline Definition

Baseline assessment is the last available scheduled assessment prior to time of the first dose unless it is specified otherwise. If there are multiple assessments for a given measurement collected on the same scheduled time, the average of these assessments will be used.

The following table indicates the baseline day to be used in the study:

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Parameter Baseline Days Collected Baseline To Be Used in Analysis / SummariesScreen Pre-Dose

Day 1Safety :Laboratory X X Pre-Dose Day 1Vital Signs X X Pre-Dose Day 1ECG X Screen

If the pre-dose at day 1 assessment is not available, then assessment at screening will beused for the baseline value.

8.5. Derived and Transformed Data

8.5.1. Change from Baseline

The change from baseline will be calculated by subtracting the baseline values from the individual post-randomisation values. If either the baseline or post-randomisation value is missing, the change from baseline is set to missing as well.

Change from baseline in PD/biomarker data will be calculated by dividing the baseline values from the individual post-dose values.

8.5.2. Pharmacokinetic Parameters

For the purposes of calculating summary statistics and for statistical analysis, all PK parameters except for Tmax and T1/2 will be loge transformed.

Between subject coefficient of variation CVb(%) will be calculated according to the following methods:

Untransformed Data: 100 * (SD/Mean)

Transformed Data: 100 * (sqrt(exp(SDlog2)-1))

where SDlog is the standard deviation of the loge-transformed data.

8.5.3. Multiple Measurements at One Timepoint

Where multiple measurements are recorded for a particular assessment at the same time point, the mean of the measurements will be calculated and used in any derivation of summary statistics. However all available data will be listed.

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8.6. Values of Potential Clinical Importance

Laboratory Values of Potential Clinical Importance (Healthy Volunteers)

Hematology Analyte Effect Relative – Low

(Multipliers of LLN)

Relative – High

(Multipliers of ULN)

White Blood Cell Count 0.67 1.82

Neutrophil Count 0.83

HemoglobinMale 0.90 1.03

Female 0.90 1.13

HematocritMale 0.90 1.02

Female 0.90 1.17

Platelet Count 0.67 1.57

Lymphocytes 0.81

Chemistry Analyte Effect Relative – Low

(Multipliers of LLN)

Relative – High

(Multipliers of ULN)

Serum Creatinine mg/dL NA 1.15

Creatinine clearance–ml/min

0.8 NA

Albumin (mmol/L) 0.86

Blood Urea Nitrogen (mg/dL) (BUN)** (UREA)

NA1.13 men

1.29 women

Calcium (mmol/L) 0.91 1.06

Glucose (mmol/L) 0.71 1.41

Potassium (mmol/L) 0.86 1.10

Sodium (mmol/L) 0.96 1.03

Total CO2 (mmol/L) 0.86 1.14

Note: The relative-low and relative-high values would be used as multiples of each site’s ULN or LLN in order to obtain the PCI for that laboratory.

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Liver Function Test (Healthy Volunteers)

Liver Function Test Analyte

EffectPotential Clinical Importance (PCI) Range

Unit

ALT/SGPT High ≥ 2x ULN U/LAST/SGOT High ≥ 2x ULN U/LAlkPhos High ≥ 2x ULN U/LT. Bilirubin High ≥ 1.5x ULN mol/L

T. Bilirubin + ALT High≥ 1.5x ULN T.Billirubin

+≥ 2x ULN ALT

mol/L

U/L

ECG Values of Potential Clinical Importance (Healthy Volunteers)

ECG Parameter Potential Clinical Importance (PCI) Range Unit

Absolute QTc Interval >450 Msec

Increase from Baseline QTc >60 Msec

PR Interval <110 and >220 Msec

QRS Interval <75 and >110 Msec

Also QTc interval will be categorized as follows:

ECG Parameter Potential Clinical Importance (PCI) Range Unit

Absolute QTc Interval >450 to ≤480 msec

Absolute QTc Interval >480 to ≤500 msec

Absolute QTc Interval >500 msec

Increase from Baseline QTc ≤30 msec

Increase from Baseline QTc >30 to ≤60 msec

Increase from Baseline QTc >60 msec

Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)

VS Parameter Potential Clinical Importance (PCI) Range Unit

Systolic Blood Pressure <85 and >160 mmHg

Diastolic Blood Pressure <45 and >100 mmHg

Heart Rate <40 and >110 bpm

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9. STUDY POPULATION

Study population data will be summarised by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.

The tables will use the Safety population unless otherwise specified.

9.1. Subject Disposition

A summary table will be generated to provide the count of subjects included in eachanalysis population for the study and this table will be displayed by treatment and overall.

The end of study record will be listed and summarized by treatment. The listing will include whether subjects prematurely withdrew from the study, the reason for premature discontinuation, along with the date of study drug dosing and the date of completion or premature discontinuation from the study.

9.2. Demographic and Baseline Characteristics

Demographic data include year of birth, age, gender, race, ethnicity, height, weight and body mass index (BMI). Demographic data will be summarized and listed for the safety population. Race will be summarized and listed separately from the other demographic characteristics.

9.3. Concomitant Medications

Concomitant medication verbatim text will be coded and classified by generic code and preferred term using a standardized GSK coding system: GSK DRUG. Concomitant medications will be listed by treatment and subject. It will also be summarized by treatment if sufficient data exist to warrant a summary.

9.4. Treatment Compliance and Protocol Deviations

Information on each subject who did not receive the correct treatment during each treatment period, the reason for not receiving the correct treatment, and any other protocol deviations will be listed by treatment and subject. Subjects who did not satisfy all inclusion and exclusion criteria and corresponding criteria that were violated will be listed.

10. SAFETY ANALYSES

Safety data will be summarised and listed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.

No formal statistical analysis of safety data will be conducted.

The tables will use the “Safety” population unless otherwise specified.

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10.1. Extent of Exposure

A by-subject listing of data on subject exposure will be generated including dose date and time, unit and route.

10.2. Adverse Events

Adverse event verbatim text will be coded and classified by system organ class (SOC) and preferred term using a standardized GSK coding system: MedDRA. The relationship of AE system organ class, preferred term, and verbatim text will be listed. All AEs will be listed by treatment and subject, and summarized by treatment.

10.3. Deaths and Serious Adverse Events

Deaths and other serious adverse events will be listed if any of these events occur.

10.4. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events

Adverse events leading to discontinuation of investigational product (IP) and/or withdrawal from the study will be listed by treatment and subject. A summary by treatment will also be provided if there are sufficient data. A listing of all AEs for subjects who withdrew from the study due to AEs will be provided.

10.5. Pregnancies (as applicable)

If any female subjects became pregnant during the study, a listing of such subjects will be provided.

10.6. Clinical Laboratory Evaluations

A listing of reference ranges for clinical laboratory tests performed during the study will be generated. Hematology, urinalysis and clinical chemistry data will be listed by treatment, subject, visit, and actual date and time. The data will also be summarized by treatment and visit. If any laboratory test results are outside of the reference range, they will be flagged with high/low and/or toxicity grade in the listing.

A listing of hematology and clinical chemistry data for subjects with abnormalities of potential clinical importance will be provided.

Incidence of liver event will be summarized by treatment. Liver biopsy details and liver imaging details will also be summarized by treatment if data is available. The corresponding listing will also be provided.

10.7. Other Safety Measures

Vital sign data (BP, PR and Temperature) will be summarized by treatment, visit, and planned time and listed by treatment, subject, visit, planned time, and actual time. In

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addition, a listing of vital signs for subjects with abnormalities of potential clinical importance will be provided.

ECG values will be summarized by treatment, visit, and planned time and listed by treatment, subject, visit, planned time, and actual time. Safety ECG findings will be listed and summarized. In addition, summaries of category of safety QTc data and category of change from baseline QTc data will be generated. Clinically significant ECG abnormalities will be listed by treatment, subject, visit, planned time, and actual date and time.

11. PHARMACOKINETIC ANALYSES

The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences (CPDS), GlaxoSmithKline.

The merge of PK concentration data, randomisation and CRF data will be performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.

Derivation of pharmacokinetic parameters will be performed by, or under the direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline.

Statistical analysis of PK parameters will be performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.

The tables will use the PK concentration or parameter population unless otherwise specified.

11.1. Drug Concentration Measures

Plasma GSK933776 concentrations will be listed by treatment, subject, visit, and actual plasma sampling time and summarised by treatment, visit, and nominal time. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, geometric mean, CV%, minimum and maximum). Refer to the standard operating procedure, SOP-CPK-0001, for information regarding the treatment of plasma concentrations below the assay’s lower limit of quantification (BQL).

Individual subject plasma GSK933776 concentration-time profiles will be plotted for all subjects in the PK Concentration Population, and median/mean profiles for plasma GSK933776, with profiles from each treatment superimposed, will be plotted for all of the subjects in the PK Concentration Population. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). Plots for individual and group median/mean plasma GSK933776 concentration-time profiles with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the absorption profile.

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11.2. Deriving and Summarizing Pharmacokinetic Parameters

The following PK parameters will be determined from the plasma concentration-time data for GSK933776: AUC(0-), AUC(0-t) if AUC(0-) is not reportable, AUC(0-672hrs) (for Treatment Arms A and C only), AUC(0-168hrs) (for Treatment Arms A and C only), Cmax, Tmax, T1/2, CL/F, V/F (F=1 for Treatment Arm A).

Additional PK parameters may be calculated. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.

The pharmacokinetic parameters will be calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin 6.3 orhigher, and according to the standard operating procedures described in the document “Non-Compartmental Analysis of Pharmacokinetic Data” (GUI-CPK-3001). Actual elapsed time from dosing will be used in the derivation of all PK parameters. The derivation of PK parameters will be performed by, or under the auspices of CPMS.

1. The first occurrence of the maximum observed plasma concentration (Cmax) will be determined directly from the raw concentration-time data.

2. The time at which Cmax is observed (Tmax) will be determined directly from the raw concentration-time data.

3. The apparent terminal elimination half-life (T1/2) obtained as the ratio of ln2/z, where z is the terminal phase elimination rate constant estimated by linear regression analysis of the log transformed concentration-time data.

4. The area under the plasma concentration-time curve to the last quantifiable concentration (AUC(0-t)) will be determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

5. The AUC extrapolated to infinity (AUC(0-)) will be calculated, where data permit, as the sum of AUC(0-t) and Ct/λz, where Ct is the last post-dose quantifiable plasma concentration.

6. The percentage of the AUC(0-) that is extrapolated (%AUCex) will be calculated as the ratio of [AUC(0-) minus AUC(0-t)] to AUC(0-).

7. The apparent clearance (CL/F) will be calculated as CL/F = Dose/AUC

8. The volume of distribution (V/F): V/F = CL/F / λz

9. In the event that AUC(0-) cannot be derived, AUC(0-t) will be the primary end point.

All the derived parameters described above will be listed. For each of these parameters, except Tmax and T1/2, the following summary statistics will be calculated for each treatment group: n, arithmetic mean with associated 95% CI, standard deviation, median, minimum, maximum, geometric mean with associated 95% CI, standard deviation of logarithmically transformed data, and CVb(%). For Tmax and T1/2, median, maximum, minimum, arithmetic mean and standard deviation will be calculated.

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11.3. Statistical Analyses

Following loge-transformation, the PK parameters AUC(0-∞), AUC(0-t), AUC(0-672hrs) (Treatment Arms A and C only), AUC(0-168hrs) (Treatment Arms A and C only), Cmax, CL/F and V/F of GSK933776 will be separately analyzed using an analysis of variance (ANOVA) model with fixed effect terms for treatment. Point estimates and their associated 90% confidence intervals (CIs) will be constructed for the differences, B - A, C - A and D - A. For the comparison of C - A the parameter AUC(0-168hrs) will be dose normalized. The point estimates and their associated 90% CIs will then be back-transformed to provide point estimates and 90% CIs for the ratios test/reference on the original scale.

Tmax and T1/2 of GSK933776 will be separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B - A, C - A and D - A.

Additional subgroup analyses may also be conducted.

12. PHARMACODYNAMIC/BIOMARKER ANALYSES

PD/biomarker endpoints includes plasma total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22. PD/biomarker concentrations will be listed by treatment, subject, visit, and actual plasma sampling timeand summarised by treatment, visit, and nominal time. PD/biomarker concentration changes from baseline will also be summarized. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, minimum and maximum).

Individual subject plasma concentration-time profiles will be plotted by analyte for all subjects in the PD Population, and median/mean profiles and median/mean changes from baseline profiles by analyte, with profiles from each treatment superimposed, will be plotted for all of the subjects in the PD Population. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). Plots for individual and group median/mean, and median/mean changes from baseline plasma GSK933776 concentration-time profiles with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the absorption profile.

Immunogenicity endpoint includes the measurement of antibodies to GSK933776 in serum samples. Immunogenicity data will be summarized and a by-subject listing will also be provided.

The tables will use the PD population unless otherwise specified.

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES

The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta (Aβ) will be explored as data permit. Exploratory plots of GSK933776 concentration-time profiles overlaid with PD/biomarker concentration-time profiles or PD/biomarker concentration change from baseline-time profiles will be

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produced where it is possible to examine the PK/PD relationship. Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the profile.

If an apparent concentration-effect relationship exists, a population PK/PD model will be attempted using nonlinear mixed effect modelling technique with NONMEM software. Data from the present study may also be combined with previous PK/PD data from studies in patients with AD (BA1106006 and BA1113043) and the ongoing study in patients with GA (BAM114341) to develop a general model of GSK933776 PK-PD following IV, SQ, and IM administration in patients and volunteers.

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14. REFERENCES

Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. Feb 2004;78(2):243-256.

GlaxoSmithKline Document Number SC2009/00016/01. GSK933776 Investigator's Brochure (Version 03, Supplement 1). Effective Date: 23-FEB-2011

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. Nov 2004;93(11):2645-2668

Sperling RA. Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Brundman M, Siemers ER, Feldman HH, Schindler, RJ.. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia. 2011; 7: 367-385

Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.

Westlind-Danielsson, A, Arnerup, G. Spontaneous in vitro formation of supramolecular beta-amyloid structures, “Betaamy balls”, by beta amyloid 1-40 peptide. Biochemistry 2001 Dec 11; 40(49): 14736-43

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15. ATTACHMENTS

15.1. Table of Contents for Data Display Specifications

For the Clinical Pharmacology Study Report the following section numbering will apply:

Section 9: Study Population

Section 10: Safety

Section 11: Pharmacokinetic

Section 12: Pharmacodynamic/Biomarker

Section 13: Pharmacokinetic/Pharmacodynamic

Listed below are the planned figures, tables and listings to be produced for inclusion in the BA1116891 clinical study report:

The ‘IDSL No. / Example Shell”’ column refers to the relevant example in the Integrated Data Standards Library (IDSL) database

Unless otherwise indicated, these refer to the core IDSL data standards located under: o ‘Data Standards’ ‘By Component’ in the IDSL database

‘CP’ refers to the Clinical Pharmacology (CP) modified core IDSL standards located under:

o ‘Supporting Documentation’ ’TST Use of IDSL Core Choices’ ‘Clin Pharm’ in the IDSL database

‘PD’ refer to the Clinical Pharmacology data standards located under ‘Data Standards’ ‘By Therapeutic Component’ ‘Clin Pharm’ in the IDSL database.

If there is no data for the table/listing, ‘No data to report’ will be presented

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15.1.1. Study Population Tables and Listings

Tables

Table No.

Population IDSL No. / Example Shell

Title Additional Programming Notes Responsibility Deliverable Priority

9.1 Safety

POP1or

ING114556, Table 9.1

Summary of Study Population

By treatment and combined overall.Subjects are included in the Safety Population if they have taken at least one dose of study medication.Subjects are included in the PKConcentration Population if they have evaluable GSK933776 concentration.Subjects are included in the PK Parameter Population if they have evaluable GSK933776 PK parameter.Subjects are included in the PD Population if they have evaluable biomarker concentration.Subjects are included in the PK/PD AnalysisPopulation if they have evaluable GSK933776 concentration and evaluable biomarker concentration.

Programming SAC

9.2 Safety ES1 Summary of Subject Disposition Programming SAC9.3 Safety DV1A Summary of Protocol Deviations Programming SAC

9.4 Safety DM1Summary of Demographic Characteristics

By treatment and combined overall.Remove the age group segment.

Programming SAC

9.5Safety

DM6Summary of Race and Racial Combination Details

By treatment and combined overallBe the GSK race.

Programming SAC

9.6 Safety CP_CM1 Summary of Concomitant Medications Summarize by treatment Programming SAC

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Listings

ListingNo.


Title Programming Notes Responsibility Deliverable Priority

9.1 Safety CP_TA1Listing of Randomized and Actual Treatments

List by treatment, no Centre ID, no Cohort. Programming SAC

9.2 Safety See Mockups Listing of Subjects excluded from Analysis Populations

Programming SAC

9.3Safety

CP_ES10Listing of Reasons for Study Withdrawal/Completion

List by treatment.Programming SAC

9.4 Safety IE3 Listing of Protocol Deviations List by treatment. Programming SAC9.5 Safety DM2 Listing of Demographic Characteristics List by treatment. Programming SAC9.6 Safety DM9 Listing of Race List by treatment. Programming SAC

9.7Safety

CP-CM3Listing of Concomitant Medications (Including Some Optional Items)


15.1.2. Safety Tables and Listings

Tables

Table No.



10.1

Safety

CP_AE1p Summary of All Adverse Events

Summarize by treatment.If a subject has multiple occurrences of an AE, the subject is presented only once in the respective subject count.Table presents number and percentage of subjects (n (%)) and number of events (E). N = Total number of subjects in dose group.Percentages are based on the number of subjects in the respective dose group.

Programming SAC

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Table No.



10.2

Safety

CP_AE1pSummary of Adverse Events Related to Study Treatment

Summarize by treatment.If a subject has multiple occurrences of an AE, the subject is presented only once in the respective subject count.Table presents number and percentage of subjects (n (%)) and number of events (E). N = Total number of subjects in dose group.Percentages are based on the number of subjects in the respective dose group.

Programming SAC

10.3 Safety LB1 Clinical Laboratory Summary by Visit Summarize by treatment. Programming SAC

10.4Safety

LB2Summary of Abnormal Laboratory Results

Summarize by treatment.Programming SAC

10.5 Safety UR3 Summary of Urinalysis Data Programming SAC10.6 Safety VS1 Summary of Vital Signs Summarize by treatment. Programming SAC

10.7Safety

VS1Summary of Vital Signs Changes from Baseline


10.8 Safety EG1 Summary of ECG Findings Summarize by treatment. Programming SAC10.9 Safety EG2 Summary of ECG Values Summarize by treatment. Programming SAC

10.10Safety ING113096,

Table 10.17Summary of Category of QTc Data by Treatment and Time

Check the original program codes of t_qtcchg_cat.sas, population definition

Programming SAC

10.11Safety ING113096,

Table 10.18Summary of Category of QTc Change from Baseline by Treatment and Time

Programming SAC

10.12Safety

OLIVER2 or See Mockups

Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event


10.13Safety

See MockupsSummary of Time on Treatment Before Liver Event


10.14 Safety See Mockups Summary of Liver Biopsy Details Summarize by treatment Programming SAC10.15 Safety See Mockups Summary of Liver Imaging Details Summarize by treatment Programming SAC

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Listings

Listing No.



10.1 SafetyEX3, ING114556

10.1Listing of Exposure to Component Listed by treatment

Programming SAC

10.2Safety

AE2Listing of Relationship Between System Organ Class and Verbatim Text

Programming SAC

10.3Safety

CP_AE8 Listing of All Adverse EventsList by treatment, no Centre ID, no Investigator, no Onset Cycle/Cycle day.

Programming SAC

10.4Safety

CP_AE8a Listing of Serious Adverse EventsList by treatment, no Centre ID, no Investigator, no Onset Cycle/Cycle day.

Programming SAC

10.5Safety

CP_AE8Listing of Adverse Events Leading to Withdrawal from the Study

Programming SAC

10.6 Safety See Mockups Listing of Pregnancy Programming SAC

10.7Safety

LB13Listing of Laboratory Tests and Associated Reference Ranges

PCI: Potential Clinical ImportanceProgramming SAC

10.8 Safety LB5 Listing of All Laboratory Data List by treatment. Programming SAC

10.9Safety

CP_LB5Listing of Laboratory Data for Subjects with Lab Values Outside of Normal Range


10.10Safety

CP_LB5Listing of Laboratory Data for Subjects with Lab Values of Potential Clinical Importance


10.11 Safety CP_EG5 Listing of Abnormal ECG Findings List by treatment. Programming SAC

10.12Safety

CP_EG3Listing of All ECG Values for Subjects with any Value of Potential Clinical Importance


10.13 Safety VS4 Listing of Vital Signs List by treatment. Programming SAC

10.14Safety

VS5Listing of Vital Signs with Values of Potential Clinical Importance

Programming SAC

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15.1.3. Pharmacokinetic Figures, Tables and Listings

Figures

Figure No.



11.1PK

ConcentrationPK17, pkcf2

Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Programming SAC

11.2PK

ConcentrationPK17, pkcf2

Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.

Programming SAC

11.3PK

Concentration PK18, pkcf3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Programming SAC

11.4PK

Concentration PK18, pkcf3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)


Programming SAC

11.5PK

Concentration PK16a, pkcf1pIndividual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)

Treatment is showing in the figuresubtitle.

Programming SAC

11.6

PK Concentration

PK16a, pkcf1pIndividual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.Treatment is showing in the figure subtitle.

Programming SAC

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Tables

Table No.



11.1PK

ConcentrationPK01,pkct1

Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]

Summarize by treatment.Include geometric mean and CV% between Median and Min.Please follow the PK summary standard, if number of imputed>1/3 of n, then SD will be missing. If mean, median, min and max is below NQ value, they will show as ‘NQ’ instead of calculated numeric statistics.

Programming SAC

11.2PK

ParameterPK06, pkpt4

Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters

Tmax and T1/2 will not have geometric mean and 95% CI, SD(log) and %CVb.Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.

Programming SAC

11.3PK

ParameterSee Mockups

Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters

Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.

Programming SAC

11.4 PK Parameter See MockupsMedian Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters

Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.

Programming SAC

Listings

ListingNo.



11.1PK

ConcentrationPK07, pkcl1p

Listing of Plasma GSK933776 Pharmacokinetic Concentration-Time Data


11.2 PK Parameter PK13, pkpl1pListing of Derived Plasma GSK933776 Pharmacokinetic Parameters

List by treatment.NC = Not calculableND = Not determined

Programming SAC

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15.1.4. Pharmacodynamic Figures, Tables and Listings

Figures

Figure No.



12.1 PD PK17, pkcf2Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)

Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.

Programming SAC

12.2 PD PK17, pkcf2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)

Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.

Programming SAC

12.3 PD PK17, pkcf2Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.

Programming SAC

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Figure No.



12.4 PD PK17, pkcf2 Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.

12.2 PD

12.5 PD PK18, pkcf3Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)


Programming SAC

12.6 PD PK18, pkcf3 Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)


12.3 PD

12.7 PD PK18, pkcf3Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.

Programming SAC

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Figure No.



12.8 PD PK18, pkcf3 Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.

12.4 PD

12.9 PD PK16a, pkcf1pIndividual Plasma PD Concentration-Time Plot (Linear and Semi-Log)

Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Treatment is showing in the figure subtitle.

Programming SAC

12.10 PD PK16a, pkcf1pIndividual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)

Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Treatment is showing in the figure subtitle.

Programming SAC

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Tables

Table No.



12.1 PD PD1Summary of Plasma PD Concentration-Time Data [ng/mL]

Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints as well as Immunogenicity endpoints. PD endpoints as well as Immunogenicity endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Immunogenicity endpoints: refer to the data.

Programming SAC

12.2 PD PD2Summary of Log Transformed Plasma PD Concentration-Time Data [ng/mL]

Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints as well as Immunogenicity endpoints. PD endpoints as well as Immunogenicity endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Immunogenicity endpoints: refer to the data.

Programming SAC

12.3 PD PD3 Summary of Plasma PD Concentration Change from Baseline-Time Data

Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints. PD endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.

Programming PD

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Listings

ListingNo.



12.1 PD PD10Listing of Plasma PD Concentration-Time Data

List by treatment.Present all PD endpointsPD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.

Programming SAC

12.2 PD PD10Listing of Immunogenicity Concentration-Time Data

List by treatment. NQ= Not QuantifiablePresent all immunogenicity endpoints.

Programming SAC

15.1.5. Pk/PD Figures

Figure No.



13.1 PK/PD See MockupsMean Plasma GSK933776 Concentration and Mean PD endpoint versus Nominal Time by Treatment


Programming SAC

13.2 PK/PD See Mockups 13.1

Mean Plasma GSK933776 Concentration and Mean PD Endpoint Change from Baseline versus Nominal Time by Treatment


13.1 PK/PD

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Figure No.



13.3 PK/PD See Mockups

Mean Plasma GSK933776 Concentration and Mean PD Endpoint versus Nominal Time by Treatment (Truncated)

Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.

Programming SAC

13.4 PK/PD See Mockups13.3

Mean Plasma GSK933776 Concentration and Mean PD Endpoint Change from Baseline versus Nominal Time by Treatment (Truncated)

Repeat this figure for all PD endpoints. PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.Note: PD endpoint change from baseline is calculated by dividing the baseline value from the individual post-dose value.

13.2 PK/PD

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15.2. Data Display Specifications (Example Shells)

Protocol: BA1116891 Page x of yPopulation: Safety

Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event

Treatment A(N=100)

Treatment A(N=100)

Treatment C(N=100)

Treatment D(N=100)

Subjects with liver signal and/or event 33 (33%) 28 (28%) 28 (28%) 28 (28%)Subject with liver event 15 (15%) 12 (12%) 12 (12%) 12 (12%)

Subjects with liver signal/event occurring while receiving study treatment

12 (12%) 10 (10%) 10 (10%) 10 (10%)

Subject with liver signal/event occurring after stopping study treatment

3 (3%) 2 (2%) 2 (2%) 2 (2%)

Total number of Liver events 20 18 18 18

Worst Criteria typeLiver event stopping criteria 10 (10%) 5 (5%) 5 (5%) 5 (5%)Liver event interruption criteria 5 (5%) 7 (7%) 7 (7%) 7 (7%)Liver monitoring criteria 18 (18%) 16 (16%) 16 (16%) 16 (16%)

Criteria involved in liver event [1]ALT (alanine aminotransferase) 15 (15%) 12 (12%) 12 (12%) 12 (12%)Total Bilirubin 14 (14%) 10 (10%) 10 (10%) 10 (10%)INR 4 (4%) 3 (3%) 3 (3%) 3 (3%)Signs and symptoms 7 (7%) 6 (6%) 6 (6%) 6 (6%)

USER ID:/PROGRAM PATH/PROGRAM DATE TIME

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Table 10.13 Summary of Time on Treatment Before Liver Event

TRT A TRT B TRT C (N=106) (N=113) (N=104) -------------------------------------------------------------------------------------------------- Subjects reporting at least one liver event 2 (2%) 0 0 Subject with events occurring while receiving study treatment 2 (2%) 0 0 Subject with events occurring after stopping study treatment 0 0 0 Days from first dose to start of event n 1 0 0 Mean 1.0 SD Median 1.0 Min. 1 Max. 1 Days from last dose to start of event # n 1 0 0 Mean 1.0 SD Median 1.0 Min. 1 Max. 1

[#] For events which occur during treatment, time from treatment to event is set to one day

USER ID: /directory/program.sas 31JAN2008 05:38

Note: This is only a mock-up.

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Table 10.14 Summary of Liver Biopsy Details

TRT A TRT B TRT C (N=106) (N=113) (N=104) --------------------------------------------------------------------------------------------------------- Subjects undergoing Liver Biopsy 1 (<1%) 0 0 Biopsy size n 1 0 0 Mean 19.0 SD Median 19.0 Min. 19 Max. 19 Final diagnosis n 1 0 0 Normal 0 0 0 Alcoholic hepatic 1 (<1%) 0 0 Cirrhosis 1 (<1%) 0 0 Primary biliary cirrhosis 1 (<1%) 0 0 Liver architecture n 1 0 0 Normal 0 0 0 Interface hepatitis (periportal hepatitis 1 (<1%) 0 0 or piecemeal necrosis) Cirrhosis 1 (<1%) 0 0 Description of liver cells/hepatocytes n 1 0 0 Normal 1 (<1%) 0 0 Liver cell/hepatocyte inclusion/vacuole n 1 0 0 No inclusions 1 (<1%) 0 0 USER ID: directory/program.sas 30JAN2008 04:56Note: This is only a mock-up.

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Table 10.15 Summary of Liver Imaging Details

TRT A TRT B TRT C (N=106) (N=113) (N=104) --------------------------------------------------------------------------------------------------------- Subjects undergoing liver imaging test 2 (2%) 1 (<1%) 0 Liver imaging method Ultrasound - transabdominal 2 (2%) 0 0 Ultrasound - endoscopic 0 0 0 Other specify 0 1 (<1%) 0 Are images technically adequate

Optimal 2 (2%) 0 0 Readable, but not optimal 0 0 0 Not readable 0 1 (<1%) 0 Other specify 0 0 0 Liver size Normal size 2 (2%) 0 0 Hypertrophy (or enlarged) 0 0 0 Atrophy (or smaller than normal) 0 0 0 Segmental hypertrophy 0 0 0 Other specify 0 0 0 Liver texture Normal 2 (2%) 0 0 Heterogeneous 0 0 0 Suggestive of fibrosis 0 0 0 Nodular or suggestive of cirrhosis 0 0 0 Other specify 0 0 0

USER ID: directory/program.sas 31JAN2008 04:23


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Protocol: BA1116891 Page x of yPopulation: PK Parameter

Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters

Parameter Comparison Geometric LSMean Ratio 90% ConfidenceTest vs Reference (Test/Ref) Interval for Ratio

n Test n RefAUC(0-inf)(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx) [Reference treatment A]AUC(0-t)(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx) [Reference treatment A]Cmax(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx)

[Reference treatment A]



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Protocol: BA1116891 Page x of yPopulation: PK Parameter

Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters

Parameter Comparison Median Difference 90% ConfidenceTest vs Reference (Test-Ref) Interval for Difference

n Test n RefTmax [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx)

[Reference treatment A]


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Protocol: BA1116891 Page x of yPopulation: PK/PD

Figure 13.1 Mean Plasma GSK933776 concentration and Mean PD endpoint versus Nominal Time by Treatment

Repeat this figure for all PD endpoints.

PD endpoints are spelled out in the figure title.

PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.


Note: This is only a mock-up

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Protocol: BA1116891 Page x of yPopulation: PK/PD

Figure 13.3 Mean Plasma GSK933776 concentration and Mean PD endpoint versus Nominal Time by Treatment (Truncated)

Repeat this figure for all PD endpoints.

PD endpoints are spelled out in the figure title.

PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.




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CRF REPORT

GlaxoSmithKline Research & Development Limited

BA1116891

P4950-1

Site Number:

Screening Number:

Subject Number:

Principal Investigator: Dr. Leese

Sponsor: GlaxoSmithKline Research & Development Limited

COPYRIGHT AND PROPERTY OF QUINTILES TRANSNATIONAL CORP.The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or reproduction is strictly prohibited.

3/18/2014 9:23:32 AM Page 1 of 17Version 1.0.0

1


DEMOGRAPHICSSample ID: Date/Time: Period:

Date of Birth (YYYY):

Gender:

Ethnicity:

Race:

Child bearing Potential

Comment:

SUBJECT ASSIGNMENT (ASSIGN ENROLMENT NUMBER)Sample ID: Period:The subject is only eligible for randomization if he/she fulfills all of the Inclusion and none of the Exclusion Criteria.Assigned Number Date of Randomization Comments

SUBJECT ASSIGNMENT (ASSIGN SUBJECT NUMBER)Sample ID: Period:

The subject is only eligible for randomization if he/she fulfills all of the Inclusion and none of the Exclusion Criteria.Assigned Number Date of Randomization Comments



Screening NumberProtocolBA1116891

Subject Number

2


INFORMED CONSENTSample ID: Period:

Did the subject agree to the consent form?

Indicate the date which the informed consent was signed by the subject.

Indicate the time which the informed consent was signed by the subject.

Informed Consent Version Date:

Comment:

SCREENING ELIGIBILITYSample ID: Period:Did the subject meet all of the inclusion criteria and none of the exclusion criteria?

Actual Date/Time of Eligibility

Comment:

INCLUSION/EXCLUSION (ADMISSION ELIGIBILITY)Sample ID: Period:

Does the subject still meet all of the inclusion criteria and none of the exclusion criteria?

Actual Date/Time of Eligibility

If subject did not comply with all inclusion/exclusion criteria, please list the criteria not met.Inclusion Criteria Not Met:

Exclusion Criteria Not Met:Comment:

PHYSICAL EXAMINATION (COMPLETE) (NOT TO BE SENT TO GSK)

Sample ID Period Actual Date/Time of Examination Comments




Subject Number

3


PHYSICAL EXAMINATION (BRIEF) (NOT TO BE SENT TO GSK)Sample ID Period Actual Date/Time of Examination Comments

MEDICAL HISTORY (NOT TO BE SENT TO GSK)Sample ID: Date/Time: Period:

Body System Description Start date Stop date Ongoing at this Visit

HEIGHT/WEIGHT (BMI)Sample ID Period Date and Actual Time of

VitalsHeight(cm)

Weight(kg)

BMI(kg/m²)

Comments

WEIGHT (WEIGHT)Sample ID Period Date and Actual

Time of VitalsWeight

(kg)Comments




Subject Number

4


12-LEAD ECGSample ID Period Date/

Time of ECGParameters Interpretation

VentricularHR

(bpm)

If abnormal (NCS, CS), please describe:

PR Interval(msec)

RR Interval(msec)

QRS Interval(msec)

QT Interval(msec)

QTc Interval(msec)

QTcBInterval(msec)

QTcFInterval(msec)

Comment:

BLOOD PRESSURE (SITTING VITALS BP/PULSE/TEMP/RESP)Sample ID Period Date and

ActualTime of

Vitals

SystolicBP

(mmHg)

DiastolicBP (mmHg)

PulseRate

(bpm)

Resp.Rate(bpm)

Temperature(ºC)

Comments




Subject Number

5


BREATHALYZER (NOT TO BE SENT TO GSK)

Sample ID Period Date/Time of Exam Result Comments

INFUSION (GSK 933776 200MG IV INFUSION)Sample ID Period Start Date/Time of

InfusionEnd Date/Time of

InfusionComment

Infusion Flow Rate: Infusion Flow Rate Unit (mL/h):

Actual Quantity Infused: Dosage Unit: mL

What location was the dose given in?

Did the subject receive the correct treatment?

Was there an Infusion interruption?

Any AE’s

DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time

of AdministrationActual

Quantity(mg)

What location was the dose

given in?

Did the subject

receive the correct

treatment?

Comments



Quantity(mg)


given in?

Did the subject

receive the correct

treatment?

Comments

DOSE (GSK 933776 200MG IM INJECTION)Sample ID Period Start Date/Time


Quantity(mg)


given in?

Did the subject

receive the correct

treatment?

Comments




Subject Number

6




Quantity(mg)


given in?

Did the subject

receive the correct

treatment?

Comments



Quantity(mg)


given in?

Did the subject

receive the correct

treatment?

Comments



Quantity(mg)


given in?

Did the subject

receive the correct

treatment?

Comments




Subject Number

7


INFUSION RECORD3Sample ID Period Date/Time Comment

Infusion Flow Rate Unit (mL/h): Dose Description:(1) Date/Time (Interruption Start) (1) Volume Infused at time of

Interruption (mL):(1) Infusion Rate (prior to Interruption):

(1) Reason for Interruption

(1) Due to AE?

(2) Date/Time (InterruptionStopped/Infusion Restart)

(2) Infusion Rate (afterInterruption):

(3) Date/Time (Interruption Start) Volume Infused at time of Interruption (mL):

(3) Infusion Rate (prior to Interruption):

(3) Reason for Interruption

(3) Due to AE?

(4) Date/Time (InterruptionStopped/Infusion Restart)

(4) Infusion Rate (afterInterruption):

BLOOD (BIOCHEMISTRY)Sample ID Period Actual Date/Time

of CollectionIs the volunteer

fasting?Comments




Subject Number

8


BLOOD (BIOMARKERS/PHARMACODYNAMIC MARKERS)Sample ID Period Actual Date/Time of Collection Comments

BLOOD (COAGULATION)Sample ID Period Actual Date/Time of Collection Comments

BLOOD (HAEMATOLOGY)Sample ID Period Actual Date/Time of Collection Comments

BLOOD (HBA1C)Sample ID Period Actual Date/Time of Collection Comments

BLOOD (IMMUNOGENICITY)Sample ID Period Actual Date/Time of Collection Comments

BLOOD (PHARMACOKINETICS)Sample ID Period Actual Date/Time of Collection Comments

SEROLOGYSample ID Period Actual Date/Time of Collection Comments




Subject Number

9


URINESample ID Period Date/Time Comments

URINE (URINE DRUG SCREEN)Sample ID Period Date/Time Control Positive results Result contest

Drugs:Benzodiazepines(BZO) Opiates(OPI) Ecstasy(MDMA)

Cocaine(COC) Methadone(MTD) Phencyclidines(PCP)

Marijuana(THC) TricyclicAntidepressants(TCA)

Amphetamines(AMP)

Methamphetamines(MET)

Oxycodone(OXY) Barbiturates(BAR)

Comment:

SITE REACTIONSample ID Period Date/Time of Exam Comment

Site Reaction Location SiteCatheter Leakage Swelling Measurable

Swelling Area (cm^2) Swelling ListInduration Measurable Induration Area (cm^2)Discoloration Measurable Discoloration Area (cm^2)Discoloration TendernessIntolerability Itching ReactionItchiness Burning SensationRash BruisingSwelling Diameter (mm) Erythema Diameter (mm)Erythema BurningWarm Sensation Cutaneous PainRash (severity) ItchingPhlebitis Scale




Subject Number

10


LIVER EVENTSSample ID Period Date/Time of Exam Comment

Question #1: Is this liver event a serious adverse event?Question #2: Notification Sent?

Sender: Sample Date/TimeQuestion #3: Which liver chemistry result reached or exceeded protocol-defined investigational product stopping / interruptioncriteria? Check all that apply.

Question #4: Is the subject age 55or older?

Question #5: If Female, is the subject pregnant?

Question #6: Were any diagnostic imaging tests of the liver or hepatobiliary system performed?

Question #7: Were any liver biopsies performed?

Question #8: Does the subject use herbals, complementary or alternative medicines, food supplements (vitamins) or illicit drugs?

Question #9: Did the subject undergo significant dietary change in the past week?Question #10: When did the liver event occur?Start Day/Start Month/Start Year Stop Day/Stop Month/Stop Year

LIVER EVENT REPORTINGSample ID Period Date Liver Signal /Event

first detected in chemistry lab results

Date Liver Signal /Event resolved, as

indicated in chemistry lab

results

Comment




Subject Number

11


PHARMACOKINETICS (LIVER)Sample ID Period Date/Time of Exam Comment

Question #1: Was a pharmacokinetic blood sample obtained?

Sample Date/Time

Question #2: If Yes, date and time of last oral GSK 1265744B dose prior to PK sample:

Sample Date/Time

Question #3: If Yes, date and time of last oral MOXIFLOXACIN dose prior to PK sample:

Sample Date/Time

LIVER MEDHXSample ID Period Date/Time of Exam Comment

Question #1: Acute Viral Hepatitis A Question #2: Chronic Hepatitis B

Question #3: Chronic Hepatitis C Question #4: CytomegalovirusHepatitis

Question #5: Epstein Barr Virus Infectious Mononucleus

Question #6: Herpes Simplex Hepatitis

Question #7: Alcoholic Liver Disease Question #8: Non-alcoholicSteatohepatitis

Question #9: Fatty Liver Question #10: Hepatic Cirrhosis

Question #11: Hemochromatosis Question #12: AutoimmuneHepatitis

Question #13: Gallbladder Disease Question #14: Drug related liver disease

Question #15: Other Liver Disease Conditions, Specify Conditions:

Status:

Question #16: Drug Allergies Question #17: Rheumatoid Arthritis

Question #18: Psoriasis Question #19: Thyroid Disease

Question #20: Inflammatory Bowel Disease

Question #21: Lupus

Question #22: Sjogren’s Syndrome Question #23: Vitiligo




Subject Number

12


LIVER ALCOHOLSample ID Period Date/Time of Exam Does

volunteerconsumealcohol?

If Yes, average units of Alcohol Consumed Per

Week

Comment

LIVER IMAGING

Sample ID Period Date/Time of Exam Comment

Question #1: Date of hepatic or liver imaging test

Question #2: What method was used for this imaging test?

Other, Specify

Question #3: Are Images technically adequate?

Other, Specify

Question #4: Indicate the liver size Other, Specify

Question #5: Indicate the liver texture Other, Specify

Question #6: Grade the diffuse and /or geographic fatty infiltrate of the liver

Other, Specify

Question #7: Ascites present Other, Specify

Question #8: Are Focal Hepatic Lesions characterisable?

Other, Specify

Question #9: Gallstones or gallbladder lesions?

Other, Specify

Question #10: Biliary ductal lesions? Other, Specify

Question #11: Portal / Hepatic vein abnormalities?

Other, Specify




Subject Number

13


LIVER BIOPSYSample ID Period Date/Time of Exam Comment

Question #1: Date of liver biopsy

Question #2 Approximate size of liver biopsy

Question #3 Biopsy size unit MM

Question #4: Final Diagnosis Other, Specify

Question #5: Liver Architecture Other, Specify

Question #6: Description of Liver Cells or Hepatocytes

Other, Specify

Question #7: Liver Cell or Hepatocyte Inclusions or Vacuoles

Other, Specify

Question #8: Hepatocyte or Liver Cell Nuclear Abnormalities

Other, Specify

Question #9: Liver or Lobular Infiltrates

Other, Specify

Question #10: Portal Tract Inflammation

Other, Specify

Question #11: Bile Ducts Other, Specify

Question #12: Portal Veins Other, Specify

Question #13: Liver Infections Other, Specify

Question #14: Parasites of Ova Other, Specify

Question #15: Histologic Staining or Additional Studies Obtained

Other, Specify




Subject Number

14


ADVERSE EVENTSDiagnosis

Adverse Event number/Sample ID

Sample Date (Start Date) Sample Time (StartTime)

Unknown Start Time

Stop Date Stop Time

Unknown Stop Time

Severity

Frequency

Action Taken with Study Drug

Other Action Taken

Specify Other Action taken

Relationship to Study Drug

Outcome

Did the subject withdraw from the Study as a result of this AE?Comment




Subject Number

15


SERIOUS ADVERSE EVENTSAdverse EventAE NoAdverse Event number/Sample IDSample Date (Start Date) Sample Time (Start Time)Stop Date Stop TimeAE Caused by Study Procedure?Date AE Met Criteria for Serious AEDate Investigator Aware of Serious AEAE is serious due to:DeathPersistent or Significant Disability/IncapacityLife ThreateningCongenital Anomaly or Birth DefectRequires or Prolongs HospitalizationOther Serious / Important Medical EventDate HospitalizedDate DischargedPrimary Cause of DeathSecondary Cause of DeathDate of DeathAutopsy PerformedCausality Assessment (to other than investigational drug):AE caused by Additional Drug 1? Additional Drug 1:AE caused by Additional Drug 2? Additional Drug 2:AE caused by Other Medication? Other Medication:AE caused by Study Procedure? Study Procedure:Description of AEInvestigator’s signatureComments




Subject Number

16


PRIOR AND CONCOMITANT MEDICATIONSMedication (trade or generic)Medication number/Sample IDStart Day/Month/Year/TimeTreatment prior to study startEnd Day/Month/Year/TimeOngoingRouteOther RouteDose/UnitFrequencyOther Frequency

IndicationAdverse Event Adverse Event NumberComments

STUDY EXITSample ID: Date/Time: Period:Did the subject complete the study?

Date/Time of Study Exit

Date of Last Contact

Reason for Withdrawal

Other, please specify

Adverse Event Number(s):

Comment




Subject Number

17


CONFIDENTIAL

1

LIST OF INVESTIGATORS AND IECS/IRBS FOR BA1116891

Investigator Sub-Investigator Investigator

no./Center no.

Description of Research

Facility, Hospital/ Institution,

and Address

Name of IEC/IRB Committee,

Address, Committee Chair

United States

Leese, Philip T. MD,

CPI

Craven, Kelli M. MD

Hall, Anne M. MD

Holkins, Sally L. RN, MSN,

APRN

Kelly, Christina J. PA-C

Lisbon, Eleanor A. MD, MPH,

CPI

Lomeli, Barbara K. MD

Mathews, David R. MD, CPI

Murtaugh, Thomas E. MD, CPI

Newland, William L. MD

Rasmussen, Scott C. MD

Schutz, Ralph A. MD, CPI

Quintiles Phase One Services,

LLC, 6700 West, 115th Street,

Overland Park, Kansas, 66211,

United States United States

Chairperson:

All centres participated in the study under the US IND.

2014N211143_00BA1116891

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy

Version 2 Print Initials __ __ __Approved by on 11/26/13

FOR QUINTILES USE ONLY

STUDY NAME: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers.

PROTOCOL I.D.: BA1116891STUDY I.D.: 4950PURPOSED USE: Geographic atrophy (GA) secondary to Age-related macular degeneration

(AMD)TYPE OF STUDY: Phase I – HEALTHY SUBJECTSDATE APPROVED:DATE REVISED:

INFORMED CONSENTWHAT IS INFORMED CONSENT?WHAT DO YOU NEED TO KNOW ABOUT THIS STUDY?You have been asked to take part in a clinical research study of an investigational drug. You must be informed so you can decide whether to participate. Being informed means that you understand the possible risks and that there are no direct benefits to you for taking part in this study.

Only you can decide if you want to take part in this study. You should only make your decision

after reading all of the information in this form. You may talk to your family, friends and or

your family doctor to help make your decision. You can take as much time as you like to decide.

After you have read the entire form, you will be given the chance to ask any questions that you

may have. When you have had the chance to ask any questions and they have been answered to

your satisfaction, if you decide to take part, sign the pages at the end of this form to show that

you agree to be part of the study. This is called “giving your consent”.

Even after you have signed this study consent form you can change your mind and decide not to

participate in the study. You do not have to give a reason.

This consent form has been reviewed and approved by an Independent Review Board (IRB).

This board reviews research studies to protect the rights and well-being of the people taking part.

Some of the information in this consent form is required by law.

DOCTOR IN CHARGE OF THIS STUDY Philip Leese, MD, CPIQuintiles Phase One Services6700 W. 115th StreetOverland Park, KS 66211

1


Page 2 of 16Protocol Number #BA1116891

STUDY ID #4950

Version 2 Print Initials __ __ __

Approved by on 11/26/13

Please let us know if you are not comfortable talking about this informed consent in a group of volunteers, and we can speak with you individually.

NAME OF STUDY DRUG

The Investigational or study drug that you may take in this study is named GSK933776. “Investigational” means that the drug has not been approved by the Food and Drug Administration (FDA) for sale for any indication.

USE

Animal studies have shown that GSK933776 may be effective as a potential treatment for geographic atrophy (a loss of vision in the center of the visual field) that can occur with age-related macular degeneration.

PURPOSE

This is a research study involving about 36 healthy volunteers. The purpose of the study is: To compare how much of the drug gets into the blood and how long the body takes to get

rid of it, after the drug is given in different ways and as a single dose or multiple doses To find out if the drug has any important side effects, and investigate how the drug enters

and leaves the blood and body tissues over time To investigate whether the body produces antibodies to the drug after it is given

The study medication GSK933776 is a monoclonal antibody not yet approved by regulatory authorities for doctors to treat patients with GA.

REQUIREMENTS

You cannot participate in this study if you have participated in a prior study within the past 60

days. You agree that under no circumstance will you dose with two investigational medications

during the time period of this study, because it may cause you serious physical harm.

You will need to have the following exams, tests or procedures to find out if you can be in the

study. The information and samples collected as part of these screening activities will be kept

and used like the rest of the study results. These tests are sometimes part of regular medical care.

They may be done even if you do not join the study.

Medical history: You will be asked about your health and any illnesses you may have orhad in the past. You will be asked about medicines you are taking (including over-the-counter medicine, vitamins or herbal treatments)

Physical examination: You will receive a complete physical examination

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STUDY ID #4950



Electrocardiogram (ECG): This will record the electrical activity of your heart. Malessubjects may need to have their chest hair shaved before the ECGs so the ECG patcheswill stick to your skin. Female subjects will not be allowed to wear bras

Vital signs: Your weight, height, blood pressure, heart rate and breathing rate will all bechecked

Blood tests: A small amount of your blood (about 4 teaspoons) will be drawn from avein for clinical lab tests

You will give a urine sample to screen for the presence of drugs

You will be tested for the presence of alcohol by a urine sample or a breath test

Testing for certain diseases such as Hepatitis B, Hepatitis C, and HIV

You will be tested for the HIV antibody. HIV is a virus that causes AIDS. You will alsobe tested for Hepatitis B and C viruses as part of the screening blood tests. All of theabove test results must be negative in order for you to qualify for the study. The positiveresults must be reported, by name, to the Health Department by Quintiles, as required bylaw. The Quintiles study doctor will inform you of this and answer any questions youmay have about this matter. If Quintiles becomes aware during your participation in thisstudy that there is any change in the HIV or Hepatitis results, or other testing during thestudy shows a change, you may be removed from the study.

These screening tests will help determine if you are qualified for the study. The studydoctor may ask you to undergo additional testing to help confirm your eligibility for thestudy. If indicated, a copy of your results from lab tests and other screening procedureswill be available for you to pick up directly, or they will be sent by U.S. mail to yourhome address on file. If any of your test results are assessed to be abnormal andmedically important by the study doctor, you will be asked to share the results with aprimary care or consulting physician who would evaluate you further.

You must read, and agree to follow, the House Rules at the study site if you want to takepart in this study. The House Rules discuss proper behavior at the study site. HouseRules are important to make sure the study results are accurate. You may be fined if youdo not follow the House Rules. You may also be removed from the study and study siteif you do not follow the House Rules.

The study staff will review all of your screening study data (including your medicalhistory, questionnaires, physical exam, electrocardiogram [ECG], vital signs, and labfindings) to make sure you meet all study criteria before you can begin the study.

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STUDY ID #4950



PROCEDURES

1. Approximately 36 subjects, ages 18-50, will take part in this study at Quintiles, OverlandPark Kansas. Quintiles will be the only study site. There are 4 different ways planned togive this drug to volunteers (referred to as ‘treatments’). The treatments are labeled as A,B, C and D and are as follows:

TREATMENT:A. 200 mg GSK933776 given once by IV infusion (an infusion into the vein)B. 200 mg GSK933776 given once by SQ injection (an injection into the fatty tissue

under the skin). This treatment will require 4 injections of 50 mg GSK933776 to be given at the same time to get the total dose of 200 mg

C. 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks (an injection into the fatty tissue under the skin)

D. 200 mg GSK933776 administered once by IM injection (an injection into the muscle)

If you qualify for the study, you will be randomly assigned to one of these treatmentgroups. A computer will put people into treatment groups by chance. Neither you nor the study doctor can choose a group. You have a 25% chance of being placed in each group. You will remain on this treatment group for the entire study. You will only receive one of the treatments.

2. Length of Stay: The length of stay will depend on the treatment to which you arerandomly assigned. You will be assigned to the treatment group on the day you check-into Quintiles to start the study.

Treatments A, B, and D: You will stay at Quintiles for 1 day on one occasion, therewill not be any overnight stays required. You must also be available to come back toQuintiles for about 11 follow up visits.

Treatment C: You will stay at Quintiles for 1 day on four separate occasions,there willnot be any overnight stays required. You must also be available to come back for about25 follow up visits.

3. The length of the study is about 18-20 weeks, depending on the part of the study you are

assigned.

Please keep in mind how the study tests and visits described here will affect your workand family schedules. Consider if you need transporation to and from the clinic. Youmay find that these tests and visits need some planning. Some tests may beuncomfortable. Ask the study doctor if you have any questions about the tests andprocedures for the study.

4



STUDY ID #4950



4. This is an “open-label” study. This means that you and other subjects, the Quintiles staff

members and the Quintiles Pharmacist will know what drug you are receiving and by

what route (injection in the veins, muscle or fatty tissue) you will be receiving it.

5. There is no placebo (an inactive substance like a sugar pill) planned for this study. This

means you will receive the study drug while you are on the study.

6. You will be on a standard House diet while you are at Quintiles. This means that youwill be allowed only the food and drinks that are approved by Quintiles during the study.Meal substitutions (food or drink) will not be allowed. No alcohol is allowed during thestudy for 24 hours prior to the start of dosing and until the collection of the final samplesduring each session. An alcohol test will be given prior to the start of each session.

7. For your safety, you must not:

Take any other medicines without first speaking with the study doctor (Thesemedicines include prescription or over-the-counter drugs taken by mouth; appliedto skin; taken by nose or inhaled; placed in eyes or ears; vitamins, herbal ordietary supplements)

Participate in another studyThese restrictions are to be followed during the study and for at least 85 days after the last dose of the study drug that was given to you.

8. Your blood will be taken approximately 20 times during the study if you are assigned toTreatments A, B or D. If you are assigned to Treatment C, your blood will be takenapproximately 35 times. This will be done by individual needle sticks or by intravenous(IV) catheter. An IV catheter is a small plastic tube inserted into your arm or hand veinby a needle. The needle is removed but the tube temporarily remains in your vein. Thistube allows the removal of blood without having to stick you each time. If the catheterstops working, a new one may be placed. The amount of blood that will be taken inTreatments A, B or D is about 7 ounces (210 ml) throughout the entire study. If you areassigned to Treatment C, the amount of blood that will be taken is about 12 ounces (350ml) throughout the entire study. This compares to a standard blood donation of about 2cups (500ml). It is possible that more than one try may be needed to get enough blood.

9. You will have several sets of vital signs taken during the study. Physical exams will also

be completed on days over the course of the trial.

10. Several ECGs (electrocardiograms) will be done during the study.

5



STUDY ID #4950



RISKS

This drug has been tested in a relatively small number of humans, and there is always a possibility for side effects that we do not know about to occur. As with all study drugs, some of these unknown side effects may be life-threatening.

What side effects or risks can I expect from this study?

You may experience side effects from the study drug. Everyone in the study will be watched carefully for any side effects. Side effects may be mild or serious. If you experience a side effect, the study staff may give you medicines to help lessen these effects. Some side effects may go away as soon as you stop taking the drug. In some cases, side effects can be serious, long-lasting or may never go away.

Possible side effects and risks from GSK933776:

This drug has not yet been given to healthy volunteers. There have been 2 completed clinical trials in Alzheimer’s Disease subjects and there is 1 ongoing clinical trial in subjects with geographic atrophy secondary to age-related macular degeneration (an eye disease).

GSK933776 has been given to 36 patients in 2 Alzheimer’s Disease trials and to at least 87

subjects in the ongoing eye disease trialAdverse events so far reported have been short lived and

mostly mild to moderate in nature.

The most commonly reported adverse events (>5% incidence) were fatigue/tiredness, nausea, headache, vomiting, diarrhea, dizziness, musculoskeletal signs and symptoms such as pain and stiffness.

GSK933776 is thought to lower levels of a small protein called amyloid beta. Based on current knowledge, the human body does not need amyloid beta for its normal activities, therefore it is not expected that its elimination by the study medicine would disturb the normal functions of your body.

During the study we will collect information on your blood and urine as well as your general health. We will also be testing your blood to see if antibodies against GSK933776 are made.Usually the body makes antibodies as part of the body’s defense against infection and foreign proteins. It is possible that some people given GSK933776 might produce antibodies against this drugWe will be testing your blood to see if this happens.

Potential side effects related to the use of GSK933776 (and monoclonal antibodies in general)

might include:

Infusion/injection related reaction - When GSK933776 is given to you, the infusion needlemay cause temporary pain, bruising, swelling and/or irritation to your arm or area where thestudy drug is injected. Some people develop a reaction to protein infusions, which although

6



STUDY ID #4950



rare, may cause fever, shivering, nausea and a general feeling of being unwell to start soon after the dose has been given.

Allergic reaction consisting of, but not limited to, nausea, facial flushing, itchy rash, difficulty breathing, fever, and muscle aches may occur.

Acute anaphylaxis - Anaphylaxis is a severe allergic reaction affecting the whole body. Subjects at particular risk are those who have been exposed to monoclonal antibodies in the past which is why subjects exposed to monoclonal antibodies in the past cannot participate in this study. We do not expect this to occur but you will be closely monitored for this. If anaphylaxis occurs, you may require emergency treatment, including additional drugs and potentially breathing assistance.

If an anaphylactic reaction should occur, study medication will be stopped immediately and you will be removed from the study. You will be asked to come back to the clinic for an early withdrawal visit.

You will be monitored for a time period after the study drug is administered. You can not leave the facility until approved by the study doctor. This is so that the study doctor can watch for any potential or possible side effects that may be caused by the study drug.

There may be other side effects that may happen that are not known now. Certain problems can become worse if not treated quickly. Call the study doctor right away if:

You feel very tired or faint You feel pain or sick in your stomach and do not want to eat You bruise easily or develop itching You have yellow eyes or skin, or dark urine You become confused

If you experience certain serious problems (such as an allergic reaction, swelling, difficulty breathing, a bad skin rash, liver or kidney damage, or changes in your heart rhythm), you may be asked to return to the clinic for more assessments, which may include more blood tests. Your doctor will explain these tests to you if they are needed. You may also need to stop taking the study drug after talking with your study doctor.

You should not take part in this study if you are pregnant or able to become pregnant.

7



STUDY ID #4950



ADDITIONAL RISKS

1. There may be side effects of drawing blood with a needle and/or IV tubes. They may

include fainting, bruising, soreness, blood clots and tenderness at the needle site. On

rare occasions, it may cause an infection. If you experience any of these symptoms or

have any other problems, you must tell a Quintiles staff member right away. You

should tell a study nurse, study director, or you may also tell the doctor.

2. You must not give blood for 30 days after the study is over because of the amount of

blood that we will take during this study.

3. Possible side effects from the patches that are put on your skin when the ECG is

performed may be a rash, redness, or minor irritation of the skin.

4. You must clearly understand that while you are on this study, the use of other

investigational drugs, alcohol or illegal drugs (such as marijuana, cocaine, etc.) may

cause you serious harm and is strictly prohibited.

5. As with all medicines or procedures, there may be risks that we do not know about.

6. The study doctor or a member of his/her staff will tell you about any important new

information that relates to the study drug and that may affect your decision to remain

in this study. If this happens, you must decide if you want to keep taking part in this

study. You will be asked to agree, in writing, that you were told about these new

findings. You may also be given an additional form to the Informed Consent. This

will be provided if more information becomes available about side effects that have

been seen with subjects in this research study. If this happens, you will be asked to

read and sign the additional form.

You should talk with the study doctor or research staff if you have any questions about these risks. Ask your study doctor if you have any questions about side effects.

INFORMATION ON BIRTH CONTROL

Women who can get pregnant will not be allowed to participate in this study. Men with partners who can get pregnant will need to use birth control while in this study, as will their partner. Some methods may not be approved for use during this study.

8



STUDY ID #4950



FEMALES

The treatments or procedures performed during this study may pose unknown risks

to an unborn baby. Women who are pregnant or breastfeeding must not participate

in this study. You MUST be a woman of non-child bearing potential to participate

in this trial. The following are acceptable proof of non-child bearing potential:

Surgery to prevent pregnancy (hysterectomy, which is removal of the uterus; oophorectomy, which is removal of both ovaries; tubal ligation, which is having the fallopian tubes tied; tubal occlusion, which is a procedure which results in the blockage of the fallopian tubes). You may be asked to provide proof of your surgery or procedure to participate in the study.

Confirmed as being postmenopausal by not having a menstrual cycle for at least 12 months. You may also need to provide a blood sample to test forblood hormones which would confirm this.

You must not be currently breastfeeding. If, at any time during the study, you think you may be pregnant, you must immediately contact the study doctor, Phillip Leese, MD at

MALES

The drug used in this study could harm an unborn child. The effect of the study drug on the male reproductive system is unknown. Therefore, you MUST agree to use an acceptable form of birth control throughout the study and for at least ninety (90) days after the last dose of the study drug (even if you have had a vasectomy). You must also abstain from sperm donation until 90 days after your last dose of study medication. Acceptable birth control methods are:

Condom (during non-vaginal intercourse with any partner - male or female)OR

Condom OR occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)

Abstinence, defined as sexual inactivity consistent with your preferred and usual lifestyle

Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception

9



STUDY ID #4950



You must not be actively trying to father a child during the time period of the entirestudy and for 90 days after the last dose of the study drug.

If you think that your partner may be pregnant at any time during the study, you must immediately contact the study doctor, Phillip Leese, MD at

BENEFITS TO YOU AND OTHER SUBJECTS:

The goal of this research study is to provide scientific information. You and other participants will not receive any direct medical benefits.

ALTERNATE THERAPY:

This is a research study. It is not treatment or therapy. You may choose not participate in the study.

COMPENSATION RELATED TO STUDY PARTICIPATION

1. Compensation will depend on the treatment group to which you are assigned.

Treatments A, B, and D: You will be compensated a total of $3,850.00 if you are accepted

for the study and finish all the tests. You will be compensated in the following way:

Day 2: $400.00 Day 10: $900 Day 29: $850 Day 57: $800 Day 85: $900

Treatment C: You will be compensated a total of $7,000.00 if you are accepted for the

study and finish all the tests. You will be compensated in the following way:

Day 2: $400 Day 9: $1000 Day 16: $1000 Day 23: $1000 Day 43: $900 Day 50: $800 Day 78: $900 Day 106: $1000

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STUDY ID #4950



2. According to the IRS (Internal Revenue Service) guidelines, you will be responsible for paying taxes on any compensation that you receive from your study participation. Quintiles will send you a 1099-form for this purpose. Quintiles will also report to the IRS any compensation that you receive that totals $600.00 or more for the calendar year. You should tell Quintiles Phase One Services, LLC. of your new mailing address if you move after your participation in a study. This is to make sure you receive your 1099 for your year-end tax reporting.

3. If, for any reason you cannot finish the study, or we decide to discharge you, you will be compensated for your time during the study on a pro-rated basis. You will receive this compensation at the end of the study.

4. You do not have to pay for any study-related medicines, procedures or treatment at Quintiles during the study.

COMPENSATION FOR INJURY

1. Medical care will be given to you, at no cost, if you are injured as a result of being in this study.

2. You and your insurance company will continue to pay for your regular health care.

3. GSK will pay the costs for reasonable and necessary care if you are hurt by the study drug or a procedure that is done to you only because you are part of this study. To pay these medical expenses, GSK will need to know some information about you like your name, date of birth, and social security number. This is because GSK has to check to see if you receive Medicare, and, if you do, report the payment it makes to Medicare. GSK will not use this information for any other purpose.

4. While you are in the study, you may be injured because of your personal conduct or during activities which are not part of the study. There are no plans to pay you for these types of injuries.

5. Signing this consent form does not change any legal rights you may have.

WHO IS PAYING FOR THE STUDY AND WHAT DO THEY DO?

GlaxoSmithKline (also called “GSK”) is a company that discovers and makes vaccines, medicines and other health products. GSK pays the study doctor and Quintiles to run this study.

YOUR PARTICIPATION IN THE STUDY

1. Do I have to stay in the study? No. Your participation in this study is completely voluntary. You may choose to stop

taking part in the study at any time, without giving a reason. Tell the study staff if you

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STUDY ID #4950



want to stop being in the study. Your decision will not affect your medical care now or

in the future. It will not affect other benefits you receive outside of the study.

You may be asked to leave the study if: The results of certain tests show that you are not right for this study or for the study

drug. You do not follow study instructions for treatment or follow-up visits. You get new health problems during the study that might not work well with the

study set-up. You get pregnant. The study doctor thinks it is best for you to stop.

New information may become available or known that might affect your choice to stay in the study. Such information will be shared and discussed with you. This new information may include updated safety information about the study drug.GSK (the study sponsor), the regulatory authority, or the study doctor may choose to stop the study at any time. Should this occur, the reason will be provided at that time.

If you decide to leave the study, you and the study doctor will discuss the best way to do this.

2. You may be photographed during the screening or enrollment process. These

photos will not identify you, but will record physical conditions before a study

begins. These photos may be used to compare to photos taken after dosing with study

drug. If you have any side effect, photos may be taken of side effects on your body

after dosing, such as if you develop a rash during the study. These photos will not

identify you. They may be used for treatment and/or research purposes. All

photographs will be the property of Quintiles and/or the Sponsor.

3. If you have health problems, you will get medical attention. You may be

withdrawn from the study by the study doctor and/or the Sponsor of the study without

your consent, if it is in your best medical interest. It is possible that the study doctor

and/or Sponsor may think you can stay on the study. You must decide what you want

to do.

4. If you do not complete the study, for any reason, you will be asked to receive a

complete physical exam, lab tests, vital signs, and ECG before you leave. This is

needed to protect your safety.

5. All the information you gave us before you left the study will still be used for the

study.

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STUDY ID #4950



What happens to my personal and medical information?

It is very important that your personal and medical information stay confidential and secure. GSK will protect your information in accordance with current law.

When you sign this consent form you agree that GSK can use your personal and medical information as described here:

Your personal and medical information may be checked by GSK and others (like agencies that approve and monitor studies). This is to make sure that the study is being run properly.

Besides that, only the researchers at this study site can use information that identifies you (such as name and address) and only for the purpose of the study.

Your study information will be labelled with a code number (for example, It will not include your name or address. The study doctor will have the link between your name and the code number.

The link between your name and the code number will not be shared. Only the code number and coded information will be sent to GSK.

GSK will use your coded information for research only.

GSK may:

keep your coded information electronically, and analyse it by computer to find out what the study is telling us. This may be done by GSK or a third party, in which case GSK will ensure that the third party is required to keep your data secure,

share the information with regulatory agencies that approve new medicines,

share the information with people who check that the study is done properly (like the ethics committee or review boards),

combine the information with results from other studies to learn more about the medicine and other medicines. This may help us to assess the risks and benefits of GSK (or other) medicines, or to improve disease understanding,

publish study results for medical journals, meetings and on the internet for other researchers to use; your name will not appear in any publication,

share coded information with other companies, organisations or universities to carry out research.

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STUDY ID #4950



Personal and medical data collected during the study may be moved, stored and used in the

country where you live or another country where GSK or those working with GSK work.

Use of this information may take place in countries with lower data protection rules than the

country where you live. GSK will make sure that if your data are moved to another country, it

will still be treated as stated in this Informed Consent Form.

A description of this clinical study will be available on the GSK Clinical Study Register:

http://www.gsk-clinicalstudyregister.com/ and may also appear in clinical trial/study registries in

countries in which the clinical study is conducted.

CONFIDENTIALITY OF RECORDS

Quintiles will handle the medical information obtained in this study with the strictest confidence. It will be protected as required by laws and/or regulations. It will not be made publicly available. If the results of this study are published you will not be identified by name.

Some people and organizations can look at and copy your medical record and the information collected during this study. They include:

Employees of the FDA (Food and Drug Administration) or other government authorities;

The Sponsor or its agents; Quintiles, and its agents (consulting physicians or specialists); Members of the The IRB is a group of

individuals from the community responsible for the review and approval of research proposed to be conducted on human subjects.

By signing this consent, you authorize Quintiles to verify your study participation history with other businesses that conduct clinical research studies.

WHAT HAPPENS TO MY BLOOD/TISSUE SAMPLES?

If you take part in this study, you will be asked to give blood samples for safety testing and blood samples to find out information about the drug. Similar to information collected in the study, your samples may also be used by GSK or shared by GSK with other companies or universities to better understand GA, other diseases or conditions, or to further develop the study drug or other drugs.

Your blood samples will be given the same code as your other study information and kept in locked storage. Anyone who works with your samples will hold the information and results in confidence.GSK may store your tissue samples for up to 15 years after the end of the study after which time your samples will be destroyed.

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STUDY ID #4950



PERSONS TO CONTACT FOR QUESTIONS, CONCERNS, OR COMPLAINTS

If you have any questions, concerns or complaints about this study, you can call the study doctor Phillip Leese, MD, CPI at

If you have questions about your rights, general questions, complaints or concerns about this research, or questions about your rights as a person taking part in this study, call the

at or If, at any time during or after your participation in this research, you would like information or to offer input about your research experience, you can call the at the number above or you can go to the website at and give us your comments. Either way, you do not have to give us your name, if you do not want to.

You have the right to ask any questions concerning the potential and/or unknown hazards of this study, at any time. If you have any questions concerning your participation in this study, or if at any time you feel you have experienced a research-related injury or a reaction/side effect to the study drug, contact Philip Leese, MD, CPI at

For General questions you may contact the study director, at

LEGAL RIGHTS

You will not lose any of your legal rights to which you are otherwise entitled by signing this consent form.

15



STUDY ID #4950



DO YOU HAVE ANY QUESTIONS?

Do you have any questions that you would like to discuss with the study doctor? ____NO ___ YES

If yes, I as an Investigator, have addressed and answered the participant’s questions.

Investigator’s Initials _________________ Date_______________

SUBJECT STATEMENT- (Subject is to read this out loud to staff)

I can speak and read the English language. I have read this Informed Consent Document. I have had enough time to read this information. I have been given a chance to ask questions. I have received answers to my questions, and I am satisfied with those answers. I understand this consent and the information given to me.

I am signing this form freely and am not being forced. If I do not take part in the study, I will not lose any benefits. I have the legal capacity to enter into contract, and no Guardian has been appointed

for me. If I leave the study, I will not lose any benefits. If I leave the study, I will not lose any legal rights. My participation in this study is completely voluntary.

I agree to cooperate with all the medical personnel. I agree to take the medicines and treatments as directed. I agree to do the actions required by as discussed in this informed consent. I understand it is my duty to tell the study doctor or Quintiles staff about all changes

in my physical or mental health during the study. I have given and will give truthful and complete information about my health and

medical history to the study physician/staff.

By signing this consent form, I am agreeing to the release of my medical records to the FDA

(Food and Drug Administration) or other government authorities, the Sponsor or its agents,

Quintiles and its agents, the and any third party required

by law. I understand that I will receive a signed and dated copy of this form to keep for my

records.

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STUDY ID #4950



Subject’s Printed Name Subject’s Signature

Date

:

Time

Person Obtaining Consent Form Signature Date

Printed Name of Person Obtaining Consent Form

17


Generated by on Mon Mar 30 12:24:05 EDT 2015 / Page 1

Final Schedule Detail ReportStudy ID: BA1116891Schedule Number: 2Schedule Version: 1.0

Study DescriptionGSK933776 PH 1 HV PK Bioavailability study to compare IM and SQ administrationwith IV administration

Schedule DescriptionBA1116891 Bioavailability Study Schedule 2

Schedule DefinitionsStrata Description Block Size Rand. No. RangeALL 4

Group Code Group Description Ratio1 200 mg GSK933776 administered by IV infusion -

PARALLEL1

2 200 mg GSK933776 administered by SQ injection -PARALLEL

1

3 50 mg GSK933776, administered by SQ injection onceweekly for 4 weeks - PARALLEL

1

4 200 mg GSK933776 administered by IM injection -PARALLEL

1

Treatment Group and Treatment Definitions

Treatment GroupTreatmentCode Treatment Description Period

1 1 200 mg GSK933776 administered by IV infusion 1

2 2 200 mg GSK933776 administered by SQ injection 1

3 3 50 mg GSK933776, administered by SQ injection onceweekly for 4 weeks

1

4 4 200 mg GSK933776 administered by IM injection 1

Randomisation Schedule - Treatment Group Assignments

Stratum: ALLRandomisationNumber Treatment Group

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THIS IS THE LAST PAGE OF THE REPORT.


ICH Data Listings Page

Listing 9.1 Listing of Randomized and Actual Treatments (Safety Population) ....... Listing 9.2 Listing of Subjects excluded from Analysis Populations (Safety

Population) ................................................................................................... Listing 9.3 Listing of Reasons for Study Withdrawal/Completion (Safety

Population) ................................................................................................... Listing 9.4 Listing of Protocol Deviations (Safety Population) ................................. Listing 9.5 Listing of Demographic Characteristics (Safety Population) .................. Listing 9.6 Listing of Race (safety Population) ........................................................ Listing 9.7 Listing of Concomitant Medications (Safety Population) ....................... Listing 10.1 Listing of Exposure to Component (Safety Population) ....................... Listing 10.2 Listing of Relationship Between System Organ Class and Verbatim

Text (Safety Population) .............................................................................. Listing 10.3 Listing of All Adverse Events (Safety Population) ................................ Listing 10.4 Listing of Serious Adverse Events (Safety Population) ....................... Listing 10.5 Listing of Adverse Events Leading to Withdrawal from the Study

(Safety Population) ...................................................................................... Listing 10.6 Listing of Pregnancy (Safety Population) ............................................ Listing 10.7 Listing of Laboratory Tests and Associated Reference Ranges

(Safety Population) ...................................................................................... Listing 10.11 Listing of Abnormal ECG Findings (Safety Population) ..................... Listing 10.12 Listing of All ECG values for Subjects with any Value of Potential

Clinical Importance (Safety Population) ....................................................... Listing 10.13 Listing of Vital Signs (Safety Population) ........................................... Listing 10.14 Listing of All Vital Signs for Subjects with any Value of Potential

Clinical Importance (Safety Population) ....................................................... Listing 10.101 Listing of All Clinical Chemistry Laboratory Data for Subjects with

PCI Abnormalities (Safety Population) ......................................................... Listing 10.102 Listing of All Hematology Laboratory Data for Subjects with PCI

Abnormalities (Safety Population) ................................................................ Listing 10.103 Listing of All Urinalysis Data for Subjects with PCI Abnormalities

(Safety Population) ...................................................................................... Listing 10.801 Listing of All Clinical Chemistry Laboratory Data (Safety

Population) ................................................................................................... Listing 10.802 Listing of All Hematology Laboratory Data (Safety Population) ....... Listing 10.803 Listing of All Urinalysis Laboratory Data (Safety Population) ........... Listing 10.901 Listing of Clinical Chemistry Laboratory Data for Subjects with Lab

Values Outside of Normal Range (Safety Population) ................................. Listing 10.902 Listing of Hematology Laboratory Data for Subjects with Lab

Values Outside of Normal Range (Safety Population) ................................. Listing 10.903 Listing of Urinalysis Laboratory Data for Subjects with Lab Values

Outside of Normal Range (Safety Population) .............................................

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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

Other Data Listings Page

Listing 11.1 Listing of Plasma GSK933776 Pharmacokinetic Concentration-Time Data (Pharmacokinetic Population) ..............................................................

Listing 11.2 Listing of Derived Plasma GSK933776 Pharmacokinetic Parameters (PKParameter Population) ...........................................................................

Listing 12.1 Listing of Plasma Abeta Pharmacodynamic Concentration-Time Data (Pharmacodynamic Population) ...................................................................

Listing 12.2 Listing of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data (Pharmacodynamic Population) .................................................

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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL GlaxoSmithKline

VALIDATION REPORT

Validation of the ELISA Method

“Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”

Sponsor: GlaxoSmithKline Pharmaceuticals GSK Document No.: 2013N182307_00

Alliance Pharma Study No.: 130825

Alliance Pharma Report No.: V130825.01

Document Issued on 27 Nov 2013

Prepared by

Alliance Pharma, Inc. 17 Lee Boulevard

Malvern, PA 19355 USA

GSK Document No.: 2013N182307_00

Page 1 of 52

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CONFIDENTIAL Report No.: V130825.01 GSK Document No.: 2013N182307_00

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STUDY INFORMATION

Title Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”

Bioanalytical Principal Investigator

Ph.D. Alliance Pharma Tel: Fax: E-mail:

Sponsor GlaxoSmithKline Pharmaceuticals 709 Swedeland Road King of Prussia, PA 19406

Sponsor Reviewers E-mail:

E-mail:

Bioanalysis Facility Alliance Pharma 17 Lee Boulevard Malvern, PA 19355

GSK Document No. 2013N182307_00

Alliance Pharma Study No. 130825

Experimental Start Date 27 Aug 2013

Experimental End Date 15 Oct 2013

Document Issued 27 Nov 2013

Total Number of Pages 52

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LIST OF CONTRIBUTORS

Title: Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”


Ph.D.


M.Sc.

Analyst

M.D.

Analyst

Lin, M.Sc.

Analyst

B.Sc.

Analyst

2014N211143_00BA1116891

Report No.: V130825.0lGSK Document No.: 20l3N182307 00

SIGNATURE PAGE

Title: Validation of the ELISA Method "Quantification of GSK933 776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"


Ph.D.


Alliance Pharma

Date

13Management

Alliance Pharma

40f52

Date

2014N211143_00BA1116891

Report No.: V130825.01GSK Document No.: 2013N182307 00

COMPLIANCE STATEMENT

Title: Validation of the ELISA Method "Quantification of GSK933776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"


I certify that the bioanalytical study was conducted in compliance with the relevant AlliancePharma Standard Operating Procedures (SOPs). The information given in this report fully andaccurately reflects the raw data generated during the study.

Ph.D.


Alliance Pharma

50f52

Date

2014N211143_00BA1116891

Report No.: V130825.01aSK Document No.: 2013N182307 00

QUALITY ASSURANCE STATEMENT

Title: Validation of the ELISA Method "Quantification of GSK933776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"


This validation report has been audited by the Quality Assurance Unit for adherence to thevalidation plan and corresponding Alliance Pharma standard operating procedures (SOPs).Within the scope of the audit, this report is considered an accurate description of the method andpresentation of the results.

Date Reported toStudy Phase Inspected Date of Inspection Bioanalytical Principal

Investigator/Management

Raw Data Audit27 Sep 2013

03 Oct 201330 Sep to 01 Oct 2013

Report Audit30 Sep to 01 Oct 2013 03 Oct 2013

21 to 22 Oct 2013 22 Oct 2013

Date

Quality Assurance Auditor

Alliance Pharma

60f52

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%Bias Difference between measured value and nominal value expressed as a percentage

%CV Coefficient of variation expressed as a percentage

D.F. Dilution factor

ELISA Enzyme-linked immunosorbent assay

HQC High quality control

hr Hour(s)

LLOQ Lower limit of quantification

LQC Low quality control

mg Milligram

µL Microliter

mL Milliliter

MQC Medium quality control

n Number of samples

n/a Not available / not applicable

ng Nanogram

PA Precision and accuracy

QC Quality control

OD Optical Density

RT Room temperature

SD Standard deviation

SOP Standard operating procedure(s)

STD Standard

ULOQ Upper limit of quantification

VS Validation sample(s)

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TABLE OF CONTENTS

STUDY INFORMATION ...............................................................................................................2

LIST OF CONTRIBUTORS ...........................................................................................................3

SIGNATURE PAGE .......................................................................................................................4

COMPLIANCE STATEMENT .......................................................................................................5

QUALITY ASSURANCE STATEMENT ......................................................................................6

LIST OF ABBREVIATIONS ..........................................................................................................7

LIST OF TABLES ...........................................................................................................................9

LIST OF FIGURES .......................................................................................................................10

LIST OF APPENDICES ................................................................................................................11

1. INTRODUCTION ..................................................................................................................12

2. METHOD VALIDATION SUMMARY ................................................................................13

3. VALIDATION PROCEDURES ............................................................................................14

3.1. Reference Standard .......................................................................................................14 3.2. Preparation of Standards and Validation Samples ........................................................14 3.3. Major Computer Systems and Data Processing ............................................................14

4. RESULTS AND DISCUSSION .............................................................................................14

4.1. Run Summary ...............................................................................................................14 4.2. Standard Curve Evaluation ...........................................................................................14 4.3. Precision and Accuracy .................................................................................................15 4.4. Dilution Linearity and Prozone Effect ..........................................................................15 4.5. Selectivity and Matrix Effect ........................................................................................15 4.6. Stability of GSK933776 ................................................................................................15

5. CONCLUSION .......................................................................................................................16

6. DEVIATION ..........................................................................................................................16

7. ARCHIVE STATEMENT ......................................................................................................16

8. REVISION HISTORY ...........................................................................................................16

9. TABLES .................................................................................................................................17

10. FIGURES ................................................................................................................................25

11. APPENDICES ........................................................................................................................26

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LIST OF TABLES

Table 1 Validation Summary for Quantification of GSK933776 in Human Plasma .................17

Table 2 Back-Calculated Concentrations of GSK933776 Calibration Standards (ng/mL) .......17

Table 3 Precision and Accuracy of GSK933776 Validation Samples .......................................18

Table 4 Precision and Accuracy of GSK933776 QC Samples ..................................................20

Table 5 Dilution Linearity and Prozone Effect of GSK933776 in Human Plasma ...................20

Table 6 Selectivity of GSK933776 in Human Plasma ...............................................................21

Table 7a Stability of GSK933776 in Human Plasma Stored at RT (Bench Top) for 24 hr ........23

Table 7b Stability of GSK933776 in Human Plasma Stored at -20ºC for 15 Days .....................23

Table 7c Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-20ºC/RT) Cycles ..23

Table 7d Stability of GSK933776 in 11-Fold Assay Buffer-Diluted Human Plasma Stored at 4°C for 24 hr .................................................................................................................24

Table 7e Stability of GSK933776 in Human Plasma Stored at -70ºC for 15 Days .....................24

Table 7f Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-70ºC/RT) Cycles ..24

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LIST OF FIGURES

Figure 1 A Representative Calibration Curve of GSK933776 (Curve Range: 100 to 5000 ng/mL) (Batch: PA-3, 5-Parameter Regression, 1/Y weighing) .........................25

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LIST OF APPENDICES

Appendix 1 Bioanalytical Method: 130825M.01V .....................................................................26

Appendix 2 Certificate of Analysis for GSK933776 ..................................................................35

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1. INTRODUCTION This report describes the validation of the ELISA method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” The method was validated based on an ELISA method originally developed by GlaxoSmithKline (GSK Method Reference No.: GSK933776HUPLVALA Version 04). GSK933776 is a humanized monoclonal antibody against beta-amyloid peptide provided by GSK. GSK933776 in calibration standards, quality controls (QCs), and human plasma samples is first bound to the amyloid peptide on the plate. This complex is then further bound to mouse anti-human IgG1 (Fc specific) antibody labeled with horseradish peroxidase (HRP), which catalyzes the chromogenic HRP substrate 3,3′,5,5′-tetramethylbenzidine (TMB). This reaction yields a blue color with a maximal absorbance at 650 nm. The blue color then changes to yellow via the addition of sulfuric acid, resulting in maximum absorbance at 450 nm for the final readout. The absorbance at 450 nm is proportional to the amount of GSK933776 in the calibration standards, QCs, and samples.

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2. METHOD VALIDATION SUMMARY Title Validation of the ELISA Method “Quantification of GSK933776 in Human

Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” Analyte GSK933776 Matrix Human Plasma with K2 EDTA as anticoagulant Range of Standard Curve 100 – 5000 ng/mL Lower Limit of Quantification 100 ng/mL Sample Volume 50 µL Capture Reagent Beta-amyloid peptide 1-16 Detection Reagent Mouse anti-human IgG1 labeled with horseradish peroxidase (HRP) Standards Inter-Assay Precision and Accuracy for Standards

100, 200, 400, 800, 1500, 2500, 4000 and 5000 ng/mL %CV: 1.03% to 5.18% %Bias: -1.77% to 5.16%

Validation Samples (VS) 100, 300, 1000, 3800 and 5000 ng/mL Intra-Assay Precision for VS %CV: 0.85 to 24.79% Intra-Assay Accuracy for VS %Bias: -16.55 to 20.89% Inter-Assay Precision for VS %CV: 2.83 to 8.15% Inter-Assay Accuracy for VS %Bias: -8.74 to 6.61% Dilution Integrity 7600-fold dilution VS: %CV: 4.28% and %Bias: 0.12%

600-fold dilution VS: %CV: 1.44% and %Bias: -1.85% Prozone Effect Prozone effect was not observed at 2.28 mg/mL of GSK933776 in human

plasma Selectivity No significant matrix effect was observed in ten lots of human plasma with

each lot being derived from an individual donor Stability in Matrix

Bench top: 24 hr Freeze-thaw (-20ºC/RT, 70ºC/RT): 6 cycles Assay buffer-diluted samples at 4oC: 24 hr Long term storage at -20ºC and -70 ºC: 15 days

Run Acceptance Criteria Calibration Standards • Precision (%CV): ≤ 20% (≤ 25% at LLOQ and ULOQ)

• Accuracy (%Bias): within ±20% (±25% at LLOQ and ULOQ) At least 6 non-zero calibration standards should meet the above criteria.

Quality Control/Validation Samples

• Precision (%CV): ≤ 20% (≤ 25% at LLOQ and ULOQ) • Accuracy (%Bias): within ±20% (±25% at LLOQ and ULOQ)

At least ⅔ of the QC samples and at least 50% at each level should meet the above criteria.

SOP Reference Method Validation for Ligand Binding Assays

Alliance Pharma SOP BP-001-V02

Validated Method Appendix 1. Alliance Pharma Bioanalytical Method: 130825M.01V

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3. VALIDATION PROCEDURES

3.1. Reference Standard

Analyte Lot Number Correction Factor for Free Base

Expiration Date Source Storage Conditions

GSK933776 101272093 n/a 28 Feb 20141 GSK -70°C

1Vendor extended expiration to 90 months from date of manufacture (31 Aug 2006). (Appendix 2)

3.2. Preparation of Standards and Validation Samples The reference standard, GSK933776 (50 mg/mL), was used to prepare calibration standards at nominal concentrations of 50, 100, 200, 400, 800, 1000, 1500, 2500, 4000, and 5000 ng/mL in normal human plasma. The 50 ng/mL calibration standard was used as an anchor point for curve fitting purposes. Prepared calibration standards were stored at -20°C. Validation samples (VS) at 5 concentration levels were prepared by spiking a known amount of reference standard in normal human plasma. The nominal concentrations in VS were 100 (VS1-LLOQ), 300 (VS2-LQC), 1000 (VS3-MQC), 3800 (VS4-HQC), and 5000 (VS5-ULOQ) ng/mL. Prepared validation samples were also stored at -20°C. Once VS were validated in the precision and accuracy (PA) batches, VS2-LQC, VS3-MQC, and VS4-HQC were used as the quality control samples (LQC, MQC, and HQC) in subsequent batches in this study.

3.3. Major Computer Systems and Data Processing Colorimetric data were acquired using a BioTek ELx800 microplate reader (Winooski, VT), which was controlled by a Dell PC workstation via BioTek Gen5TM software. The acquired data were processed using BioTek Gen5TM software and Microsoft® Excel. A standard curve was constructed by plotting the concentrations of standards in log scale (X-axis) versus their corresponding optical density units (OD, Y-axis), and fitted with a 5-parameter logistic algorithm using a 1/Y weighting. The concentration of analyte in samples was determined based on the standard curve.

4. RESULTS AND DISCUSSION

4.1. Run Summary A total of 11 assay batches were performed for this validation, and every batch met the acceptance criteria. All assays performed in this study are summarized in Table 1.

4.2. Standard Curve Evaluation The standard curve was evaluated in 11 individual assay batches. Results of this evaluation met the acceptance criteria (Table 2). Overall precision (%CV) and accuracy (%Bias) for standards ranged from 1.03 to 5.18% and from -1.77 to 5.16%, respectively. A representative standard curve is shown in Figure 1.

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4.3. Precision and Accuracy Five levels of validation samples at 100 (LLOQ), 300 (LQC), 1000 (MQC), 3800 (HQC), and 5000 ng/mL (ULOQ) were assayed in four replicates (n = 4) along with a standard curve in each batch, and a total of six batches were performed by three analysts on two different days. Intra-assay accuracy (%Bias) and precision (%CV) of the validation samples ranged from -16.55 to 20.89% and from 0.85 to 24.79%, respectively. Inter-assay accuracy and precision of the validation samples ranged from -8.74 to 6.61% and from 2.83 to 8.15%, respectively (Table 3). These 6 batches met the assay acceptance criteria. In 5 additional validation batches the precision and accuracy of QC samples at 300 (LQC), 1000 (MQC) and 3800 ng/mL (HQC) also met the assay acceptance criteria (Table 4).

4.4. Dilution Linearity and Prozone Effect GSK933776 was spiked in human plasma at 2.28 mg/mL, then further diluted to 3800 and 300 ng/mL using blank human plasma (D.F. 600 and 7600, respectively). Six replicates (n = 6) of the diluted and undiluted samples were assayed along with a standard curve and two sets of QC samples at low, medium, and high levels (n = 2).

The results from the evaluation of dilution linearity and prozone effect are summarized in Table 5. The accuracy of dilution of GSK933776 from 2.28 mg/mL to 3800 and 300 ng/mL was -1.85% and 0.12%, respectively, whereas the precision of the dilution was 1.44% and 4.28%, respectively. No prozone effect was observed at 2.28 mg/mL GSK933776 in human plasma.

4.5. Selectivity and Matrix Effect Selectivity of the method was evaluated by analyzing 10 plasma samples derived from 10 individual donors. The selectivity samples were prepared by spiking each donor’s plasma sample with GSK933776 to 100 ng/mL (LLOQ) (n = 3) and assayed along with a standard curve and two sets of quality control (QC) samples at low, medium, and high levels (n = 2).

Results from the evaluation of selectivity and matrix effect are summarized in Table 6. Eight out of ten individual human plasma samples spiked with GSK933776 at LLOQ had %Bias within ±20% of their respective nominal concentrations and all samples had %CV ≤ 20%, which demonstrated that 80% of the samples met acceptance criteria. Therefore, it is concluded that the method is selective for quantification of GSK933776 in human plasma matrix. Since no significant matrix effect was observed in 11-fold assay buffer-diluted human plasma, the 11-fold assay buffer-diluted human plasma is suitable as the assay matrix.

4.6. Stability of GSK933776 Stability of GSK933776 was assessed in human plasma and in 11-fold assay buffer-diluted human plasma. LQC (300 ng/mL) and HQC (3800 ng/mL) samples were stored on a bench top (RT condition) for 24 hr, at -20°C and -70°C for 15 days, as well as subjected to 6 freeze-thaw cycles (-20ºC/RT, -70ºC/RT). An additional set of stability samples was pre-diluted 11-fold in assay buffer and stored at 4ºC for 24 hr. Each sample

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was tested in triplicate (n = 3) along with a freshly prepared standard curve and two sets of QCs at low, medium, and high levels (n = 2).

The %Bias and %CV for all tested samples met acceptance criteria for stability (%Bias within ±20% and %CV ≤ 20%) as summarized in Tables 7a, b, c, d, e, and f. These results indicate that GSK933776 in human plasma is stable for at least 24 hr at RT, for 15 days at -20ºC and -70ºC, for 6 freeze/thaw cycles (-20ºC/RT and -70ºC/RT ), and for at least 24 hr after 11-fold dilution in assay buffer. The stability of GSK933776 in human plasma after storage at -20ºC for extended periods of time, such as 3, 6, 12, 18, and 24 months, will be evaluated and the results of the stability testing will be presented in addendums to this report.

5. CONCLUSION The data presented in this validation report demonstrate that the method for quantification of GSK933776 in human plasma is accurate and reproducible.

6. DEVIATION There were no protocol or SOP deviations during the validation.

7. ARCHIVE STATEMENT All raw data, records, and a copy of the original signed final report will be archived at Alliance Pharma for 5 years following the submission of the final report to the sponsor. After this time, the sponsor will be contacted for instructions regarding the necessity of continuing storage, transferring to the sponsor’s site, or disposing of the materials.

8. REVISION HISTORY 08 Nov 2013: Draft

27 Nov 2013: Final

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9. TABLES

Table 1 Validation Summary for Quantification of GSK933776 in Human Plasma

Batch ID Date Run Type Accepted/Rejected (Reason)

PA-1 28-Aug-13 Precision and Accuracy Accepted PA-2 29-Aug-13 Precision and Accuracy Accepted PA-3 29-Aug-13 Precision and Accuracy Accepted PA-4 29-Aug-13 Precision and Accuracy Accepted PA-5 29-Aug-13 Precision and Accuracy Accepted

PA-6 29-Aug-13 Precision and Accuracy Accepted

Dilution Linearity 30-Aug-13 Dilution Linearity and Prozone Effect Accepted

Selectivity-1 05-Sep-13 Selectivity Accepted Selectivity-2 05-Sep-13 Selectivity Accepted Stability-1 11-Sep-13 Stability Accepted Stability-2 15-Oct-13 Stability Accepted

Table 2 Back-Calculated Concentrations of GSK933776 Calibration Standards (ng/mL)

Batch ID STD STD STD STD STD STD STD STD

100 200 400 800 1500 2500 4000 5000

PA-1 107 195 387 836 1463 2526 3989 5005 PA-2 108 201 394 814 1480 2490 4101 4906 PA-3 106 199 391 810 1501 2500 3954 5059 PA-4 106 194 393 832 1453 2540 4002 4987 PA-5 110 194 398 810 1480 2546 3847 5200 PA-6 108 198 391 818 1481 2516 3990 5006

Dilution Linearity

107 193 389 819 1511 2460 4008 5027

Selectivity-1 91 203 402 802 1490 2510 3998 4998 Selectivity-2 101 190 394 838 1459 2530 3932 5077 Stablility-1 104 216 391 793 1497 2547 3889 5088 Stablility-2 109 201 393 808 1490 2517 3976 5017

N 11 11 11 11 11 11 11 11 Mean 105 198 393 816 1482 2517 3971 5034

SD 5.44 7.23 4.20 14.16 18.17 25.99 66.93 74.05 %CV 5.18 3.65 1.07 1.73 1.23 1.03 1.69 1.47 %Bias 5.16 -0.77 -1.77 2.05 -1.18 0.67 -0.71 0.67

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Table 3 Precision and Accuracy of GSK933776 Validation Samples

Nominal Concentrations of Validation Samples (ng/mL)

100 300 1000 3800 5000

PA-1 Analyst 1

85 302 966 3993 4914 287* 335 979 3851 4871 83 301 999 4042 5470 98 303 969 3875 4950

Mean 89 311 978 3940 5051 SD 8.07 16.40 14.71 91.79 281.01

%CV 9.08 5.28 1.50 2.33 5.56 %Bias -11.14 3.51 -2.17 3.69 1.03

n 3 4 4 4 4

PA-2 Analyst 2

85 309 999 4080 5456 125 343 970 4071 5049 81 300 1011 4251 5184 84 306 970 3800 4856

Mean 94 314 988 4050 5136 SD 20.81 19.29 20.75 186.44 252.11

%CV 22.19 6.14 2.10 4.60 4.91 %Bias -6.23 4.79 -1.23 6.59 2.73

n 4 4 4 4 4

PA-3 Analyst 2

93 303 973 4347 5682 114 319 958 4114 5050 92 312 1021 4544 5105 89 300 950 4187 5252

Mean 97 309 976 4298 5272 SD 11.44 8.57 31.96 190.64 286.37

%CV 11.82 2.77 3.28 4.44 5.43 %Bias -3.22 2.93 -2.44 13.11 5.45

n 4 4 4 4 4

PA-4 Analyst 1

82 282 915 3817 4891 124 336 914 3588 4471 79 284 936 4105 5546 86 285 906 3764 5014

Mean 93 297 918 3819 4980 SD 20.73 26.18 12.91 214.41 442.91

%CV 22.36 8.82 1.41 5.61 8.89 %Bias -7.28 -1.03 -8.21 0.49 -0.39

n 4 4 4 4 4

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Table 3 (Continued)

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Nominal Concentrations of Validation Samples (ng/mL)

100 300 1000 3800 5000

PA-5 Analyst 1

81 288 924 4292 6259 126 313 929 3964 5496 77 289 941 5041 6539 83 284 925 4086 5885

Mean 92 293 930 4346 6045 SD 22.81 13.36 7.94 482.87 453.67

%CV 24.79 4.55 0.85 11.11 7.51 %Bias -8.00 -2.26 -7.02 14.36 20.89

n 4 4 4 4 4

PA-6 Analyst 3

74 291 956 3860 5071 111 320 948 3783 4535 70 291 970 4046 5061 79 293 923 3723 4766

Mean 83 299 949 3853 4858 SD 18.71 14.13 19.70 140.54 258.12

%CV 22.43 4.73 2.07 3.65 5.31 %Bias -16.55 -0.48 -5.06 1.39 -2.84

n 4 4 4 4 4 Inter-run Mean 91 304 956 4051 5224 Inter-run SD 4.61 8.58 28.53 225.12 425.77

Inter-run %CV 5.05 2.83 2.98 5.56 8.15 Inter-run %Bias -8.74 1.24 -4.36 6.61 4.48

n 6 6 6 6 6 * Value rejected since this value was an outlier determined by Dixon Q-test per AP SOP BA-021

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Table 4 Precision and Accuracy of GSK933776 QC Samples

Batch ID LQC MQC HQC 300 1000 3800

Dilution Linearity

305 1040 4163 298 979 3741

Selectivity-1 322 1014 3952 329 1051 3829

Selectivity-2 298 990 4118 292 1006 3892

Stability-1 283 974 3991 297 952 3729

Stability-2 316 980 4011 337 1021 4276

Mean 308 1001 3970 SD 17.38 31.09 180.02

%CV 5.65 3.11 4.53 %Bias 2.60 0.07 4.48

n 10 10 10

Table 5 Dilution Linearity and Prozone Effect of GSK933776 in Human Plasma

300 ng/mL (1:7600 dilution)

3800 ng/mL (1:600 dilution)

2280000 ng/mL (Undiluted Sample)

Dilution Linearity

305 3739 >ULOQ 302 3765 >ULOQ 311 3755 >ULOQ 315 3787 >ULOQ 284 3690 >ULOQ 286 3643 >ULOQ

Mean 300 3730 >ULOQ SD 12.84 53.78 N/A

%CV 4.28 1.44 N/A %Bias 0.12 -1.85 N/A

n 6 6 6

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Table 6 Selectivity of GSK933776 in Human Plasma

Selectivity Samples Unspiked (0 ng/mL) Spiked (100 ng/mL)

S-1 < LLOQ < LLOQ < LLOQ 116 94 91 Mean n/a 100 SD n/a 13.66

%CV n/a 13.60 %Bias n/a 0.44

n 3 3 S-2 < LLOQ <LLOQ < LLOQ 104 127 126

Mean n/a 119 SD n/a 12.84

%CV n/a 10.80 %Bias n/a 18.90

n 3 3 S-3 <LLOQ < LLOQ < LLOQ 107 108 122


%CV n/a 7.46 %Bias n/a 12.79

n 3 3 S-4 < LLOQ < LLOQ < LLOQ 120 125 123


%CV n/a 1.76 %Bias n/a 22.57

n 3 3 S-5 < LLOQ < LLOQ < LLOQ 156 142 132


%CV n/a 8.45 %Bias n/a 43.15

n 3 3 S-6 < LLOQ < LLOQ < LLOQ 118 91 87


%CV n/a 17.27 %Bias n/a -1.31

n 3 3

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Table 6 (continued)

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Selectivity Samples Unspiked (0 ng/mL) Spiked (100 ng/mL)

S-7 < LLOQ < LLOQ < LLOQ 80 108 94 Mean n/a 94 SD n/a 13.78

%CV n/a 14.65 %Bias n/a -5.98

n 3 3 S-8 < LLOQ < LLOQ < LLOQ 92 99 110


%CV n/a 8.80 %Bias n/a 0.30

n 3 3 S-9 < LLOQ < LLOQ < LLOQ 102 103 97


%CV n/a 3.33 %Bias n/a 0.33

n 3 3 S-10 < LLOQ < LLOQ < LLOQ 128 114 114 Mean n/a 118 SD n/a 7.91

%CV n/a 6.68 %Bias n/a 18.37

n 3 3

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Table 7a Stability of GSK933776 in Human Plasma Stored at RT (Bench Top) for 24 hr

Nominal Concentration 300 ng/mL 3800 ng/mL

Stability-1 322 4227 330 4362 366 4253

Mean 339 4281 SD 23.84 71.44

%CV 7.02 1.67 %Bias 13.12 12.65

N 3 3

Table 7b Stability of GSK933776 in Human Plasma Stored at -20ºC for 15 Days


Stability-1 307 3813 299 4022 287 4010

Mean 298 3948 SD 10.37 117.15

%CV 3.48 2.97 %Bias -0.81 3.90

n 3 3

Table 7c Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-20ºC/RT) Cycles


Stability-1 296 4211 281 4307 300 4097

Mean 292 4205 SD 9.99 105.04

%CV 3.42 2.50 %Bias -2.65 10.65

n 3 3

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Table 7d Stability of GSK933776 in 11-Fold Assay Buffer-Diluted Human Plasma Stored at 4°C for 24 hr


Stability-1 280 3405 267 3476 300 3454

Mean 282 3445 SD 16.72 36.60

%CV 5.93 1.06 %Bias -5.97 -9.35

n 3 3

Table 7e Stability of GSK933776 in Human Plasma Stored at -70ºC for 15 Days


Stability-1 316 4051 329 3869 290 3843

Mean 312 3921 SD 19.95 113.24

%CV 6.40 2.89 %Bias 3.89 3.19

n 3 3

Table 7f Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-70ºC/RT) Cycles


Stability-2 321 3950 336 3899 355 4187

Mean 338 4012 SD 16.76 153.87

%CV 4.96 3.84 %Bias 12.52 5.57

n 3 3

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10. FIGURES

Figure 1 A Representative Calibration Curve of GSK933776 (Curve Range: 100 to 5000 ng/mL) (Batch: PA-3, 5-Parameter Regression, 1/Y weighing)

Curve Name Curve Formula A B C D E R²

Curve Y = (A-D)/(1+(X/C)^B)^E + D 0.086 1.22 2.69E+04 2.95 13.9 1

Calibration Curve

Conc. of GSK933776, ng/mL

OD

450

nm

1 10 100 1000 10000

0.000

0.500

1.000

1.500

2.000

2.500

3.000

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11. APPENDICES

Appendix 1 Bioanalytical Method: 130825M.01V

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...- - "'A llianceF'HARM A

CONFIDENTIAL Report No.: V130825.0 1GSK D ocument No.: 2013N182307 00

CONFIDENTIAL

Bioanalytiea l Method

Quantification of GSK933776 in Human Plas ma (Range 100 - SOOOng/mL) Using a Color imetric Immunoassay

1\ldhod 11>: 13082 5M.OIV

Prepared hy

Ph.D.Alliance Pharma. Inc.

Apprund hy

Date

---M.Sc .

Directo rBiopharmaccutica l ServicesAlliance Pharma, Inc.

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Date

( J'Oc..:' 7.-0 /3

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CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00

1 Introduction

CONFIDENTIAL ;"fcthod ID: n 01l25!\101V

This document describes the procedures to quantify GSK933776 (a humanizedmonoclonal antibody against beta-amyloid peptide from OSK) in human plasma samplesusin g a colorime tric immunoassay.

2 PrincipiI' uf Mt'thod

The beta-a myloid peptide 1·1f; is coated onto a 96-we 1l plate. and GS K9.1J7 7(' incalibration standards (STDs), qualit y controls (QCs), a nd samp les will bind 10 theam yloid pept ide 0 11 the plate . This complex will then further bind to mouse anti-humanIgGI (Fe speci fic) an tibod y labeled with horseradish peroxidase (HRP). wh ich catalyzesthe chromogenic HRP substrate 3.3 '.5,Y.telnlllldhylhenzidine (TM B). This reactionyields a b lue- co lor with a maximal absorbance- at 650 lllll . The- blu e- color the-n changes toyellow after the- addition of sulfuric ac id re-sulting in maxim um absorbance at 4 50 I1I U .

111': absorbance at either 6 50 1I1ll or 450 om is proport ional to the amount of GSK933 776ill t he- ca libra tion standards, QCs, and samples.

3 Aualyte

Th e analvtc, CiSK9]3776. is provided hy CiSK with defined concentration. 101n umber,and ex pira tion da te. '111is refe rence subs tan ce is SIOH.-d at _70 °C,

.4 Bqufpments and :\ Iat t lials

:\Iah'rials I Reegcnts Functton SUUITI'

MaxjSorp Cle-ar 96 well pla it: Sol id phase Nunc, Cat. # , 439454

Aseptic Sealing Tapes Plat e- Sealing NUllC. Cat. # . 236366

Buplln' Sodium Carbonate- Coating 'lo,,"TTI1O Scient ific, Cat. #: 2X3X2Bicarbonate Huffer Pack s Buffe r Sa lt

Beta-Amyloid-Pe ptide (1-16) Capture Bachcm . Cal. # : 11-29 5XAgent

Sodium Ch lor ide, ACS grade Salt VW R Cal. #: BDllnX6

Tris Base BuU".:r EMD ~li ll ipor.: Chemicals. Cat. #: TX 1529-5

Tween 20 Detergent Sigma . Cat. #: P1379

SuperBlock in TBS Blocking Thermo Scient ific, Cat. # : 37535Sol ution

20fX

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CONFIDENTIAL ;"fcthod ID: n 01l25!\10 \V

:'o rat t rials I Reageuts Func t ion S Oli IT('

Bovine Serum Albumin Buffer Fisher Scient ific Cat. #: ICN810034(IlSA) Protein

Hum an Plasma with K2 Assay Matrix Bioreclamation. Inc. Cal. # : m,lI'LEDTA2EDTA me; ant i-coagulant

HR P La beled Mouse anti- Repo rter Tag Invitrogen. Cal. #: /\- 1064XHuman IgGl(Fc Speci fic)

l -Skp Ultra P ..IB- ELiSi\ HR I' Thermo Scientific , Cal. #; 34029Substrate Subs trate

18 ~[Sulfuric Acid Acid Sigma . Cat . #: 25&105Concentrate

Deion ized Water Solvent In house, Milli-Q Water

ELx800 Microplate Reader Plate Reader Bio-Tck Instrum ents Inc.

EL.,,4()S Microplate Washer Plate wash...rr- Bio -Tc k.. Instrumen ts Inc.

Note: Alte rnative equivalent consumablcs and cquipm cnts may he use d as approp riate.

R('a jl('nts Function Prepurarlon

I 1\1 Tr is-CL plI 7.5 Buffer Dissolve 12 1.14 grams ofTris Base. adjust pHSo lution to 7'j with concentrated Hydroc hloride Acid.

and add deionized water to \ J.iter.

5 ~I NaCl Salt Stoc k Dissolve 292 .2 grams of Sod ium Ch loride inSo lutio n deionized water to adj ust final volume to I

Liter.

tux Tris Buffered Saline Assay/Wa Combine 100 mL of I ~I Tris-C I. p li 7.5, 300Sol utio n e m S) ( 100 m M sh Buller m l . 5 i\l NaCI and GOO m i . deionized wate r andTr is-Cl , 1.5 ~I J','"aCI, pH 7.5) mix .

50 m~1 Sodium Carbo nate - COOling Empty I pouch Bupl! Sodium Carbonate-bicarbon ate Bufl"er. pH 9.4 Butler Bicarbonate Buller Pack into a conta iner

containing 2.0 L de ionized water. Stir todissolve.

1 mg .ml. Beta-A myloid Coating Add I m L of deionized water to I mg ofbeta-Pept ide ( 1-16) Stock amy lo id peptide ( 1-\6) and vortex . Make (,() ~LI ,

Solution aliq uots and store the aliquot s at -70"C.

] ot X

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R('a~('nts Funct ion Prepnrnrlon

3.0 p.g/mL beta-am yloid Coal ing Add 54 ul, lmg/ml, Beta-Amyloid Pept ide intopeptid e 1·\6 in the Coa ling Solution llU ) m L o f Coatin g Huffer. Vort ex. S IOTe a t

Bulla RT for fresh usc.

10 m~\1 I ris, 150m~I NaCI, Assay Add 900 m l, deionized wate r, 100 O1L tux IDS,O. J% lIS A, O_ l~';' Tw een 20, Buffer pll 7.5, !.Og BS A, and 1.0 ml ,Tween 20 to ap1l 7.5 (Ali ) glass container . Stir 10 dissol ve. Filter through

0.2 micron filtration unit and store at 4°C for upto 3 months.

10 111 \1 Tris. 150 lu r-.I Nae l. Wash Combine 3.6 L deionized water. 4()() 1111, lOx0.1% Twee n 20, pH 7.5 Bufl~r rns, pH 7.5, and 4.0 ml . Tween 20. !\fix .

I :\00 IIRP Working Stock IIRP Reconstitute JlRP La be led Mous e anti-HumanSolution Substrate IgOI (Fe Specific) ant ibod y acc ording to

manufacture r's instructions. Dilut e an aliquotof the I[liP -antihod y conjugate InO-fold inGua rdian Peroxidase Conjugate Stabiliz er(T herm o Scienti fic , Cat . #: 37548). Store at4<>C for up to 6 months.

HR P Labeled Mouse anti- Reporter Add 138 III of 1:100 HRP Wo rking StockHuma n IgO I Conjug ate Tag Solution to I I mL of Assay Bulle r and vortexSol ution Solution ( 1:8,000 fina l dilut ion"). Store at RT for fresh

m e.

• '111.: dilu tion ma y be adjusted based on theactivit y of the HRP.antibody.

1.8 ~ l Sulfuric Ac id H.ID Sto p Slowly add 100 IIlL I8 M Sulfuric Acid into aSol ution beake r con taini ng <JOOml deionized wa ter while

stirring with a stir bar. After the solut ion coolsdown to RT, trausfcr tc a reag ent bott le.

Note: The act ual amounts can he scaled up or down us needed .

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6. Prncedures

CONFIDENTIAL ;"fcthod ID: n 01l25!\10 \V

6.1 Preparation of GSK9JJ776 Standa rd and Q ua lit:y Cont rol Stock Solut ions

Prep are two sets of master s tock sol utions (SS) hy acc urately measuring the required volume ofre ferenc e stan dar d GSK9.B776 into !'BS to obtain J.OOO,OOO ngsml , stock so lut ions . One isused for calibration standards (SS-S"ID - l ) and the other is used for qua lity control /va lidationsam ple s (SS-QC- l ). "111<:: tota l \'Ol11l11C prepared ma y he scaled up or down as req uired. All stock

solutions are stored at · 20"C.

Working Fina lvolume or Spiking " olu me of

T ot a l \'"Iullw inSttK'k Conccut m non Co ntl 'o l \ Iatrix

So lut iull (n~/lII l,)Solut io n :\la t rix (J.lL)

()'L)

SS-STD~2 100,000 I00 ~lI , of 88-STD-I 900 1,000

SS-STI)-3 I O,(}()(J 100 ,lLofSS~STD-2 '){ J(} l ,(JOO

SS-ST D-4 1000 100 ul . or88-sT1)-] 9()0 1,000

SS-QC· 2 J(Kl.OOO 100 ~lL of SS-QC-I '){J(} l ,OOO

SS-QC-] 10,000 100 ~lL of SS-QC·2 900 1,000

SS-QC·4 1000 !OO f.lL or SS-QC-] 900 1.000

6.2 Prepa ratlon of GSK9J3776 Sta nda rd Workin j:! Solut ions

Ca libration standards are prepared as shown in the table below and stored at · 200C. The tota lvolume prepared may be sealed up or down as required.

ST HVnhrme of\Vm'kin~ Sto('k

vefumc ofSolut ion (uJ ,' Tolnl volume

STD ID Cencenrranon l\lat l1x(ng/ mL)

SS STD-3 SS ST])-~(J.l.L)

( J.l.L)10,000 nezm l. 1,000 nefm L

8TD -50 50 50 950 WOO

STD-leX} JOO \00 900 1000

STD-200 200 200 800 1000

STD-400 400 400 (,00 1000

STD-XeX} XOO ROO 200 1000

STO- 1500 1500 150 850 1000

STD-2500 2500 250 750 1000

STD-4000 4000 400 600 1000

STD-5000 5000 "JO 500 1000

5 orR

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CONFIDENTIAL

6.3 Prcparatlon of GSK933776 Qu ality Control Sll lll[lin

;"fcthod ID: n 01l25!\10 \V

Quality controls (QCs ) and Validation Samples (VS) are prepared as shown in the table below.The to tal volume prepared may be scale d lip or down a" required. Replicate 100 ~L.L aliq uotsshould be transfe rred to appropriate assa y tub es for storage at • 20°C.

V c/VS QC/VS ""Iu ml' nf Spikin l!: Solut ion ("...1,) ' "olulIIl' ufTotal

( 'OIU"l'lIf r.lti o ll SS-Q C-3 SS-QC-.f :\Iatrh:"O) UIII(' ( IJ,L )In (lI ~/mL) 10,00U nglm L 1.000 n glmL (",. )

1.I.oQ- 1OO100 lOll 900 1000

(V'Sl )

LQC.300)00 300 700 1000

( VS2)

),fQC·1OOO1000 100 900 1000

(VS3)

I1QC.38003800 380 620 1000

(VS4)

ULOQ- 50005000 500 500 1000

(VSS )

Note: \is I and VSS arc prepared only Ior rncahod validation.

6.-1 Prcparatton of Sa mpl e Dilution

The assa y mat rix is human plasma dilute d II -fold in assa y buffe r, which is 9.09% humanplasma(c.g. 50 1-1 1. STD. QCs, or study samples into 500 1-11. assay buffer). Unknow n study samplesmay need 10 be pre-diluted into hU1IIan plasma 10 [111 within the assay range. Alte rnat ively , theunknown study samples can be first diluted I I- fold in assay buffer. then further diluted in theass"'f maIn " \\,'h""" sampl" is ,1;1,,1,,<1 . " ,l il,,1i"n QC (IX)C) n,,,',ls I" h" ",,,,ty>,<'<1 " r"ne w ;lh

the diluted samples. f or reference. the tab le below provides an example of how a DQC at:200.000 ng'ml, is prepared. The actual concentration of'thc 1)QC can be adjusted based on thecouc cntretion of OSK933776 in the samples and the dilution factor required for them to fitwithin the calibrat ion cur ve. Replicate I00 ul. aliquot s of DQCs are stored at -2ifC.

volume of Sp iking

QC DQC Sulutioll (~ ,) v clumc ufTota l Volume

Co ncenrra n on :\IatrhIlJ (ng/ mL) SS-Q C- l

(f'L )(",. )

1,000,000 ng/IllL

DQC-200000 200.000 200 800 1000

oors

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7. Immunoassay Procedures

CONFIDENTIAL ;"fcthod ID: n 01l25!\10\ V

St tp P rocedures for :\ 1('111011 10: 130825:\1.01 V

1 Prepare ).0 IJ.g/mJ . beta-am yloid peptide 1-16 in Coat ing Buffer as co alingso lut io n (For-example, add 5 1 ~IL 1 mg/ml., bet a- am yloid stock so lution 10 17 mLCOllling Huffer for coating Z plates)

2 Add 80 ul. coating solution per well in 96- wd l plate , seal with aseptic sealingtape , and incubate for 24 ± 12 hours at 4~C_

3 Wash the plate .5 ti mes w ith 30 0 ul, wash Duffer pe r wel l usin g a plate washer

4 Add 200 ~IL blocking buffer per well, sea l with asepti c scaling tape. and incubatefor \.3 hour at RT or 4"C for up to 11 week.

5 Dilute STDs. Qes a nd Sa mples l l x in Assay Buffer (50 ~lL Plasma Samples to500 ~ . Assay Buffer) and dilute samples and DQC if' necessar y.

(, Wash the plate vumes with 300 ul. Wash Buffer per wellusing a plate washe r

7 Add 1DO IJ-l .po.:r well of Assay Buffered-diluted standards, QCs, and samples, sealwith aseptic sealing tape, and incubate fo r 2 hours at 37"C.

x Wash the plate 5 times with 300 pl. Wash Buffer per well using a plate washe r

9 Prepare Reporter Tag Solution by di luting IIRP Working Stock Solut ion (1: 100)1':0 fold ( I :1': ,000 final dilution'"). For exa mple, add 131': p.l, HRP Working StockSolution (1:100) to 11 mL Assay Butler.

* TIle di lution may be adjusted based on the act ivity of the Hkp-conj ugatedantibody .

10 Add 100 ul , Reporter Tag Solution per well. seal with aseptic sealing tape , andincubate tor I hou r at 37°C.

11 Transfer I I rn l , I -Step Ultra T!l.1B !IRP substrate P~T plate into a tube and leave itat RT to prc-wann the substrate.

12 Wash the plate 5 t imes with 300 pL Was h Buffer per well using a plate washer

13 Add I{)O jJ.I , the pre-warmed Ultra T \ IH HRI' subs trate per well and incubatewith shaking for 8 - 20 minutes at RT.

14 Add 100 pl , T \ 111 Stop Solution per well and incubate with shaking for 5 minutesat RT.

15 Measure absorbance at 450 nm using a plate reader.

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8. Ce k ulat ton


TIle data is acquire d using a Bio -Tek microplate reader and processed using Gen5 software orLI~IS system. Additional calculations can be performed using Microsoft Excel. A standardcurve is constru...-tcd by plotting the concentrat ions of standards in a log scale [Xvaxis) versus thecorresponding absorbance (Opt ical Density, (0) (Y-axis ), and Iitting with a s-parameter logisticalgorithm using a l lY weightin g. 1110.:: concentration of GSK933776 is determine d based 011 thestandard curve.

9. Ilul..rmeut Hi stoI1'

version :\"0. ElTt'din' Date Cu mmenrs

01 22 Aug 20 B New Document

OIV 18 Oct 2013 Validak d Method

x of S

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CONFIDENTIAL Report No.: V130825.01GSKDocurnentNo.: 2013N182307 00

Appendix 2 Certificate of Analysis for GSK933776

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System Numbe r:Document Alias:Document Title:

Co ntent Ow ner :


Gll1xoSmithKl ine

She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093

COVER PAGE

Ownin g Department :Local Bu siness Unit:Bu siness Department:

Description:

Printed by :

Effect ive:

R&D BPe: Upper MerionR&D BPC Upper MerionBPM Release Stability Testu -q

Shelf uie Justifica tion for GSK933776 (aBAM) Reference Standard, 50mglml,Product Code AC, Balch 101272093

cdmsview (cdmsv iew) for cornsvew (cdmsview) on 20 Mar 2013 (G MT)

14 Feb 201313 2 9:14 GMT

APPROVAL AND AUTHORISA TIONCompletion of the fo llow ing signature bloc k has been carried out t.¥ Electron ic Signature

Cocument Appro va l :Signed ByDeci sion ApprovedDecision Date ' 13 Feb 2013 20 54 53 GMTRole : AuthorPurpose : Shell-life JustificationMeanlrg Of S ignature This document is suitable for issue

Signed By 'Deci sion ApprovedDecision Date : 13 Feb 2013 20:59:24 GMTRole : AuthorPurpose : Shelf-life JustificationMeaning Of S ignature : 'r t us document is suitable for issue

Signed By 'Deci sion ApprovedDeci sion Date : 14 Feb 201313 :26:24 GMTRole : App roverPurpose : Shelf-life JustificationMeaning Of Signature : This document is SUitable for issue

End of Cover Page

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1.


GlllxoSmithKline

She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfm L,Product Code AC, Batch 101272093

INTRODUCTION

"Ib is document pro vides the Shelf 1.ifc Justification for GSK93J 776 (aBA~I) RcfcT'-'IlCCStandard (RS). 50 mg/ml, Product Cnde AC, Hatch IOI272 0'J3.

Table 1 GSK933776 RS Balch 101272093 Details

Protect GSK933776GenericName ,BAMProduct Code ACccnet ItemCode: BS159809Fe rn SolutionSiren th SOm ImLRS Batch Number: 101272093Source OSBatch NUrrDer 061123159Manufacture Date 31Au 2006DPSrte ofManufacture Nova teooretodes ltdSta bil ~y Protocol INS_8350 (Batch 061120310)

iSTAB 3460(Balch061 12(310)iSTAS 4013 (Batch 101 272093)

Stabilrty Study' BPB_ST20053 (Batch 061120310 from Inrt ialto 42months)iSTAS8PU1011240 (Batch 061 120310from 48to54months)iSTAS 8P1.Jl11166(Batch 101272093)

Presentat ionandPackaging Asoluhon conta inmg a target of 50 mglmL 01 GSK933776 (refer10CometComponents Item 8S159809 and DPl36208 forlormulallon corcos.ton details).

1mLfilledin 2 mLdear Type-l tubular glass vial (PC102083) sealed wnh13mmHel~lo(~t FM25~1 stopper(PC102427)and13 mmAluminiumtear-cutoverseat PCl29911

Primary StoraQe Ccooton ·7rJ'C ± IlfC ambienthumid~y (AH), protected fromlighl

2. BA CKGROUND

In acco rda nce with CC_20 10_BP_UPM_0130 , the storage temperature ofGSK933776 RSwas changed from S"C ± 3"C/All to ·70"C ± W"C/AII to allow for a longer period or use .OSK933776 RS Balch ur;t 1203 1() (Product Cude AA. Comet Item Ill' I362 ( 8) wasreassigned in Comet under the new recomme nde d storage temperature of".700C with thenew Batch 1012 720 93 (Product Cod e AC, Comet Item n SI S9R09). In order to determinethe shelf life of Batch 101 272093. the dat a co llected at SOC for Batch 06 11203 10 and thedata collected at ·70"C for Batch 10 1272093 will be combined to perform stati sticalanalysis.

3. STABILITY SUMMARY

A summary of the stab ility data that arc curre ntly available for GSK 933776 RS is listed inTabl e 2. Supporti ng stability data can he found in Tables 4-8.

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System Num be r:Document Alias:Document Title:

Table 2

Balch'061 120310101272093


Gll1xoSm ithKl ine

She lf Life Justifica tion for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093

Summary of Stability Data Cu rrent ly Ava ilable for GSK933776 RS

.7I7'C :I: l ll"C/AH ·2ll"C:I: 5"C/AH 5OC:!: 3"CIAH 25"<;/60% RH 4ll"CJ7S'4 RHNA 54 months 54months 6 months 1 month

24 months NA NA NA NA

Batch 061120310'Mls reassignedin c crret ullderthe IIBW recommended storage te~ature of ·7f1CWlththe newBatch 101272093

TIle·70ne stu dy for Batch 10 1272093 was in itiated afte r the 5"C stud y for Batch06 1120310 was completed at 54 month t ime point (Table 5). 111e 1, 3, 6,1 2, 18 and 24month time points in the -70ne study (Table 8) an: 55, 57, m , 63, ('G. 72 and 781110nlhtime points after the start ofthe 5°C study.

Stahility data indicate that the GS J..: 933776 RS Ba tch 101272093 met the acceptancecriteria set forth ill the Key Quality Attributes STD _1355X7 for all tests afte r 54 months at50C (Table 5) and 24 additional months at tile revised recommended storage temperatureof -7(JOe [Table X).

Stab ility data collected at ·20OC ± 5"C1AH. 25"C/60% RH. and 40"C175% RH re veal thatthe OSI\:93 3776 RS Batch 101272093 met the acceptance criteria for all tests after 54months at -20"e ± 5OC/AIl (Table 4). 2 months at 25°C/60~'':' RH (Table 6). and 21 days at40"C175% RII (Tabl~ 7). respectivel y.

4. STASTISTICAL ANALYSIS

1l1 ~ results of stat istica l anal ys is us ing com bined 50C and-70°C stability data with shelflife pred iction arc presen ted in Table 3 and Figures 1-6. It is a nticipated that GSK933776RS Batch 1() 1272093 will remain w ithin the ac ce ptance cri teria for at least <)0 monthswhen stored at the recommended storage conditi on of ", 70°C .

Table 3 St at ist ical Ana lysis o f GSK 933776 RS Batch 1012720931,2

Assay Acceptance Criterial PredicatedShelf Life (Months)

ELISA 050 to 150 175

SEC ~ 950% 11 5

SOS-PAGE 2: 95% 140

A280 400 10600mg1mL >312'

pH 531051 158

clEF Report results p '" O(XXX)5S'

Stab5tic~ analr-; i5W35 pedomed using Sta~s bca sollware version 8.0 Cacuanons were 00500 on sing\!batchandlineardatatransformation

2 Combined stalj ilydata includestorage coodibons oI5"C at initial, 1, 3, 6,9, 12, 18,24,36,42,48.and 54months: -7rJC al55, 57, 60, 63, 66, 72and78monlhs

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Gll1xoSmithKl ine

She lf Life Justifica tion for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093

3 Acceptancecntea aceordngto Key QuaityAttributes STD_135587

4 SMl lifewas nol foundv.ithin maximumallov.ed eJ( lr~alion timepoint of312months

5 No acceptance criteriaareset for clEF, rteretc e, the p vaue ct tte s1~e is repor1ed for inforrmbonony. Thepvaueof0000055 indcales that there isastatisbcal lysignificantscoelorclEF.There isIowccreatona/themeolineas indceted bythelowR'which indicates highvariltlityin the measured resutsand sothe trendseen may nol be allriblJ ted10 prcouct degradation.

5. RECOMMENDED SHELF LIFE

GSK933776 (aDA)'I ) RS, 50 mg/mL, Product Cod.: AC, Balch 101272093 is currentlyassign ed a 72-111onlo shelf life when stored at the rec ommended sto rage condition of 70CC± to°CIAH, protected from light .

Base d O il the results of statistical analysis of stahility data curre ntly available and theproced ure ofcurrent SOP, INS_94091 , GS K93377G (aBAM) RS, 50 mg'ml., ProductCo de AC, Batch to 1272093 wi ll he assigned a shelflife of 90 months when stored at therecomme nded sto rage con dit ion of-70~C ± lO~C/AH. protected from light.

6. CHANGES AND REASONS

Ver;;ion chance Reason3.0 This document supersedes RPT_136236(2.0) Revisionforshelf

li fe extensonUpdated all sectionswith new slClbilitydata collectedat 54 Shelf life extensionmonlh time point for Balch001120310 and at9, and 12monlh time points for Balch 101272093

Updatedall sectionswithnewdataa~~~ i S results Shelf life extensionI performed on the stabllitvdata current availableProposedextension of GSK933776 RS Batch 101272093 Shelf life extensionShelf Life from 72 months to 78months

40 Updated all sections withnew data analysis results Shelf life extensionperformed on thestability datacurrently available forShelfLife from78 months \0 90 months

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Gll1xoSmithKline

She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfm L,Product Code AC, Batch 101272093

APPENDIX SUPPORTING STABILITY DATA TABLES ANDSTATISTICAL ANALYSIS PLOTS

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Figure 1


GlaxoSmithKl ine

Shelf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093

Statist ical Plot for ELISA

Stab ilit y Plot fo r Pooled Data wil h 95% Predicti on limits

Woncs heet GSK9 33776 (aBAM) RS Balc1l101272093

Predicted Shelf Life " 175

1.4 1-- '- -- - - - - - - - ~~==:~. --~..---

USL"'1 5

1.2

~:::.; 10w Q

QQ

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Q

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LSL" 0 5

o 20 40 80 60 100 120 140 180 180

Timepoinl

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Figure 2


GlllxoSmithKl ine


Statistical Plot for SEC

Stability Plot for Pooled Data with 95'" Pred ict ion LimitWorksh eet GSK933776 (aBAM) RS e aten 101212093

Predict ed Shel f Li fe · 115

SheR Life99,O r - - _ - - --_--_- , -,

98 5 ~OO

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o

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GlllxoSmithKline

She lf Life Justification for GSK933776 (aBAM) Refe rence standard, 50rngfmL,Product Code AC, Batch 101272093

Figu re 3 Statistical Plot for 5DS-PAGE

Stabi lity Plot for Pooled Data with 95'" Prediction Limit

Worksheet GSK933 776 (aBAM) RS eaten 101212093

Pred icted Shelf Li fe · 140

S he ll L~..

---------------I

a

LSL=gs

'"

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Timepoint

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GlllxoSmithKl ine


Figure 4 Statist ical Plot for clEF

Sta bility Piol for Poo led Data with 95% preercnen Limits

Wo rksh eet GSK933n6 (aB AM ) RS Batch 10127209366

' "

" ' "' "

0 " ,ez 0 ' " " " ,

0 00 ",00

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Time poinl

Effect Paramo I Std.Err I I ,95 .00% I+95.00%P CL CL

Intercept .204 448*8j 3818+f.000000_158.72?8~2J.618~Slone ,009596 0017982 0000055 ,0 13389 ,0 05802

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Figure 5

56

54

52o

~ 50

aa

44

42


GlllxoSmithKl ine

She lf Life Justification for GSK933776 (aBAM) Refe rence standard, 50rngfmL,Product Code AC, Batch 101272093

Statist ical Plot for A280

Stability Plot for Pooled Data with 9'% Pred ict io n lim itsWorksh eet GSK933776 (aBAM) RS eaten 101212093

°000 ° a 0 0 0 0 0 0 a0 0 0 0

O - - - - · - - - - - -9- - - - ~ - - - - - ~ - - - - - - - - - - - - - . - - - - - . - - . - . - - - - - - - -

l SL"'40

Timepoinl

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Figure 6


GlllxoSmithKl ine


Statist ical Plot for pH

Sta bility Plot for Pooled Data with 95% Pred ictio n limitswcresn eee GSK933716 (aBAM) RS Balcll l01272093

Pred icted Shelf Life - 158

She ll L ~e5.75,~~~~~~~~~~~~~~~~~_-,--,

5'0 f- .- - - - - -- - - - - - - .J-505 - ------ -- ----- ----- I------5 60 O-- ~ - - - ~ -O 0

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CONFIDENTIAL Report No.: V130825.0 1GSK Document No: 2013N182307 00

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Table 4 5I a bi l ; t ~ Data lo r G5 K933776 RS 50 mgIml. Ba tch 061120310 at ·20·C

Slobil;lySludy ~btr:Baldo _ be"

BPe ST2Q653061120010

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CONFIDENTIAL Report No.: V130825.0 1GSK Document No: 2013N182307 00

GIa . o Sm llhK lin&

Sh,d u '" ..... b!'''''''.,., fo' G5K933776 (. SAIl) Rorler.. """ Slarxlard 5(IrngIrn..Prodl.<:tr"""" AC, flo"'" 10121:1rn3

Table 5 5l a bi l rt ~ Data for GSK933776 RS 50 mgIml. Batch 061120310 at IS'C

StabilityStudy Number;Bal<h Number -

BPB_ST206S3061120310

SlOrage Condrtlon:T.... i"':!"

S"C Ambient HumldllyUpflghlCompl el..

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Table S 5l a bi l rt ~ Data lor GSK933776 RS 50 mgIml. Batch 061120310 at 26"<:160'4 RH

StabilityStudy Number;Bal<h Number-

BPB_ST20653061120310

StorageCondl~on :

Testing-25°CJliOOi. RelatlYe Humidity Upl1ghtComplete

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TableT 5la bi l rt ~ Data for GSK933776 RS 50 mgIml. Batch 061120310 at 26"<:160'4 RH

StabilityStudy Number; Storage Condltloo; 4O"C 75%RelativeHumidityUpnght

" "~2 R..~t on 0 <loolo not__ 11'&$,,0.,1<.,.,.,

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T ableS Stability Data lor GSK933116 RS 50 "'IJ'mL Balch 101 272093 at -10'C

Stability StudyNumber:Batch Number:

STA BI4013 BPU111188101272093

StorageCondition:11'$1Ing"

.10"COngoing

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1

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.