FDA Arthritis Committee (AAC) FDA Introductory Remarks€¦ · FDA Arthritis Advisory Committee (AAC) FDA Introductory Remarks BLA 761057: Sirukumab for the treatment of adult patients

FDA Arthritis Advisory Committee (AAC)FDA Introductory Remarks

BLA 761057: Sirukumab for the treatment of adult patients with moderately to severely active rheumatoid

arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti‐

rheumatic drugs (DMARDs)

Janet Maynard, MD, MHSClinical Team Leader

Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)Center for Drug Evaluation and Research (CDER)

August 2, 2017

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Rheumatoid Arthritis (RA): Overview

• Chronic, systemic, inflammatory disorder that primarily involves synovial joints

• Can result in permanent joint damage and disability• Multiple therapeutic options approved over the last 20 years

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Overview

• Product: • Sirukumab (Plivensia®)

• Mechanism of action:• Human monoclonal antibody against interleukin (IL)‐6

• Proposed indication:• Treatment of adult patients with moderately to severely active

rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti‐rheumatic drugs (DMARDs)

• Proposed dosage:– 50 mg subcutaneously every 4 weeks (q4w)

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Efficacy Considerations

• Efficacy for signs and symptoms (ACR Responses, DAS28), physical function (HAQ‐DI), and radiographic outcomes

• Efficacy of 50 mg q4w and 100 mg q2w was similar• Sirukumab was not superior to adalimumab

ACR=American College of Rheumatology; DAS28=disease activity score 28; HAQ‐DI=Health Assessment Questionnaire‐Disability Index

9

Safety Considerations

• All‐cause death– Imbalance in all‐cause death with sirukumab over placebo– Rate of all‐cause death was similar with both sirukumab doses– Major causes of death include cardiovascular events, malignancy,

and infections

• Sirukumab associated with imbalances in serious adverse events and gastrointestinal (GI) perforation

• Laboratory abnormalities– Decreases in neutrophil and platelet counts – Elevations in lipid parameters and liver function tests

10

Issues for Consideration

• Efficacy of sirukumab for adults with RA • Design of 52‐week placebo‐controlled radiographic study, ARA3002

• Safety findings, with particular consideration of the imbalance in all‐cause death between sirukumab and placebo

• Dose selection for phase 3 • Overall risk/benefit of sirukumab for adults with moderately to severely active RA

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Purpose of Proceedings Before an Advisory Committee (21 CFR 14.5)

a. An advisory committee is utilized to conduct public hearing on matters of importance that come before FDA, to review the issues involved, and to provide advice and recommendations to the Commissioner

b. The Commissioner has sole discretion concerning action to be taken and policy to be expressed on any matter considered by an advisory committee

CFR=Code of Federal Regulations

FDA Arthritis Advisory Committee (AAC)Introduction and Clinical Overview

BLA 761057: Sirukumab for the treatment of adult patients with moderately to severely active rheumatoid

arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti‐


Mark Borigini, MDMedical Officer

Division of Pulmonary, Allergy, and Rheumatology ProductsCenter for Drug Evaluation and Research

August 2, 2017

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Overview of FDA Presentations

• Introduction and Clinical Overview– Mark Borigini, MD

• Dose Selection Considerations: Phase 2 Study Results– Dipak Pisal, PhD

• Review of Efficacy– William Koh, PhD

• Review of Safety and Risk/Benefit Considerations – Mark Borigini, MD

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Overview

• Product: • Sirukumab (Plivensia®)

• Mechanism of action:• Human monoclonal antibody against interleukin (IL)‐6

• Proposed indication:• Treatment of adult patients with moderately to severely active

rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti‐rheumatic drugs (DMARDs)

• Proposed dosage:– 50 mg subcutaneously every 4 weeks

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• Safety findings, with particular consideration of the imbalance in all‐cause death between sirukumab and placebo

• Dose selection for phase 3 • Overall risk/benefit of sirukumab for adults with moderately to severely active RA

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Evaluation of Radiographic Progression: Study Design Considerations

• Duration • Comparator • Escape

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Escape Options in ARA3002 and ARA3003

• Escape allowed at multiple time points – Week 18 (ARA3002 and ARA3003)

• Re‐randomized to sirukumab (50 mg q4w or 100 mg q2w)

– Week 40 (ARA3002)• Re‐randomized to sirukumab (50 mg q4w or 100 mg q2w)

– From Week 28 (ARA3002) or Week 24 (ARA3003)• Initiation or up‐titration of DMARDs/oral corticosteroids

– Escape criteria: <20% improvement from baseline in swollen and tender joint count

Q2W=every two weeks; Q4W=every four weeks

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Relevant Regulatory History (1)

• Pre‐IND (investigational new drug) meeting (March 27, 2008) – During drug development, need to develop evidence to support the choice of dose

• IND submitted (June 2008)

• End of Phase 2 (EOP2) meeting (April 5, 2011)– FDA noted concerns about the lack of efficacy data in support of the 50 mg q12w dose of sirukumab that Janssen proposed in their pivotal phase 3 trials

• Recommended either additional dose‐ranging to evaluate lower doses and/or alternative dosing intervals or choose another dose level for phase 3 utilizing a dose evaluated in phase 2 trials

22

Relevant Regulatory History (2)

• Advice/Information Request (October 12, 2012) – In proposed protocol for CNTO136ARA3002, patients randomized to

placebo could remain on placebo for up to 52 weeks• FDA noted ethical concern with respect to withholding treatment from

patients with uncontrolled disease activity for extended periods of time– Selected doses for phase 3 studies (100 mg q2w and 50mg q4w) were

acceptable and at the sponsor’s discretion, but concerns raised at EOP2 meeting were noted

• Advice/Information Request (November 21, 2012) – In follow‐up to the sponsor’s questions regarding whether the rescue

mechanisms were adequate for a 52‐week placebo control period in study CNTO136ARA3002, FDA responded that the protocol was generally acceptable

• Pre‐BLA meeting (May 18, 2016)– General agreement on content and format of BLA submission

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• Dose selection for phase 3 • Safety findings, with particular consideration of the imbalance in all‐cause death between sirukumab and placebo

• Overall risk/benefit of sirukumab for adults with moderately to severely active RA

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Dose Selection Considerations: Phase 2 Study Results

Dipak S. Pisal, PhDClinical Pharmacology Reviewer

Division of Clinical Pharmacology II Office of Clinical PharmacologyFood and Drug Administration

August 2, 2017

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Outline• Dose Selection

• Phase 2 Study

• Dose Selection for Phase 3

• End of Phase 2 (EOP2) Meeting Communication

• Summary

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Dose Selection

• The Agency’s expectation is that there will be adequate dose‐ranging in the clinical development program for Rheumatoid Arthritis (RA)

• Phase 3 Dose Selection:– PK, PD, Efficacy and Safety from dose‐ranging studies – Wide range of doses and dosing regimens– Efficacy endpoints that will be used in phase 3 studies. (e.g. ACR, DAS28)

– Dose related safety considerations (e.g. lipids, AST/ALT, hematology, etc. )

PK: pharmacokinetics, PD: pharmacodynamics; ACR 20:American College of Rheumatology score 20, DAS28: Disease Activity Score‐28, AST: aspartate aminotransferase; ALT: alanine aminotransferasehttps://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm354468.pdf

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Dose Selection in Current Application

• The proposed dose is 50 mg q4w

• In the phase 3 program, doses of 50 mg q4w and 100 mg q2w were evaluated

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Efficacy Results: ACR20 & ACR50

• A higher proportion of patients achieved ACR responses at Week 12 in each of the 4 sirukumab treatment groups compared with the placebo group

• 100 mg dose groups showed a trend of higher response

ACR 20 ACR 50

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Efficacy Summary• All sirukumab dose groups showed better response than placebo

• There was a trend with higher efficacy with higher dose towards the later time points, although no clear dose response was observed up to week 12• ACR: 100 mg dose groups showed a trend of higher response • Separation in mean change from baseline DAS28(CRP) & CDAI • No clear separation in mean DAS28 (CRP) & CDAI except the 100 mg q2w

• Selection of 100 mg every two weeks & 50 mg every 4 weeks was reasonable

• It is a study with sample size (N= ~ 30) in each treatment group

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Proposed Doses for Phase 3

• Janssen initially proposed following dosing regimens at the end of the phase 2 meeting:– Based on these efficacy, safety and exposure response modeling (serum level efficacy analysis, & PK/ACR20 E‐R model)

• 100 mg every 2 weeks • 50 mg every 4 weeks • 50 mg every 12 weeks

― It was not studied dose group in phase 2 study & lacked safety and efficacy data

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EOP2 Meeting & Discussions

IND 101073 EOP2, April 5, 2011, IND 101073, October, 12, 2012

• FDA expressed concerns about the lack of efficacy data in support of the 50 mg Q12 week dose of sirukumab and recommended additional dose ranging study to evaluate lower doses and/or alternative dosing intervals or choose another dose level for the Phase 3 trials that utilizes a Q2 or Q4 week dosing regimen

Advice/Information Request (October 12, 2012)

• Selected doses for phase 3 studies (100 mg q2w and 50mg q4w) were acceptable and at the Janssen’s discretion, but concerns raised at EOP2 meeting were noted

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Summary

• Efficacy:– All sirukumab dose groups showed better response than placebo

– There was a trend with higher efficacy with higher dose at later time points, No dose response was observed up to week 12

• Safety:– No dose response was observed for safety lab values, however all sirukumab treatment group showed larger magnitude of change

• Janssen selected 100 mg q2w and 50 mg q4w as their final doses for phase 3 studies

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Arthritis Advisory Committee MeetingBLA761057: Sirukumab for RA

Review of Efficacy

William Koh, PhD Statistical Reviewer

Division of Biometrics II, Office of Biostatistics,Office of Translational Sciences, CDER

August 2, 2017

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Outline

• Overview of phase 3 efficacy studies

– Study design

• Key efficacy results in placebo‐controlled studies

– Baseline demographics, disposition

– Signs and symptoms endpoints

– Radiographic progression results

• Key efficacy results in active‐controlled study

• Conclusions of efficacy findings

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Study ARA3002 Design• 52‐week, randomized, parallel‐group, double‐blind study in

1670 patients with active rheumatoid arthritis (RA) and inadequate response to DMARDs

• Escape for placebo subjects (to sirukumab)– Early Escape *(EE) (at Week 18)– Late Escape * (LE) (at Week 40)

• Co‐Primary endpoints– ACR20 (at Week 16)– Change from baseline in vdH‐S score (at Week 52)

• Secondary endpoints – Change from baseline in HAQ‐DI (at Week 24) – ACR50 (at Week 24) – DAS28(CRP) < 2.6 (at Week 24)– Major Clinical Response or MCR (at Week 52)

* EE/LE Criteria: <20% improvement from baseline in both swollen and tender joint countsvdH‐S : van der Heijde modified Sharp score

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Study ARA3003 Design• 24‐week, randomized, parallel‐group, double‐blind study in

878 patients with active rheumatoid arthritis (RA) and inadequate response to TNF inhibitors

• Escape for placebo subjects– Early Escape* (EE) (at Week 18)

• Primary endpoint– ACR20 (at Week 16)

• Secondary endpoints – Change from baseline in HAQ‐DI (at Week 24)– ACR50 (at Week 24) – DAS28(CRP) < 2.6 (at Week 24)

* EE Criteria: <20% improvement from baseline in both swollen and tender joint counts

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American College of Rheumatology (ACR) Response Criteria

• Multi‐component endpoint• Proportion of patients achieving a target % improvement from

baseline (20, 50, 70)• For ACR20

– At least 20% improvement in swollen and tender joint counts AND– At least 20% improvement in at least 3 out of the 5 components

• Patient global assessment (0 – 10 unit)• Physician global assessment (0 – 10 unit)• Patient pain (0 – 10 unit)• Health Assessment Questionnaire‐Disability Index (0 – 3 unit)• Laboratory test for inflammation (CRP or ESR)

• Treatment failure criteria: patients with certain background medication changes or who discontinued treatment

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Baseline Demographics

ARA3002(N=1670)

ARA3003(N=878)

Age (Years) a 53 55 65 and above 15% 22%

Female 80% 80%White 72% 75%Hispanic or Latino 18% 19%Weight (kg) a 72 76 Height (cm) a 163 162 Body Mass Index (kg/m2) ab

27 29

a : Mean; b : Weight (kg) divided by the square of height (meters)

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SF‐36 Mean Changes at Week 16

Placebo SIR50 mg Q4W

SIR100 mg Q2W

SIR50 mg Q4W vs Placebo Diff (95% CI)

SIR100 mg Q2W vs PlaceboDiff (95% CI)

SF‐36 Physical Component Summary ScoreARA3002 2.7 5.5 5.8 2.9 (2.1, 3.7) 3.2 (2.4, 4.0) ARA3003 2.0 4.7 5.3 2.7 (1.5, 3.9) 3.2 (2.0, 4.4)

SF‐36 Mental Component Summary ScoreARA3002 2.7 4.8 4.8 2.1 (1.0, 3.3) 2.1 (1.0, 3.3) ARA3003 1.6 3.4 4.4 1.8 (0.1, 3.5) 2.8 (1.1, 4.5)

SF: short form

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• van der Heijde modified Sharp or vdH‐S (range: 0 – 448) – Erosion Score (0 – 280) – Joint Space Narrowing Score (0 – 168)

• Prespecified analysis

• Important supportive analyses

Radiographic Progression Evaluation in ARA3002

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• van der Heijde modified Sharp or vdH‐S (range: 0 – 448) – Erosion Score (0 – 280) – Joint Space Narrowing Score (0 – 168)

• Prespecified analysis– Linear extrapolation (LE)

• Important supportive analyses– Observed data analysis– Mixed effects analysis

Radiographic Progression Evaluation in ARA3002

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Radiographic Progression Evaluation: Primary Analysis

Mean (SD) Change from Baseline at Week 52

Comparison to Placebo

Imputed using LE

Observed Week 52b

Treatment Differencea(95% CI)

P‐value

Placebo (N=550) 3.7 (9.3) ‐ ‐ 263 (48%) 440(80%)

SIR 50 mg Q4W (N=553)

0.5 (3.0) ‐3.2 (‐4.0, ‐2.4) <0.0001 93 (15%) 459 (83%)

SIR 100 mg Q2W(N=551)

0.5 (3.3) ‐3.2(‐4.1, ‐2.4) <0.0001 84 (15%) 460 (83%)

a : Mean difference (95% CI) based on supportive reviewer analysisb : Radiographic data collected within Week 52±28 days available for Week 52 analysis

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Radiographic Progression Evaluation: Primary Analysis

Mean (SD) Change from Baseline at Week 52


Imputed using LE

Observed Week 52b

Treatment Differencea(95% CI)

P‐value

Placebo (N=550) 3.7 (9.3) ‐ ‐ 263 (48%) 440(80%)

SIR 50 mg Q4W (N=553)

0.5 (3.0) ‐3.2 (‐4.0, ‐2.4) <0.0001 93 (15%) 459 (83%)

SIR 100 mg Q2W(N=551)

0.5 (3.3) ‐3.2(‐4.1, ‐2.4) <0.0001 84 (15%) 460 (83%)

a : Mean difference (95% CI) based on supportive reviewer analysisb : Radiographic data collected within Week 52±28 days available for Week 52 analysis

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Change from Baseline at Week 52


Treatment N Mean (SD) Difference(95% CI) P‐value

Placebo 440 3.0 (8.0)

SIR 50 mg Q4W

459 0.6 (2.9) ‐2.4(‐3.2, ‐1.6)

<0.0001

SIR 100 mg Q2W

460 0.4 (2.7) ‐2.7(‐3.4, ‐1.9)

<0.0001

Radiographic Progression Evaluation: Observed Data Analysis

Includes all radiographic data collected within Week 52±28 days

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Addressing Missing Data• Tipping point sensitivity analysis including all observed data regardless of treatment discontinuation or early escape were conducted for – ACR20 at Week 16 – HAQ‐DI at Week 16– vdH‐S at Week 52

• Sensitivity analyses conducted were supportive of the efficacy of sirukumab for both signs and symptoms and radiographic endpoints

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Study ARA3005 Design• 24‐week, randomized, active‐controlled, parallel‐group, double‐

blind study in 559 patients with active RA who failed methotrexate

• Study design– Monotherapy– Escape (EE) at Week 16

• ADA 40mg Q2W ADA 40mg QW• SIR 50mg Q4W SIR 100mg Q2W• Patients on SIR 100mg Q2W remained on their dosing

• Primary analyses based on SIR 100mg Q2W– Change from baseline in DAS28(ESR) score at Week 24– ACR50 at Week 24

• Secondary analyses – DAS28 (ESR) < 2.6 100 mg Q2W– Change from baseline in DAS28(ESR) score, ACR50 50 mg Q4W– ACR20 for 100mg Q2W, ACR20 for 50mg Q4W

DAS28(ESR)=disease activity score 28 joint count using erythrocyte sedimentation rate (ESR)

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Disposition Table for ARA3005

ADA40mg Q2W(N=186)

SIR 50mg Q4W(N=186)

SIR100mg Q2W(N=187)

Completed randomized treatment up to Week 16

172 ( 92%) 165 ( 89%) 168 ( 90%)

Qualified for early escape at Week 16 13 (7%) 17 (9%) 7 (4%)

Completed randomized treatment up to Week 24

155 ( 83%) 142 ( 76%) 163 ( 87%)

Completed randomized or escape treatment up to Week 24

167 ( 90%) 156 ( 84%) 163 ( 87%)

Discontinued prior to Week 24 19 ( 10%) 30 ( 16%) 24 ( 13%)

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Overall Efficacy Findings

• Efficacy on symptoms + function in ARA3002 and ARA3003 for both sirukumab doses– Primary Week 16 ACR20 results– Results for HAQ‐DI, secondary endpoints supportive

• Evidence of inhibition of radiographic progression in ARA3002

• Results convincing despite missing data• No consistent differences between doses• No superiority but similar improvements to adalimumab in ARA3005

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76

Overview of Safety of Approved Monoclonal Antibodies to IL‐6 Receptor

Boxed Warning: • Serious infections that may lead to hospitalization or death. Reported infections

include: tuberculosis, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens

Warnings/Precautions • Serious Infections• Gastrointestinal perforation• Laboratory abnormalities (neutropenia, thrombocytopenia, elevated liver enzymes, lipid

abnormalities)• Immunosuppression• Hypersensitivity reactions• Demyelinating disorders• Active hepatic disease and hepatic impairment• Live vaccines

*Not all Warnings/Precautions are included in the labeling of all approved IL‐6 inhibitors and there are differences in the safety information discussedIL=interleukin

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Focus of Safety Presentation

• All‐cause death• Serious adverse events (SAEs)• Major adverse cardiovascular events (MACE)• Infections• Malignancy• Gastrointestinal (GI) Perforation• Laboratory Abnormalities (lipids, neutrophil and platelet counts, and liver function tests)

• Adalimumab comparator study (ARA3005)

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91

Kaplan‐Meier Analysis of Time to Death in Studies ARA3002 and ARA3003

Source: Information request response, Figure 2, page 8, submitted 7/24/17

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All‐Cause Death Summary

• Through 18 weeks of exposure, the incidence rate of all‐cause death was the same in the placebo group and the two sirukumab groups

• Through 52 weeks of exposure, the incidence rate of all‐cause death was higher in each sirukumab group compared to placebo– The three main categories of causes of death were cardiovascular events, malignancy, and infections

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98

SAE Summary

• Through 18 and 52 weeks of exposure, the incidence rate of SAEs was higher in each sirukumab group compared to placebo– Adverse events related to infections were the most frequently reported

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• All‐cause death• Serious adverse events• Major adverse cardiovascular events (MACE)• Infections• Malignancy• Gastrointestinal (GI) Perforation• Laboratory Abnormalities (lipids, neutrophil and platelet counts, and liver function tests)


104

MACE Summary

• Through 18 and 52 weeks of exposure, the incidence rate of MACE was higher in the sirukumab 50 mg group compared to the placebo and sirukumab 100 mg groups

• Through 18 and 52 weeks of exposure, the incidence rate of MACE was similar in the sirukumab 100 mg group and the placebo group

105


• Deaths• Serious adverse events• Major adverse cardiovascular events (MACE)• Infections• Malignancy• Gastrointestinal (GI) Perforation• Laboratory Abnormalities (lipids, neutrophil and platelet counts, and liver function tests)


110

Infections Summary

• Through 18 and 52 weeks of exposure, the incidence rate of SAEs of infection and herpes zoster were higher in each sirukumab group compared to placebo– There were a limited number of cases of tuberculosis and opportunistic infections, but these cases occurred in the sirukumab arms and not in the placebo arms

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• Deaths• Serious adverse events (SAE)• Major adverse cardiovascular events (MACE)• Infections• Malignancy• Gastrointestinal (GI) Perforation• Laboratory Abnormalities (lipids, neutrophil and platelet counts, and liver function tests)


117

Kaplan‐Meier Analysis of the Time to Onset of Malignancies excluding NMSC in Studies ARA3002 and ARA3003

Source: Information request response, Figure 2, page 18, submitted 7/11/17

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Malignancy Summary

• Through 18 weeks of exposure, the incidence rate of malignancy was the same for the placebo and sirukumab 100 mg groups and lower for the sirukumab 50 mg group

• Through 52 weeks of exposure, the incidence rate of malignancy was higher in each sirukumab group compared to placebo

119




124

GI Perforation Summary

• Through 18 and 52 weeks of exposure, the incidence rate of GI perforations was higher in each sirukumab group compared to placebo

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129

Laboratory Abnormalities Summary

• Sirukumab was associated with increases in lipid parameters and liver function tests and decreases in neutrophil and platelet counts – There was no dose‐response for these laboratory changes

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134

ARA3005 Safety Summary

• Compared to adalimumab: – More adverse events of special interest, such as death, malignancy, MACE, and serious infection, with sirukumab

– Sirukumab associated with greater decreases in neutrophil counts

– Sirukumab associated with more elevations in AST, ALT, and total bilirubin, and greater mean changes in lipid parameters

135

Safety summary

• Imbalances in death, serious adverse events, MACE, serious infection, and malignancy noted in the sirukumab program

• Laboratory abnormalities – Lipid elevations, neutropenia, thrombocytopenia, and liver function test elevations

• Additional risks include hypersensitivity and GI perforation

136

Overall Risk/Benefit

• Benefits– Sirukumab superior to placebo for:

– Signs and symptoms– Physical function – Inhibition of radiographic progression

• Risks– Imbalances noted

• Death, MACE, and malignancy

– Serious infection– GI perforation – Laboratory abnormalities

– Hypersensitivity reactions

FDA Arthritis Advisory CommitteeCharge to the Committee

BLA 761057: Sirukumab for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti‐


Janet Maynard, MD, MHSClinical Team Leader

Division of Pulmonary, Allergy, and Rheumatology ProductsCenter for Drug Evaluation and Research

August 2, 2017

139

Efficacy Considerations

• Efficacy for signs and symptoms (ACR Responses, DAS28), physical function (HAQ‐DI), and radiographic outcomes

• Efficacy of 50 mg q4w and 100 mg q2w was similar• Sirukumab was not superior to adalimumab

140

Safety Considerations

• All‐cause death– Imbalance in all‐cause death with sirukumab over placebo– Rate of all‐cause death was similar with both sirukumab doses– Major causes of death include cardiovascular events, malignancy,

and infections

• Sirukumab associated with imbalances in serious adverse events and gastrointestinal (GI) perforation

• Laboratory abnormalities– Decreases in neutrophil and platelet counts – Elevations in lipid parameters and liver function tests

141

Approval of an Application 21 CFR 314.105 (c)

• “FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling”

142

Efficacy Standard21 CFR 314.125 Refusal to Approve an Application

• (b)(5) “… substantial evidence consisting of adequate and well‐controlled investigations … that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.”

143

Safety Standard21 CFR 314.125 Refusal to Approve an Application

(b)(2) “… do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.” (b)(3) “The results of the test show that the drug is unsafe for use under the conditions prescribed, recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for use under those conditions.” (b)(4) “There is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.”

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Question 1 (Discussion)

• Discuss the efficacy of sirukumab for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more disease‐modifying anti‐rheumatic drugs (DMARDs).

145

Question 2 (Voting)

• Overall, do the data provide substantial evidence of the efficacy of sirukumab for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more DMARDs?

a. If not, what data are needed?

146


• Discuss the design of the 52‐week placebo‐controlled radiographic study, ARA3002.

147


• Discuss the safety findings in the phase 3 program, with particular consideration of the imbalance in all‐cause death between sirukumab and placebo.

148


• Discuss the dose selection for the phase 3 program.

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Question 6 (Voting)

• Is the safety profile of sirukumab adequate to support approval of sirukumab for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more DMARDs?


150

Question 7 (Voting)

• Do you recommend approval of sirukumab at the proposed dose of 50 mg subcutaneously every 4 weeks for the proposed indication of the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to one or more DMARDs?


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FDA Arthritis Committee (AAC) FDA Introductory Remarks€¦ · FDA Arthritis Advisory Committee (AAC) FDA Introductory Remarks BLA 761057: Sirukumab for the treatment of adult patients