AAN 2015 alemtuzumab

THE 67TH AAN ANNUAL MEETING

Durable Effect of Alemtuzumab on MRI Activity in Treatment-Naive Active Relapsing-Remitting Multiple Sclerosis Patients: 4-Year Follow-up of CARE-MS I

Switching to Alemtuzumab From Subcutaneous Interferon Beta-1a After CARE-MS II Further Improved MRI Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis

Durable Effect of Alemtuzumab on MRI Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis Who Relapsed on Prior Therapy: 4-Year Follow-up of CARE-MS II

Improvement in Disability With Alemtuzumab Is Associated With Quality of Life Improvement Over 3 Years in Patients Who Relapsed on Prior Therapy

Durable Effect of Alemtuzumab on Disability Improvement in Patients With Relapsing-Remitting Multiple Sclerosis Who Relapsed on a Prior Therapy

Switching to Alemtuzumab From Subcutaneous Interferon Beta-1a After CARE-MS I Further Improved MRI Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis

Alemtuzumab Slows Brain Volume Loss Over 4 Years Despite Most Relapsing-Remitting Multiple Sclerosis Patients Not Receiving Treatment for 3 Years

Slowing of Brain Volume Loss in Patients With Relapsing-Remitting Multiple Sclerosis After Switching From Subcutaneous Interferon Beta-1a to Alemtuzumab

Incidence of Infection Decreases Over Time in Alemtuzumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis: 4-Year Follow-up of the CARE-MS Studies

Durable Efficacy of Alemtuzumab in Patients With Highly Active Relapsing-Remitting Multiple Sclerosis Who Relapsed on a Prior Therapy

Improvement in Clinical Outcomes in Treatment-Naive Relapsing-Remitting Multiple Sclerosis Patients Who Switched From Subcutaneous Interferon Beta-1a to Alemtuzumab

The Efficacy of Alemtuzumab Is Maintained in Patients Who Develop Thyroid Adverse Events

Durable Effect of Alemtuzumab on Clinical Outcomes in Patients With Relapsing-Remitting Multiple Sclerosis Who Relapsed on Prior Therapy: 4-Year Follow-up of CARE-MS II

Administration of Alemtuzumab on Nonconsecutive Days Does Not Impact Infusion-Associated Reactions, Efficacy, or Lymphocyte Depletion

Improvement in Clinical Outcomes Following Switch From Subcutaneous Interferon Beta-1a to Alemtuzumab: CARE-MS II Extension Study

Evaluation of Comprehensive Alemtuzumab Infusion Guidance in Patients With Relapsing-Remitting Multiple Sclerosis: EMERALD Study Design

DURABLE EFFECT OF ALEMTUZUMAB ON MRI ACTIVITY IN TREATMENT-NAIVE ACTIVE RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS: 4-YEAR FOLLOW-UP OF CARE-MS I

Douglas L Arnold,1,2 Anthony Traboulsee,3 Alasdair J Coles,4 Jeffrey A Cohen,5 Edward J Fox,6 Hans-Peter Hartung,7 Eva Havrdova,8 Krzysztof W Selmaj,9 David H Margolin,10 Yang Zhao,10 Michael A Panzara,10 D Alastair S Compston4; on behalf of the CARE-MS I Investigators

1NeuroRx Research, Montréal, Québec, Canada; 2Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 3The University of British Columbia, Vancouver, British Columbia, Canada; 4University of Cambridge School of Clinical Medicine, Cambridge, UK; 5Cleveland Clinic, Cleveland, OH, USA; 6Central Texas Neurology Consultants, Round Rock, TX, USA; 7Heinrich-Heine University, Düsseldorf, Germany; 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 9Medical University of Łódź, Łódź, Poland; 10Genzyme, a Sanofi company, Cambridge, MA, USA

OBJECTIVE:

•Examine the effect of alemtuzumab on 4-year magnetic resonance imaging (MRI) outcomes in CARE-MS I patients who entered an ongoing extension study.

BACKGROUND:

•In the CARE-MS I trial in treatment-naive patients with active relapsing-remitting multiple sclerosis (RRMS), alemtuzumab had superior efficacy versus subcutaneous interferon beta-1a, including a reduction in MRI lesion activity and brain volume loss over 2 years.

DESIGN/METHODS:

•Core study patients randomized to alemtuzumab received 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. In the extension study, alemtuzumab-treated patients could receive as-needed retreatment ≥1 year after the previous course. MRI scans were acquired at baseline and yearly thereafter. MRI outcomes included gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity, and MRI activity (absence of Gd-enhancing and new/enlarging T2 lesions).

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.246)

RESULTS:

• 349 (95.1%) CARE-MS I alemtuzumab-treated patients entered the extension; data are available through 4 years from first treatment, and follow-up is ongoing.

• Through 4 years (2 years of core study and 2 years of extension study), 73.4% of patients received only the initial 2 courses of treatment, 20.9% received 1 additional course, and 4.6% received 2 additional courses

• Fewer than 2% of patients received another DMT during the extension study

• Baseline characteristics of patients entering the extension study were similar to patients in the core study (Table 1)

Title


RESULTS:

• In Year 3 and Year 4, the proportions of patients free of Gd-enhancing (90% and 87%), new/enlarging T2 (72% and 71%), or new T1 lesions (89% and 85%) remained stable compared with the core study (Figure 1A–C)

• Most patients were MRI activity-free at Years 3 (72%) and 4 (70%) (Figure 1D)

Title


RESULTS:

•The majority of alemtuzumab-treated patients had no new lesions over 4 years (Figure 2)

•The proportion of alemtuzumab-treated patients with ≥2 new lesions remained low in Year 4 compared with Year 1 for new Gd-enhancing: 5.2% vs 7.3%, new/enlarging T2: 20.5% vs 25.1%, and new T1 lesions: 10.0% vs 10.3% (Figure 2)

CONCLUSIONS:

•The majority of alemtuzumab patients remained free of new lesions and MRI activity in Year 4 despite 73.4% of patients receiving their last treatment course 3 years prior. These data support the durable efficacy of alemtuzumab in this RRMS population

STUDY SUPPORTED BY: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals

Title


SWITCHING TO ALEMTUZUMAB FROM SUBCUTANEOUS INTERFERON BETA-1A AFTER CARE-MS II FURTHER IMPROVED MRI OUTCOMES IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS

Daniel Pelletier,1 Frederik Barkhof,2 Alasdair J Coles,3 Jeffrey A Cohen,4 D Alastair S Compston,3 Edward J Fox,5 Hans-Peter Hartung,6 Eva Havrdova,7 David H Margolin,8 Linda Kasten,9 Michael A Panzara,8 Douglas L Arnold10,11; on behalf of the CARE-MS II Investigators

1Yale School of Medicine, North Haven, CT, USA; 2VU University Medical Centre, Amsterdam, Netherlands; 3University of Cambridge School of Clinical Medicine, Cambridge, UK; 4Cleveland Clinic, Cleveland, OH, USA; 5Central Texas Neurology Consultants, Round Rock, TX, USA; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Genzyme, a Sanofi company, Cambridge, MA, USA; 9PROMETRIKA LLC, Cambridge, MA, USA; 10NeuroRx Research, Montréal, Québec, Canada; 11Montréal Neurological Institute, McGill University, Montréal, Québec, Canada

OBJECTIVE:

•Examine magnetic resonance imaging (MRI) outcomes in patients who switched to alemtuzumab after receiving subcutaneous interferon beta-1a (SC IFNB-1a) in CARE-MS II

BACKGROUND:

•In the 2-year CARE-MS II study of relapsing-remitting multiple sclerosis patients who relapsed on prior therapy, alemtuzumab demonstrated improvements in many MRI outcomes, including reductions in MRI lesion activity and brain volume loss, compared with SC IFNB-1a. A CARE-MS extension study is ongoing

DESIGN/METHODS:

•In CARE-MS II, SC IFNB-1a–treated patients received 44 μg, 3 times/week for 2 years. In the extension, former SC IFNB-1a–treated patients received annual alemtuzumab courses in Years 3 and 4 (12 mg intravenous). MRI outcomes assessed at baseline and yearly included gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity, and MRI activity-free (absence of Gd-enhancing and new/enlarging T2 lesions).

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.248).

Patients

• Of the 175 SC IFNB-1a–treated patients who completed the CARE-MS II core study, 146 (83.4%) entered the extension

• Of these patients, 12 received 1 course of alemtuzumab and 131 received 2 courses

• Baseline characteristics of patients entering the extension study were similar to that in patients in the core study (Table 1)

Title


Gd-Enhancing, New/Enlarging T2 Hyperintense, and New T1 HypointenseLesion Activity

• Proportions of patients free of Gd-enhancing (91% vs 78%), new/enlarging T2 (81% vs 48%), and new T1 (93% vs 74%) lesions significantly increased after switching to alemtuzumab (Year 4) compared with Year 2 on SC IFNB-1a in the core study (Figure 1A–C)

• Proportion of patients free of MRI activity was also significantly higher after switching to alemtuzumabcompared with Year 2 on SC IFNB-1a (81% vs 47%; Figure 1D)

Title


• The proportion of patients with ≥2 new lesions significantly decreased after switching to alemtuzumab from Year 2 to Year 4 for new/enlarging T2 lesions (41.3% to 10.7%) and new T1 lesions (16.9% to 3.1%; both P<0.0001), but only numerically decreased for new Gd-enhancing lesions (12.2% to 6.8%; P=0.14) (Figure 2)

CONCLUSIONS:

• Switching from SC IFNB-1a to alemtuzumab improved the proportion of patients MRI activity-free. These findings further confirm the superior efficacy of alemtuzumab in patients who received more than 2 years of prior disease-modifying therapy.


Title


DURABLE EFFECT OF ALEMTUZUMAB ON MRI OUTCOMES IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS WHO RELAPSED ON PRIOR THERAPY: 4-YEAR FOLLOW-UP OF CARE-MS II Anthony Traboulsee,1 Alasdair J Coles,2 Jeffrey A Cohen,3 D Alastair S Compston,2 Edward J Fox,4 Hans-Peter Hartung,5 Eva Havrdova,6 Krzysztof W Selmaj,7 David H Margolin,8 Yang Zhao,8 Michael A Panzara,8 Douglas L Arnold9,10; on behalf of the CARE-MS II Investigators

1The University of British Columbia, Vancouver, British Columbia, Canada; 2University of Cambridge School of Clinical Medicine, Cambridge, UK; 3Cleveland Clinic, Cleveland, OH, USA; 4Central Texas Neurology Consultants, Round Rock, TX, USA; 5Heinrich-Heine University, Düsseldorf, Germany; 6First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 7Medical University of Łódź, Łódź, Poland; 8Genzyme, a Sanofi company, Cambridge, MA, USA; 9NeuroRx Research, Montréal, Québec, Canada; 10Montréal Neurological Institute, McGill University, Montréal, Québec, Canada

OBJECTIVE:

•Examine the effect of alemtuzumab on 4-year magnetic resonance imaging (MRI) outcomes in CARE-MS II patients who entered an ongoing extension.

BACKGROUND:

•In the CARE-MS II trial, alemtuzumab had superior benefit versus subcutaneous interferon beta-1a, including improved MRI outcomes over 2 years, in relapsing-remitting multiple sclerosis (RRMS) patients who relapsed on prior therapy.

DESIGN/METHODS:

•Core study patients randomized to alemtuzumab received 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. In the extension study, alemtuzumab-treated patients could receive as-needed retreatment ≥1 year after the previous course. MRI scans were acquired at baseline and yearly thereafter. MRI outcomes included gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense and new T1 hypointense lesion activity, and MRI activity (absence of Gd-enhancing and new/enlarging T2 lesions).

Title


Patients:

• The extension study of CARE-MS II enrolled 393 (93%) eligible patients from the alemtuzumab arm of the core study

• Through 4 years (2 years of core study and 2 years of extension study), 67.7% of patients received only the initial 2 courses of treatment, 24.2% received 1 additional course, and 7.4% received 2 additional courses

• 5.3% of patients received another DMT during the extension study


Title


Gd-Enhancing, New/Enlarging T2 Hyperintense, and New T1 HypointenseLesion Activity

• In Years 3 and 4, the proportions of patients free of Gd-enhancing (87% and 89%), new/enlarging T2 (69% and 70%), or new T1 lesions (88% and 86%) remained stable compared with the core study (Figure 1A–C)

• Most patients were free of MRI activity at Years 3 (68%) and 4 (70%) (Figure 1D)

Title


• The majority of alemtuzumab-treated patients had no new lesions over 4 years (Figure 2)

• The proportion of alemtuzumab-treated patients with ≥2 new lesions remained low in Year 4 compared with Year 1 for new Gd-enhancing: 4.5% vs 8.9%, new/enlarging T2: 22.3% vs 24.6%, and new T1 lesions: 6.0% vs 7.8% (Figure 2)

Title


CONCLUSIONS:

• In the core CARE-MS II study, alemtuzumab significantly reduced the risk of developing new lesions in patients with active RRMS who had an inadequate response to a prior therapy

• In the extension study, the majority of alemtuzumab-treated patients continued to remain free of MRI activity in Year 4 despite most patients receiving their last treatment course 3 years prior

• These results reflect a reduction in focal white matter inflammation and are consistent with the superior clinical efficacy of alemtuzumab over SC IFNB-1a

• The durability of efficacy following dosing of alemtuzumab (at Month 0 and 12 months later for most patients) may be the result of immunomodulatory effects due to lymphocyte depletion and the distinct pattern of lymphocyte repopulation after treatment, and is a unique treatment approach for DMTs

Title



IMPROVEMENT IN DISABILITY WITH ALEMTUZUMAB IS ASSOCIATED WITH QUALITY OF LIFE IMPROVEMENT OVER 3 YEARS IN PATIENTS WHO RELAPSED ON PRIOR THERAPY

Mariko Kita,1 Jeffrey A Cohen,2 Thibault Moreau,3 Eva Havrdova,4 Rafael Arroyo González,5 Joseph Herbert,6 Linda Kasten,7

David H Margolin,8 Gavin Giovannoni9; on behalf of the CARE-MS II Investigators

1Virginia Mason Hospital and Medical Center, Seattle, WA, USA; 2Cleveland Clinic, Cleveland, OH, USA; 3Burgundy University, Dijon University Hospital, Dijon, France; 4First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 5Hospital Clinico San Carlos, Madrid, Spain; 6New York University Medical Center, New York, NY, USA; 7PROMETRIKA, LLC, Cambridge, MA, USA; 8Genzyme, a Sanofi company, Cambridge, MA, USA; 9Queen Mary University of London, Barts and The London School of Medicine, London, UK

OBJECTIVE:

•To examine the relationship between quality of life (QoL) and sustained reduction in preexisting disability (SRD).

BACKGROUND:

•In CARE-MS II, alemtuzumab-treated patients were significantly more likely to achieve SRD and had greater QoL improvements than those treated with subcutaneous interferon beta-1a. QoL improvements persisted through 3 years, suggesting durable efficacy.

METHODS:

•CARE-MS II was a 2-year, phase 3, rater-blinded study in which patients received alemtuzumab 12 mg at baseline and month 12, with as-needed retreatment in the ongoing extension. QoL was assessed using Functional Assessment of Multiple Sclerosis (FAMS; scale 0−176); Short-Form 36-Item survey physical component summary (PCS) and mental component summary (MCS; scales 1−100); and EuroQol in 5 Dimensions visual analog scale (EQ-5D VAS; scale 0−100).

•SRD was confirmed over 6 months in patients with baseline Expanded Disability Status Scale score ≥2.0. QoL change from baseline was estimated in patients with/without SRD by an unstructured covariance model (time by group interaction).

Title


RESULTS:

•A total of 426 patients were randomized to alemtuzumab 12 mg in CARE-MS II; 393 entered the extension study (Table 1)

•321 patients (75%) had EDSS score ≥2.0 at core study baseline and were thus eligible for SRD assessment

− At Year 2, 29% of patients with baseline EDSS score ≥2.0 achieved 6-month SRD (vs 13% with SC IFNB-1a); this increased to 35% at Year 32,9

•During Year 3, most patients (80%) did not receive alemtuzumab retreatment; <3% received another DMT

− Of patients with 6-month SRD in Year 3, 94% did not receive retreatment with alemtuzumab

− Of patients without 6-month SRD in Year 3, 71% did not receive retreatment with alemtuzumab

Title

AAN 2015: Poster presentation on April 21, 2015 (afternoon session) (P3.260). 2. Giovannoni G, Margolin DH, Palmer J, Herbert J. Neurology2014;82:P3.165. 9. Giovannoni G, Arnold DL, Cohen JA, et al. Neurology 2013;80:P07.120

RESULTS:

• By the end of Year 2, alemtuzumab-treated patients achieving 6-month SRD had significantly greater QoL gains from baseline than those without 6-month SRD on FAMS (difference, 8.15; P=0.0066; Figure 1), PCS (difference, 3.21; P=0.0017; Figure 2), and EQ-5D VAS (7.44; P=0.0003; Figure 4), and this continued through the end of Year 3

Title


RESULTS:

• By the end of Year 2, alemtuzumab-treated patients achieving 6-month SRD had significantly greater QoL gains from baseline than those without 6-month SRD on FAMS (difference, 8.15; P=0.0066; Figure 1), PCS (difference, 3.21; P=0.0017; Figure 2), and EQ-5D VAS (7.44; P=0.0003; Figure 4), and this continued through the end of Year 3− Difference between groups on SF-36 MCS was directionally similar but did not reach statistical significance (1.17; P=0.33; Figure 3)

Title


RESULTS:

• By the end of Year 2, alemtuzumab-treated patients achieving 6-month SRD had significantly greater QoL gains from baseline than those without 6-month SRD on FAMS (difference, 8.15; P=0.0066; Figure 1), PCS (difference, 3.21; P=0.0017; Figure 2), and EQ-5D VAS (7.44; P=0.0003; Figure 4), and this continued through the end of Year 3− Difference between groups on SF-36 MCS was directionally similar but did not reach statistical significance (1.17; P=0.33; Figure 3)

Title


RESULTS:

• By the end of Year 3, change from baseline on all QoL measures was significant in the group achieving 6-month SRD (FAMS: 12.05, P<0.0001; PCS: 4.14, P<0.0001; MCS: 3.17, P=0.0032; EQ-5D VAS: 7.56, P<0.0001)

− Mean change from baseline on all QoL measures for patients without 6-month SRD was positive; however, these did not reach statistical significance

• Between-group comparisons at Year 3 showed significantly greater QoL improvement in patients with 6-month SRD than those without 6-month SRD on FAMS (10.89; P=0.0006), PCS (difference, 3.41; P=0.0011), and EQ-5D VAS (6.474; P=0.0033)

CONCLUSIONS:

• Improvement in preexisting disability was associated with improved QoL, providing evidence that SRD is a clinically meaningful outcome measure

• Physical aspects of QoL were affected by the attainment of disability improvement more than mental aspects of QoL, consistent with the mainly physical EDSS-based definition of SRD

• The observation that a greater proportion of patients experienced SRD with alemtuzumab than with SC IFNB-1a in the core study could underlie treatment differences in QoL scores3,9

• Even though most patients did not receive alemtuzumab retreatment in Year 3, the number who experienced SRD continued to rise, and SRD remained associated with improved QoL

Title

AAN 2015: Poster presentation on April 21, 2015 (afternoon session) (P3.260). 3. Moreau T, Havrdova E, Giovannoni G, et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA,P044 9. Giovannoni G, Arnold DL, Cohen JA, et al. Neurology 2013;80:P07.120


DURABLE EFFECT OF ALEMTUZUMAB ON DISABILITY IMPROVEMENT IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS WHO RELAPSED ON A PRIOR THERAPY

Christopher LaGanke,1 Bruce Hughes,2 Regina Berkovich,3 Jeffrey A Cohen,4 Gavin Giovannoni,5 Linda Kasten,6 David H Margolin7, Eva Havrdova8; on behalf of the CARE-MS II Investigators

1North Central Neurology Associates, Cullman, AL, USA; 2Mercy Ruan Neuroscience Center, Des Moines, IA, USA; 3Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5Queen Mary University of London, Barts and The London School of Medicine, London, UK; 6PROMETRIKA LLC, Cambridge, MA, USA; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic

OBJECTIVE:

•To examine the durability of disability improvement after 4-year follow-up in patients who received alemtuzumab in CARE-MS II

BACKGROUND:

•Alemtuzumab showed superior efficacy on disability outcomes versus high-dose subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) who relapsed on prior therapy in the 2-year phase 3 CARE-MS II study

DESIGN/METHODS:

•In CARE-MS II, patients who relapsed on prior therapy received alemtuzumab (12 mg/day intravenous) at baseline and month 12. In the extension study, alemtuzumab-treated patients could receive as-needed retreatment ≥1 year apart or other disease-modifying therapies. Endpoints included change from core study baseline in Expanded Disability Status Scale (EDSS) score (stability, or ≥0.5 point increase [worsening], or ≤0.5 point decrease [improvement]) and sustained reduction in preexisting disability (SRD: ≥1-point EDSS decrease from baseline EDSS score over ≥3, 6, or 12 months [patients with baseline score ≥2.0]).

Title


Patients

• The extension study enrolled 393 (93%) eligible patients from the alemtuzumab arm of the core CARE-MS II study

• Through 4 years (2 years of core study and 2 years of extension study), 68% of patients received only the initial 2 annual courses (baseline and Year 1), 24% received 1 additional course, and 7% received 2 additional courses

• 5% received another DMT in Years 3 or 4; only 2 patients (0.5%) received alemtuzumabretreatment and another DMT

Title


Disability Improvement

• Mean EDSS score was 2.7 at core study baseline and had not increased by Year 4 (2.7; Figure 1)

− Similar results were observed for the patients receiving only 2 courses over 4 years

Title



• Most patients (71%) who received only 2 alemtuzumab courses over 4 years had an improved (43.5%) or stable (27.8%) EDSS score from core study baseline to Year 4 (Figure 2)

• The majority of all alemtuzumabpatients had improved or stable EDSS from core study baseline through Year 4 (Figure 2)

− At Year 4, 66% of patients had EDSS scores that were stable (27.6%) or improved (38.6%) from core study baseline (Figure 2)

− At Year 4, 59% of patients had EDSS scores that were stable (39.2%) or improved (20.2%) from Year 2 (data not shown)

− At Year 4, 67% of patients had EDSS scores that were stable (45.4%) or improved (21.6%) from Year 3 (data not shown)

Title



•23.6% of patients had an EDSS score improvement of ≥1 point over 4 years

− 11% of alemtuzumab-treated patients had 1-point improvement

− 5% of alemtuzumab-treated patients had 1.5-point improvement

− 7% of alemtuzumab-treated patients had 2.0-point improvement

•Of patients who had an improved EDSS score from baseline to Year 2, 14% improved further from Year 2 to Year 4 (Figure 3)

− Of patients who had a stable EDSS score from baseline to Year 2, 19% improved from Year 2 to Year 4 (Figure 3)

•A minority of patients (n=81) had an increased EDSS score in the core study; of those, 35% eventually improved in the extension

Title



• Six-month SRD was achieved in 41% of patients over 4 years (Figure 4)

− Of patients ever achieving 6-month SRD, 95% were free from 6-month SAD through Year 4

Title


Conclusion:

• In active RRMS patients who had an inadequate response to a prior therapy, disability scores improved or remained stable over 4 years in a majority of patients with alemtuzumab, even though most received their last treatment course 3 years earlier

• Sustained reduction in preexisting disability continued to improve in Year 4

• Some patients with disability improvement during the core study continued to improve further in Years 3 and 4

• The durability of efficacy following acute dosing of alemtuzumab (at Month 0 and 12 months later for most patients) may be the result of immunomodulatory effects due to the distinct pattern of lymphocyte repopulation following treatment and is a unique treatment approach for DMTs

Title



SWITCHING TO ALEMTUZUMAB FROM SUBCUTANEOUS INTERFERON BETA-1A AFTER CARE-MS I FURTHER IMPROVED MRI OUTCOMES IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS

Frederik Barkhof,1 Daniel Pelletier,2 Alasdair J Coles,3 Jeffrey A Cohen,4 D Alastair S Compston,3 Edward J Fox,5 Hans-Peter Hartung,6 Eva Havrdova,7 David H Margolin,8 Linda Kasten,9 Michael A Panzara,8 Douglas L Arnold10,11; on behalf of the CARE-MS I Investigators

1VU University Medical Centre, Amsterdam, Netherlands; 2Yale School of Medicine, North Haven, CT, USA; 3University of Cambridge School of Clinical Medicine, Cambridge, UK; 4Cleveland Clinic, Cleveland, OH, USA; 5Central Texas Neurology Consultants, Round Rock, TX, USA; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Genzyme, a Sanofi company, Cambridge, MA, USA; 9PROMETRIKA LLC, Cambridge, MA, USA; 10NeuroRx Research, Montréal, Québec, Canada; 11Montréal Neurological Institute, McGill University, Montréal, Québec, Canada

OBJECTIVE:

•Examine magnetic resonance imaging (MRI) outcomes in patients who switched to alemtuzumab after receiving subcutaneous interferon beta-1a (SC IFNB-1a) in CARE-MS I.

BACKGROUND:

•In the 2-year CARE-MS I core study of treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab treatment improved many MRI outcomes, including reductions in MRI lesion activity and brain volume loss, compared with SC IFNB-1a. A CARE-MS extension is ongoing.

DESIGN/METHODS:

•In CARE-MS I, SC IFNB-1a–treated patients received 44 μg 3 times/week. In the first 2 years of the extension, former SC IFNB-1a–treated patients received 2 annual alemtuzumab courses (12 mg/day). MRI outcomes assessed at baseline, and yearly included gadolinium (Gd)-enhancing, new/enlarging T2 hyperintense, and new T1 hypointense lesion activity, and MRI activity-free (absence of Gd-enhancing and new/enlarging T2 lesions)

Title


Patients:

• Of the 173 SC IFNB-1a–treated patients who completed the CARE-MS I core study, 144 (83.2%) entered the extension

• 91.7% received 2 alemtuzumabcourses; 4.9% received 1 alemtuzumabcourse, and 5.6% discontinued from the study.

• Baseline characteristics of patients entering the extension study were similar to that in patients in the core study (Table 1)

Title


RESULTS:

• Proportions of patients free of Gd-enhancing (96% vs 81%), new/enlarging T2 (82% vs 60%), and new T1 (95% vs 82%) lesions significantly increased after switching to alemtuzumab (Year 4) compared with Year 2 on SC IFNB-1a in the core study (Figure 1A–C)

• Proportion of patients free of MRI activity was also significantly higher after switching to alemtuzumabcompared with Year 2 on SC IFNB-1a (82% vs 59%; Figure 1D)

• Rate of new lesion formation per year declined from Year 2 on SC IFNB-1a after switching to alemtuzumab (Year 4) for new Gd-enhancing (0.31 to 0.04), new/enlarging T2 (1.60 to 0.68), and new T1 (0.47 to 0.11) lesions

• Mean percentage conversion of Gd-enhancing lesions to T1 hypointense black holes after switching to alemtuzumab (Year 3, 18.0%; Year 4, 16.7%) was numerically lower than that observed in Year 2 (24.9%)

Title


RESULTS:

•The proportion of patients with ≥2 new lesions decreased after switching to alemtuzumab from Year 2 to Year 4 for new Gd-enhancing: 4.7% to 0.0%, new/enlarging T2 (23.1% to 5.3%; P<0.0001), and new T1 lesions (8.8% to 2.3%; P=0.0225) (Figure 2)

CONCLUSIONS:

•Switching from SC IFNB-1a to alemtuzumab improved the proportion of patients free of MRI activity and reduced rate of new lesion formation. These findings further confirm the superior efficacy of alemtuzumab in RRMS patients who received prior disease-modifying therapy.

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.261).STUDY SUPPORTED BY: Genzyme, a Sanofi company, and Bayer Healthcare

Pharmaceuticals

ALEMTUZUMAB SLOWS BRAIN VOLUME LOSS OVER 4 YEARS DESPITE MOST RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS NOT RECEIVING TREATMENT FOR 3 YEARS

Alasdair J Coles,1 Douglas L Arnold,2,3 Jeffrey A Cohen,4 Edward J Fox,5 Hans-Peter Hartung,6 Eva Havrdova,7 Krzysztof W Selmaj,8 David H Margolin,9 Linda Kasten,10 Michael A Panzara,9 Alastair S Compston1; on behalf of the CARE-MS Investigators

1University of Cambridge School of Clinical Medicine, Cambridge, UK; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4Cleveland Clinic, Cleveland, OH, USA; 5Central Texas Neurology Consultants, Round Rock, TX, USA; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Genzyme, a Sanofi company, Cambridge, MA, USA; 10PROMETRIKA LLC, Cambridge, MA, USA

OBJECTIVE:

•Examine alemtuzumab’s effect on brain volume change over 4 years in patients who participated in the CARE-MS studies and ongoing extension

BACKGROUND:

•In 2 phase 3, head-to-head trials in active relapsing-remitting multiple sclerosis (RRMS) patients, alemtuzumab had superior efficacy versus subcutaneous interferon beta-1a (SC IFNB-1a), including a 42% greater reduction in brain volume loss than SC IFNB-1a over 2 years in treatment-naive patients (CARE-MS I) and 24% greater reduction than SC IFNB-1a in patients who relapsed on prior therapy (CARE-MS II).

DESIGN/METHODS:

•Core study patients randomized to alemtuzumab received 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. In the extension, alemtuzumab-treated patients could receive as-needed retreatment ≥1 year after previous course. Magnetic resonance imaging scans were acquired at baseline and yearly thereafter. Brain volume loss was measured by brain parenchymal fraction (BPF) change

Title


RESULTS:

• 349 (95.1%) CARE-MS I and 393 (92.9%) CARE-MS II alemtuzumab patients entered the extension phase; data are available through 4 years from first treatment with ongoing follow-up.

• Baseline demographic characteristics of patients entering the extension study were similar to patients in the core study

• Among CARE-MS I patients, 20.9% received 1 and 4.6% received 2 additional courses during the extension. Among CARE-MS II patients, 24% received 1 and 7% received 2 additional courses during the extension

Title


RESULTS:

• Alemtuzumab slowed the reduction in BPF by 42% versus SC IFNB-1a at the end of the core CARE-MS I study. The slowing of brain volume loss was maintained over 4 years (Figure 1)

• Median rate of BPF loss decreased progressively over time in CARE-MS I (Year 1: –0.59%, Year 2: –0.25%, Year 3: –0.19%, Year 4: –0.15%) (Figure 2)

Title


RESULTS:

• Alemtuzumab slowed the reduction in BPF by 24% versus SC IFNB-1a at the end of the core CARE-MS II study. The slowing of brain volume loss was maintained over 4 years (Figure 3)

• Median rate of BPF loss progressively slowed over 3 years in CARE-MS II and remained low in Year 4 (Year 1: –0.48%, Year 2: –0.22%, Year 3: –0.10%, Year 4: –0.19%) (Figure 4)

Title


CONCLUSION:

• In both populations of active RRMS patients who were treatment-naive and who had an inadequate response to a prior therapy, there was a slowing of brain volume loss beginning in the core studies.

• These results reflect a reduction in inflammation and are consistent with the superior clinical efficacy of alemtuzumab over SC IFNB-1a

• The durability of efficacy following acute dosing of alemtuzumab (at Month 0 and 12 months later for most patients) may be the result of immunomodulatory effects due to the distinct pattern of lymphocyte repopulation following treatment and is a unique treatment approach for DMTs


Title


SLOWING OF BRAIN VOLUME LOSS IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS AFTER SWITCHING FROM SUBCUTANEOUS INTERFERON BETA-1A TO ALEMTUZUMAB

Jeffrey A Cohen,1 Douglas L Arnold,2,3 Alasdair J Coles,4 Edward J Fox,5 Hans-Peter Hartung,6 Eva Havrdova,7 Krzysztof W Selmaj,8 David H Margolin,9 Linda Kasten,10 Michael A Panzara,9 Alastair S Compston4; on behalf of the CARE-MS Investigators

1Cleveland Clinic, Cleveland, OH, USA; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4University of Cambridge School of Clinical Medicine, Cambridge, UK; 5Central Texas Neurology Consultants, Round Rock, TX, USA; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Genzyme, a Sanofi company, Cambridge, MA, USA; 10PROMETRIKA LLC, Cambridge, MA, USA

OBJECTIVE:

•To examine brain volume changes in patients who switched to alemtuzumab after receiving subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS core studies.

BACKGROUND:

•In two phase 3 head-to-head trials in active relapsing-remitting multiple sclerosis (RRMS) patients, alemtuzumab demonstrated superior efficacy versus SC IFNB-1a, including reduction in brain volume loss over 2 years by 42% in treatment-naive patients (CARE-MS I) and by 24% in patients who relapsed on prior therapy (CARE-MS II).

DESIGN/METHODS:

•In the CARE-MS studies, SC IFNB-1a–treated patients received 44 μg 3 times/week for 2 years. These patients subsequently entered an extension study and received alemtuzumab 12 mg/day intravenously on 5 consecutive days and on 3 consecutive days 12 months later. Magnetic resonance imaging scans were acquired at baseline and yearly thereafter. Brain volume loss was measured by brain parenchymal fraction (BPF) change.

Title


RESULTS:

• The extension enrolled 144 (83.2%) SC IFNB-1a–treated patients from CARE-MS I– 91.7% of these patients received 2 alemtuzumab courses in the extension. Baseline characteristics of the core and extension populations are shown in Table 1

• The extension enrolled 146 (83.4%) SC IFNB-1a–treated patients from CARE-MS II – 89.7% of these patients received 2 alemtuzumab courses in the extension. Baseline characteristics of the core and extension population are shown in Table 2

Title


RESULTS:

• In CARE-MS I SC IFNB-1a–treated patients, a slowing of BPF loss was observed after switching to alemtuzumab (Figure 1)

• Among CARE-MS I patients, the median yearly rate of BPF loss was reduced from –0.50% in Year 2 of SC IFNB-1a treatment to –0.13% in the second year after switching to alemtuzumab (Year 4). (Figure 2)

Title


RESULTS:

• In CARE-MS II SC IFNB-1a–treated patients, a slowing of BPF loss was observed after switching to alemtuzumab (Figure 3)

• Among CARE-MS II patients, the median yearly BPF loss was reduced from –0.35% in Year 2 of SC IFNB-1a treatment to –0.06% in the second year of alemtuzumab treatment (Year 4).

Title


CONCLUSIONS:

• The yearly rate of brain volume loss was markedly reduced after switching from SC IFNB-1a to alemtuzumab. These findings further confirm the superior efficacy of alemtuzumab in RRMS patients who received at least 2 years of prior SC IFNB-1a disease-modifying therapy.


INCIDENCE OF INFECTION DECREASES OVER TIME IN ALEMTUZUMAB-TREATED PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS: 4-YEAR FOLLOW-UP OF THE CARE-MS STUDIES

Lily Jung Henson,1 Douglas L Arnold,2,3 Jeffrey A Cohen,4 Alasdair J Coles,5 Edward J Fox,6 Hans-Peter Hartung,7 Eva Havrdova,8 Kryszstof W Selmaj,9 David H Margolin,10 Bella Ertik,10 Jeffrey Palmer,10 Michael A Panzara,10 D Alastair S Compston5; on behalf of the CARE-MS Investigators

1Swedish Medical Center, Seattle, WA, USA; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4Cleveland Clinic, Cleveland, OH, USA; 5University of Cambridge School of Clinical Medicine, Cambridge, UK; 6Central Texas Neurology Consultants, Round Rock, TX, USA; 7Heinrich-Heine University, Düsseldorf, Germany; 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 9Medical University of Łódź, Łódź, Poland; 10Genzyme, a Sanofi company, Cambridge, MA, USA

OBJECTIVE:

•To evaluate risk of infection during 4-year follow-up of the pooled CARE-MS studies.

BACKGROUND:

•Alemtuzumab demonstrated superior efficacy over subcutaneous interferon beta-1a (SC IFNB-1a) and manageable safety in the 2-year, phase 3 CARE-MS I and II studies in patients with relapsing-remitting multiple sclerosis. Infections were more common with alemtuzumab (67%−77%) than with SC IFNB-1a (45%−66%).

DESIGN/METHODS:

•Patients who were treatment-naive (CARE-MS I) or had relapsed on prior therapy (CARE-MS II) received alemtuzumab 12 mg/day intravenous on 5 consecutive days at baseline and 3 consecutive days 12 months later, and as-needed alemtuzumab retreatment in an ongoing extension study. Herpes prophylaxis was introduced per protocol amendment (acyclovir 200 mg twice daily, during each alemtuzumab course and 28 days thereafter).

Title


RESULTS:

• A total of 811 patients were treated with alemtuzumab 12 mg in the core studies; 742 patients entered the extension

• Over 4 years, 70.4% of extension study patients received only the 2 initial alemtuzumab courses in the core studies

− 22.6% received 3 courses and 6.1% received 4 courses over 4 years

− 3.6% received other disease-modifying therapy in Year 3 or 4

Infections:

• Infection incidence was highest in Year 1 after alemtuzumab treatment and declined thereafter (Figure 1)

• First incidence of infection occurred in Year 1 for most patients; additional patients developing infections declined every year thereafter (Year 2, 12.6%; Year 3, 5.6%; and Year 4, 3.0%)

Title


• The rate of infection (events/patient-year) declined with each treatment course (Figure 2)

Title


• Infections were mostly mild or moderate in severity (Table 1)

Title


Infections:

• The most common infections were nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes simplex (Table 2)

Title


Serious Infections

•Yearly serious infection incidence was low (≤1.8%) from Year 1 to Year 4

•The most common serious infection was pneumonia, which occurred in 9 patients (1.1%) over 4 years

•Other serious infections that occurred in >1 patient were appendicitis (n=5), herpes zoster (n=5), gastroenteritis (n=3), sepsis (n=3), influenza (n=2), subcutaneous abscess (n=2), and tooth infection (n=2)

•Two patients developed Grade 4 infections

− Seven months after the second course of alemtuzumab, one patient developed Grade 4 pneumonia in the setting of rib fractures and Grade 2 pleural effusion and was hospitalized; pneumonia resolved after 15 days

− Another patient developed Grade 4 sepsis during Year 4, was hospitalized and treated with antibiotics, and recovered

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.265). 1. Cohen JA, Coles AJ, Arnold DL, et al. Lancet 2012;380:1819-28.

• One death due to infection occurred (Year 3; previously reported)1

− The patient was hospitalized for pancytopenia, prematurely discontinued steroid treatment upon return to his home, experienced arecurrence of pancytopenia, and died from subsequent sepsis

Herpetic Infections and Acyclovir Prophylaxis

• In core studies, acyclovir reduced herpetic infection incidence in the month after treatment (Course 1, 0.5% with acyclovir vs 4.6% without; Course 2, 0.8% vs 2.6%)12

• Herpes simplex incidence (including herpes simplex, oral herpes, genital herpes, and herpes simplex ophthalmic) was 13.3% overall and declined each year (Year 1- 9.0%; Year 2- 5.4%; Year 3- 3.1%; Year 4 - 2.5%)− Rate of herpes simplex infection declined with each course (Course 1: 0.127 events/patient-year; Course 2: 0.050; Course 3: 0.021; Course 4: 0)

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.265). 12. Havrdova E, Arnold DL, Cohen J, et al. Presented at:ECTRIMS; October 2-5, 2013; Copenhagen, Denmark, P603.

• Herpes zoster incidence (including multidermatomal) was 9.2% overall (Year 1, 2.1%; Year 2, 2.7%; Year 3, 3.4%; Year 4, 2.2%)

• The rate of herpetic infections by treatment course was low throughout the study and decreased from Course 1 to Course 4 (Table 3)

• Over 4 years, there were a total of 331 herpetic infections

CONCLUSIONS:

• Infections were common with alemtuzumab but were predominantly mild or moderate. Infection risk declined over time, and successive courses of alemtuzumabwere not associated with an increased rate of infection

Title



DURABLE EFFICACY OF ALEMTUZUMAB IN PATIENTS WITH HIGHLY ACTIVE RELAPSING-REMITTING MULTIPLE SCLEROSIS WHO RELAPSED ON A PRIOR THERAPY

Barry Singer,1 Edward J Fox,2 Stephen Krieger,3 Hans-Peter Hartung,4 Lilyana Amezcua,5 David H Margolin,6 Linda Kasten,7

Alasdair J Coles8; on behalf of the CARE-MS II Investigators

1MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, USA; 2Central Texas Neurology Consultants, TX, USA; 3Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4Heinrich-Heine University, Düsseldorf, Germany; 5Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 6Genzyme, a Sanofi company, Cambridge, MA, USA; 7PROMETRIKA, LLC, Cambridge, MA, USA; 8University of Cambridge School of Clinical Medicine, Cambridge, UK

OBJECTIVE:

•Evaluate alemtuzumab efficacy/safety over 3 years in the patient subset with highly active relapsing-remitting multiple sclerosis (MS) despite prior therapy.

BACKGROUND:

•In the 2-year, phase 3 CARE-MS II study, alemtuzumab significantly reduced relapses, disability, and magnetic resonance imaging (MRI) lesions versus subcutaneous interferon beta-1a in patients with highly active disease at baseline (≥2 relapses in the year before randomization and ≥1 baseline gadolinium [Gd]-enhancing lesion)

DESIGN/METHODS:

•Patients received alemtuzumab 12 mg infusions at baseline and month 12, and retreatment if indicated in an ongoing extension study. Improved EDSS score defined as ≥0.5-point decrease from core study baseline. Sustained accumulation of disability (SAD) is ≥1-point EDSS score increase (≥1.5-point if baseline EDSS=0). MS disease freedom was defined as absence of MRI (new Gd-enhancing lesions and new/enlarging T2 lesions) and clinical (SAD and relapse) disease activity.

Title


Patients

• Of 435 patients treated with alemtuzumab 12 mg in CARE-MS II, 103 (23.7%) patients met highly active disease criteria at baseline

• Of these 103 patients with highly active disease, 92 entered the extension study

• Two patients were randomized to alemtuzumab 24 mg but received the 12-mg dose; these patients are included in safety analyses but not efficacy analyses for the 12-mg arm

• 75 (81.5%) patients did not receive any treatment after the initial 2 courses of alemtuzumab at Month 0 and Month 12

• Prior MS therapy in patients randomized to SC IFNB-1a and alemtuzumab were SC IFNB-1a (50% vs 35%), IFNB-1a intramuscular (24% vs 34%), IFNB-1b (33% vs 31%), glatiramer acetate (21% vs 41%), and natalizumab (7% vs 7%)

Title


Patients

• Baseline characteristics were well balanced across treatment groups (Table 1)

Title


Efficacy

• Among alemtuzumab-treated patients with highly active disease at baseline, annualized relapse rate (ARR) remained low in Year 3 (Figure 1)− In Year 3 - 94% of patients were

relapse-free

Title


Efficacy

• With alemtuzumab, mean EDSS score remained below baseline level at Year 2 (-0.21; P=0.0181) and did not increase above baseline at Year 3 (-0.09; P=0.27)

• A majority of patients had improved or stable EDSS scores over 3 years (Figure 2)

− From Year 2 to Year 3 - 62% had improved (23%) or stable (39%) EDSS scores

• Over 3 years, 83% of patients were free from 6-month SAD

• Over 3 years, 6-month sustained reduction in disability was achieved by 34% of patients

Title


Efficacy

• In Year 3, a majority of patients were free of either Gd-enhancing, new/enlarging T2 hyperintense, or new T1 hypointense lesions (Figure 3)

Title


Efficacy

• Mean MRI lesion volume was significantly lower than baseline over 3 years

− T2 hyperintense lesion volume mean change from baseline: Year 1, -1.20 cm3; Year 2, -1.44; Year 3, -1.08; all P<0.05 versus baseline

− T1 hypointense lesion volume mean change from baseline: Year 1, -0.35 cm3; Year 2, -0.16; Year 3, -0.33; all P<0.05 versus baseline

• Annual brain volume loss slowed from Year 1 (median percent change, -0.56%) to Years 2 (-0.26%) and 3 (-0.006%) with alemtuzumab, and there was no significant change in brain volume from Year 2 to Year 3 (P=0.62; Figure 4)

Title


Efficacy

• In Year 3, freedom from MS disease activity (NEDA) was achieved by 54% of patients in the highly active subgroup, and a majority were free of either clinical (84%) or MRI activity (65%; Figure 5)

Title


Safety:

• The profile of adverse events (AEs) with alemtuzumab in the highly active cohort over 3 years was similar to that of the full study cohort

• Incidences of treatment withdrawal (3%) and study discontinuation (1%) owing to Aes were low

• Infusion-associated reactions (91%; 3% serious), infections (88%; 7% serious), and thyroid AEs (42%; 5% serious) were prevalent but mainly non-serious, and there were no cases of immune thrombocytopenia or glomerulonephritis

• One death occurred in the highly active subgroup, owing to a motor vehicle accident (previously reported)6

CONCLUSIONS:

• Alemtuzumab demonstrated durable improvements in clinical and MRI outcomes in patients with highly active disease at Year 3, despite most patients receiving their last treatment course 2 years prior.


Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.269) 6. Callegaro D, Krieger S, Arnold DL, et al. Presented at: LACTRIMS; November 26-29, 2014; Lima, Peru, P124.00

IMPROVEMENT IN CLINICAL OUTCOMES IN TREATMENT-NAIVE RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS WHO SWITCHED FROM SUBCUTANEOUS INTERFERON BETA-1A TO ALEMTUZUMAB Hans-Peter Hartung,1 Gavin Giovannoni,2 Douglas L Arnold,3,4 Alasdair J Coles,5 Edward J Fox,6 Eva Havrdova,7 Krzysztof W Selmaj,8 David H Margolin,9 Jeffrey Palmer,9 Michael A Panzara,9 D Alastair S Compston4; on behalf of the CARE-MS I Investigators

1Heinrich-Heine University, Düsseldorf, Germany; 2Queen Mary University of London, Barts and The London School of Medicine, London, UK; 3NeuroRx Research, Montréal, Québec, Canada; 4Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 5University of Cambridge School of Clinical Medicine, Cambridge, UK; 6Central Texas Neurology Consultants, Round Rock, TX, USA; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Genzyme, a Sanofi company, Cambridge, MA, USA

OBJECTIVE:

•To examine the efficacy and safety of switching to alemtuzumab in patients who received subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS I core study

BACKGROUND:

•In the 2-year CARE-MS I core study of treatment-naive patients with active relapsing-remitting multiple sclerosis, alemtuzumab-treated patients experienced significantly reduced annualized relapse rate (ARR) compared with SC IFNB-1a–treated patients, with manageable tolerability and safety

DESIGN/METHODS:

•In the core study, SC IFNB-1a–treated patients received 44 μg 3 times/week. In the first 2 years of the extension study, these patients received 2 annual alemtuzumab courses (12 mg intravenous). Disability was assessed quarterly with the Expanded Disability Status Scale (EDSS); relapses were assessed as needed. Efficacy outcomes were assessed by raters blinded to patients’ earlier treatment assignment. Endpoints that were evaluated included ARR, change in EDSS score, and 6-month sustained reduction in preexisting disability (SRD)

Title


RESULTS:

Patients

• The extension study enrolled 144 (83%) SC IFNB-1a–treated CARE-MS I patients

− Of these, 132 received 2 courses of alemtuzumab and 7 received only 1 course

• Patient characteristics at core study baseline are shown in Table1

Title


Relapse

• Two years after entering the extension study, in which patients received alemtuzumabtreatment at Months 0 and 12, ARR decreased by 69% compared with the 2 years in CARE-MS I (0.39 vs 0.12) (Figure 1A) and a higher proportion of patients were free of relapse (Figure 1B), compared with the previous 2 years on SC IFNB-1a in the core study

Title


Disability

• EDSS scores after 2 alemtuzumab courses were stable/improved in 73% of patients. After switching to alemtuzumab, an additional 17% of patients achieved 6-month SRD

• Of those patients whose EDSS score had worsened over the 2 years on SC IFNB-1a (n=29), EDSS scores after 2 alemtuzumabcourses were improved or stable in 72.4% of patients (Figure 2)

− Patients who worsened on SC IFNB-1a, then improved after switching (31.0% [n=9]), had a 1.44-point mean reduction in EDSS score

Title


Safety

• The safety profile of alemtuzumab after switching from SC IFNB-1a was similar to that seen for alemtuzumab-treated patients in the core study (Tables 2 and 3)1

− Most AEs were mild to moderate in severity

− Infections were more frequent following the switch to alemtuzumab than while receiving SC IFNB-1a (63% vs 45%, respectively), and of a similar incidence to that in alemtuzumab-treated patients in the core study (67%)1

• The annual incidence of thyroid AEs was 2.2% during the first year after switching to alemtuzumab and increased to 6.5% during the second year, following a similar time course to that observed in alemtuzumab-treated patients in the core study

• No events of ITP or nephropathy occurred over the 2-year extension

• Two of 139 (1.4%) patients withdrew from alemtuzumab treatment due to Aes. These AEs (n=1 each) were non-serious chest pain and pruritus (both Grade 2)

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.270) 1. Coles AJ, Twyman CL, Arnold DL, et al. Lancet 2012;380:1829-39.

CONCLUSIONS:

• In patients with active RRMS who were treatment-naive in the core CARE-MS I study, patients who switched from SC IFNB-1a to 2 annual courses of alemtuzumab in the extension study experienced further improvement in both relapse and disability outcomes

• The efficacy and safety profile of alemtuzumab in patients who switched from SC IFNB-1a was similar to that observed in patients treated with alemtuzumab in the core study

• These findings support the favorable benefit-risk profile of alemtuzumab in patients who received prior disease-modifying therapy


Title


THE EFFICACY OF ALEMTUZUMAB IS MAINTAINED IN PATIENTS WHO DEVELOP THYROID ADVERSE EVENTS

Samuel F Hunter,1 Douglas L Arnold,2,3 Alasdair J Coles,4 Jeffrey A Cohen,5 Edward J Fox,6 Hans-Peter Hartung,7 Eva Havrdova,8 David H Margolin,9 Bella Ertik,9 Jeffrey Palmer,9 Michael A Panzara,9 D Alastair S Compston4; on behalf of the CARE-MS Investigators

1Advanced Neurosciences Institute, Franklin, TN, USA; 2NeuroRx Research, Montréal, Québec, Canada; 4University of Cambridge School of Clinical Medicine, Cambridge, UK; 9Genzyme, a Sanofi company, Cambridge, MA, USA 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 5Cleveland Clinic, Cleveland, OH, USA; 6Central Texas Neurology Consultants, Round Rock, TX, USA; 7Heinrich-Heine University, Düsseldorf, Germany; 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic;

OBJECTIVE:

•To determine whether thyroid adverse events (AEs) impact alemtuzumab efficacy

BACKGROUND:

•Alemtuzumab showed superior efficacy over high-dose subcutaneous interferon beta-1a and manageable safety in relapsing-remitting multiple sclerosis (RRMS) patients in phase 3 CARE-MS studies; efficacy was sustained for 4 years in the extension study. Alemtuzumab’s consistent safety profile includes an identified risk of predominantly non-serious autoimmune thyroid disorders.

DESIGN/METHODS:

•In the 2-year core studies, RRMS patients who were treatment-naive (CARE-MS I) or relapsed on prior therapy (CARE-MS II) received alemtuzumab 12 mg/day intravenous on 5 consecutive days at baseline and 3 consecutive days 12 months later, with as-needed alemtuzumab retreatment in the ongoing extension. Sustained accumulation of disability (SAD) was defined as ≥1-point Expanded Disability Status Scale score increase confirmed for ≥6 months (≥1.5-point if baseline score=0). Thyroid function testing was performed at baseline and quarterly using a comprehensive monitoring program.

Title


RESULTS:

Patients

•In the core studies, 811 patients were treated with alemtuzumab 12 mg; of these, 742 entered the extension (CARE-MS I, 95% [n=349]; CARE-MS II, 93% [n=393])

•During Years 0–4, most patients received only the initial 2 alemtuzumab courses (CARE-MS I, 73%; CARE-MS II, 68%)

•During Years 3 and 4, few patients received another disease-modifying therapy (CARE-MS I, 2%; CARE-MS II, 5%)

Overview of Thyroid AEs Through Year 4 Follow-up

•In total, 38% of CARE-MS I and 35% of CARE-MS II patients experienced ≥1 thyroid AE over the 4-year period

− The onset of thyroid AEs was delayed after first administration, and the proportion of alemtuzumab 12 mg patients with any thyroid event peaked at Year 3 and subsequently declined in Year 4 (Figure 1 [pooled CARE-MS I and II population]), following a similar time course to that previously reported for the phase 2 CAMMS223 study6,8

− Female patients were more likely to experience thyroid AEs than male patients; the presence/absence of thyroid AEs was not influenced by baseline age, EDSS score, and time since MS onset6

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.272) 6. Twyman CL, Oyuela P, Palmer J, et al. Neurology 2014;82:P2.199. 8. ColesAJ, Fox E, Vladic A, et al. Neurology 2012;78:1069-78.

RESULTS:

Overview of Thyroid AEs Through Year 4 Follow-up

Title


pooled CARE-MS I and II population

RESULTS:

Relapses in Patients With and Without Thyroid Aes

•ARRs during Years 0–4 were similar between patients who had ≥1 thyroid AE and those without thyroid AEs (Figure 2)

•The proportions of patients free from relapse during Years 0–4 were similar in patients with and without thyroid AEs (Figure 3)

Title


RESULTS:

Disability in Patients With and Without Thyroid Aes

• Proportions of patients free from 6-month SAD during Years 0–4 were similar in patients with and without thyroid AEs (Figure 4)

Title


CONCLUSIONS:

• The occurrence of autoimmune thyroid disorders had no impact on the efficacy of alemtuzumabas measured by the risk of relapse or disability accumulation over the course of the 2-year core studies and for an additional 2 years of the extension study

• These findings support the favorable benefit-risk profile of alemtuzumab in RRMS patients

Title



DURABLE EFFECT OF ALEMTUZUMAB ON CLINICAL OUTCOMES IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS WHO RELAPSED ON PRIOR THERAPY: 4-YEAR FOLLOW-UP OF CARE-MS II

Eva Havrdova,1 Gavin Giovannoni,2 Douglas L Arnold,3,4 Alasdair J Coles,5 Edward J Fox,6 Hans-Peter Hartung,7 Krzysztof W Selmaj,8 David H Margolin,9 Jeffrey Palmer,9 Michael A Panzara,9 D Alastair S Compston5; on behalf of the CARE-MS II Investigators

1First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 2Queen Mary University of London, Barts and The London School of Medicine, London, UK; 3NeuroRx Research, Montréal, Québec, Canada; 4Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 5University of Cambridge School of Clinical Medicine, Cambridge, UK; 6Central Texas Neurology Consultants, Round Rock, TX, USA; 7Heinrich-Heine University, Düsseldorf, Germany; 8Medical University of Łódź, Łódź, Poland; 9Genzyme, a Sanofi company, Cambridge, MA, USA

OBJECTIVE:

•Examine alemtuzumab’s 4-year efficacy and safety in the CARE-MS II extension study.

BACKGROUND:

•In the 2-year core study, alemtuzumab had superior clinical efficacy versus subcutaneous interferon beta-1a with manageable tolerability and safety in relapsing-remitting multiple sclerosis patients who relapsed on prior therapy. Alemtuzumab’s efficacy was subsequently shown to be durable through 3 years

DESIGN/METHODS:

•In CARE-MS II, patients received alemtuzumab 12 mg at baseline and month 12. In extension, alemtuzumab-treated patients received as-needed alemtuzumab retreatments ≥1 year apart. Endpoints included annualized relapse rate (ARR), improved/stable/worsened EDSS score (≥0.5-point decrease [improvement] or ≥0.5-point increase [worsening] from core baseline), sustained accumulation of disability (SAD; ≥1-point EDSS increase over ≥6 months [≥1.5-point if baseline EDSS=0]), and sustained reduction in preexisting disability (SRD; ≥1-point EDSS decrease from baseline over ≥6 months [patients with baseline score ≥2.0])

Title


RESULTS:

Patients

• The extension study enrolled 393 of 423 (93%) alemtuzumab 12 mg–treated patients who completed CARE-MS II

− Through 4 years, 68% received only the initial 2 treatment courses, 24% received 1 additional course, 7% received 2 additional courses

− 5% of patients received another DMT during Years 3 or 4

− To date, 18 of 435 (4.1%) patients who received alemtuzumab 12 mg in CARE-MS II have withdrawn from treatment due to Aes


Title


Relapse

• A low ARR was maintained from Year 3 to Year 4 (Figure 1A), and the proportion of patients free from relapse increased compared with the core study (Figure 1B)

• Over 4 years, the cumulative ARR was 0.24 (95% CI, 0.21–0.27)

Title


Disability

• Disability, as assessed by EDSS change, either remained stable or improved from core study baseline to the end of Year 4 in most patients (Figure 2)

− Of patients who enrolled in the extension study, 22% improved, 45% remained stable, and 33% worsened from Year 3 to 4

Title


Disability

• At Year 4, 76% of alemtuzumab-treated patients were free from 6-month SAD

• Improvement in preexisting disability, as measured by 6-month SRD, was newly achieved by some patients in Years 3 and 4 (Table 2)

− Of those patients achieving 6-month SRD, 95% were free from 6-month SAD through Year 4

Title


No Evidence of Disease Activity

• The proportion of alemtuzumab-treated patients achieving freedom from MS disease activity remained stable in Years 3 and 4 (Figure 3)

Title


Safety

• Incidence of overall AEs was greatest after the first treatment course, and most Aes were mild to moderate in severity (Figure 4A)

• Infection incidence was also highest after the first treatment course

− The most common infection types over 4 years were nasopharyngitis, urinary tract infection, upper respiratory tract infection, and sinusitis

• Thyroid AE incidence peaked in Year 3 and declined in Year 4 (cumulative incidence over 4 years, 34.7%), similar to the observed pattern in other studies4,5

• ITP occurred in 6 patients in Year 4 (cumulative incidence over 4 years, 2.5%)

• IARs were the most common AE, were serious in <2% of patients with each course, and were most prevalent after the first course (Figure 4B)

• Other than thyroid AEs, first incidence of AEs occurred in Year 1 for most patients; additional patients experiencing AEs declined sharply thereafter (Figure 4C–D)

• No deaths occurred during the extension period

• During Year 4, AEs leading to treatment withdrawal occurred in 3 patients:

− ITP: Serious, Grade 4 AE (alemtuzumab 12 mg Course 2)

− Hemolytic anemia: Serious, Grade 4 AE (alemtuzumab 12 mg Course 3)

− ITP and neutropenia: Both serious, Grade 4 AEs (alemtuzumab 12 mg Course 2)

Title

4. Coles AJ,Fox E, Vladic A, et al. Neurology 2012;78:1069-78. 5. Miller T, Arnold DL, Cohen JA, et al. Neurology 2013;80:P01.173

Safety

Title


CONCLUSIONS:

• Alemtuzumab’s efficacy was maintained over 4 years despite most patients not having received additional treatment over the previous 3 years. The safety profile during extension study was consistent with the core study; no unexpected adverse events occurred. These findings support the durable efficacy and favorable benefit-risk profile of alemtuzumab in this population.


• Aspects of the work described in this abstract were presented at the 2014 Joint ACTRIMS-ECTRIMS Meeting, September 10–13, 2014, Boston, MA, USA, poster P043. Mult Scler J. 2014;20(S1):67–284.

Title


ADMINISTRATION OF ALEMTUZUMAB ON NONCONSECUTIVE DAYS DOES NOT IMPACT INFUSION-ASSOCIATED REACTIONS, EFFICACY, OR LYMPHOCYTE DEPLETION

Sibyl Wray,1 Alexey N Boyko,2 Tiffany J Braley,3 Omar Khan,4 David H Margolin,5 Jeffrey Palmer,5 Alasdair J Coles6; on behalf of the CARE-MS Investigators

1Hope Neurology, Knoxville, TN, USA; 2Moscow Multiple Sclerosis Center, Moscow, Russian Federation; 3University of Michigan Multiple Sclerosis and Sleep Disorders Centers, Ann Arbor, MI, USA; 4Wayne State University School of Medicine, Detroit, MI, USA; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6University of Cambridge School of Clinical Medicine, Cambridge, UK

OBJECTIVE:

•Assess the frequency of infusion-associated reactions (IARs), efficacy, and lymphocyte pharmacodynamics of alemtuzumab administered as a nonconsecutive course among subjects with relapsing-remitting multiple sclerosis (RRMS) in the CARE-MS studies.

BACKGROUND:

•Alemtuzumab administration is recommended as an infusion on 5 consecutive days for first annual course 1 and on 3 consecutive days for the second annual course 12 months later for RRMS. However, clinical practice may necessitate alemtuzumab infusion administration on nonconsecutive days.

DESIGN/METHODS:

•IARs were assessed in CARE-MS I and II subjects who received alemtuzumab infusions on nonconsecutive days (defined as course 1 over >5 calendar days; course 2 over >3 days). Subjects completing course 1 over 6–10 nonconsecutive days, or course 2 over 4–8 nonconsecutive days, were evaluated for relapses and sustained accumulation of disability (SAD; ≥1-point EDSS score increase confirmed for ≥6 months [≥1.5-point if baseline EDSS=0]) over 2 years; gadolinium (Gd)-enhancing and new/enlarging T2-hyperintense lesions within year of treatment; and lymphocyte counts 1 month after treatment.

Title


RESULTS:

• A total of 811 patients were treated with alemtuzumab 12 mg in the CARE-MS studies

• 771 (95.1%) patients completed Course 1 with 5 infusions on 5 consecutive days, and 762 (96.6%) patients completed Course 2 with 3 infusions on 3 consecutive days

• A total of 58 (7.2%) patients had a prolonged treatment course over nonconsecutive days (Course 1, n=40; Course 2, n=19; 1 patient had both courses prolonged)

− 25 patients completed Course 1 over 6–10 nonconsecutive days, and 15 completed Course 2 over 4–8 nonconsecutive days

Title


IARs:

• The incidence of IARs in the overall CARE-MS population was highest during Course 1 and declined in subsequent courses; serious IARs were infrequent (Figure 1)8,9

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.277). 8. Mayer L, Casady L, Clayton G, et al. Presented at: INS; May 3-8, 2014; Phoenix, AZ. 9. Mayer L, Casady L, Clayton G, et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, P880.

IARs:

• The incidences of IARs and serious IARs with nonconsecutive infusions were similar to those observed in the overall study population (Table 1)

Title


IARs:

•Of patients receiving alemtuzumab over 6−10 days or 4−8 days, 1 patient (Course 1, 10 days) had 2 serious IARs (bradycardia, pleurisy); both were deemed probably related to alemtuzumab

− These events occurred prior to the interruption in treatment

− Bradycardia resolved on the same day, and pleurisy resolved 3 days later

− Alemtuzumab treatment was resumed 5 days after IAR onset

•There were no Grade 3 or higher IARs or serious IARs when dosing resumed after the break in treatment (Table 2)

Title


Lymphocyte Counts:

• Depletion of total lymphocytes and CD4+, CD8+, and CD19+ subsets was similar with nonconsecutive infusions versus the total study population (Table 3)

Title


Efficacy:

• Most patients completing Course 1 over 6–10 nonconsecutive days or Course 2 over 4–8 nonconsecutive days remained free from clinical and MRI activity

− Relapse-free over 2 years (Course 1, 12/18 patients; Course 2, 9/10 patients)

− Free from 6-month SAD over 2 years (Course 1, 13/18 patients; Course 2, 8/10 patients)

− Free of Gd-enhancing lesions (Course 1, 15/17 patients; Course 2, 9/10 patients)

− Free of new/enlarging T2 hyperintense lesions (Course 1, 12/16 patients;Course 2, 8/10 patients)

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.277). STUDY SUPPORTED BY: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals

Conclusions:

• Administration of alemtuzumab infusions over nonconsecutive days did not increase IARs, reduce treatment efficacy, or affect lymphocyte pharmacodynamics. These findings suggest that prolonging treatment courses by up to additional 5 days does not impact treatment outcomes among RRMS patients.

IMPROVEMENT IN CLINICAL OUTCOMES FOLLOWING SWITCH FROM SUBCUTANEOUS INTERFERON BETA-1A TO ALEMTUZUMAB: CARE-MS II EXTENSION STUDY

Edward J Fox,1 Gavin Giovannoni,2 Douglas L Arnold,3,4 Alasdair J Coles,5 Hans-Peter Hartung,6 Eva Havrdova,7 Krzysztof W Selmaj,8 David H Margolin,9 Jeffrey Palmer,9 Michael A Panzara,9 D Alastair S Compston5; on behalf of the CARE-MS II Investigators

1Central Texas Neurology Consultants, Round Rock, TX, USA; 2Queen Mary University of London, Barts and The London School of Medicine, London, UK; 3NeuroRx Research, Montréal, Québec, Canada; 4Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 5University of Cambridge School of Clinical Medicine, Cambridge, UK; 6Heinrich-Heine University, Düsseldorf, Germany; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 8Medical University of Łódź, Łódź, Poland; 9Genzyme, a Sanofi company, Cambridge, MA, USA

OBJECTIVE:

•To examine the efficacy and safety of switching to alemtuzumab in patients who received subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS II core study

BACKGROUND:

•In the 2-year CARE-MS II core study of patients with relapsing-remitting multiple sclerosis who relapsed on prior therapy, alemtuzumab significantly reduced the annualized relapse rate (ARR) and risk of disability accumulation compared with SC IFNB-1a, with manageable tolerability and safety

DESIGN/METHODS:

•In the core study, SC IFNB-1a–treated patients received 44 μg 3 times/week. In the first 2 years of the extension study, these patients received 2 annual alemtuzumab courses (12 mg). Disability was assessed quarterly with the Expanded Disability Status Scale (EDSS); relapses were assessed as needed. Efficacy outcomes were assessed by raters blinded to patients’ earlier treatment assignment. Endpoints that were evaluated included ARR, change in EDSS score, and 6-month sustained reduction in preexisting disability (SRD).

Title


RESULTS:

Patients

• The extension study enrolled 146 (83%) SC IFNB-1a–treated patients from CARE-MS II

• Of these, 131 received 2 courses of alemtuzumab and 12 received only 1 course. Patient characteristics at core study baseline are shown in Table 1

Title


RESULTS:

Relapse

• Two years after entering the extension study, in which patients received alemtuzumab treatment at Months 0 and 12, ARR decreased by 71% compared with the 2 years in CARE-MS II (0.52 vs 0.15) (Figure 1A) and a higher proportion of patients were free of relapse (Figure 1B), compared with the 2 years on SC IFNB-1a in the core study

Title


− 11% of patients experienced 6-month SAD, compared with 21% during the 2 years on SC IFNB-1a in the core study. Of those SC IFNB-1a patients experiencing 6-month SAD over the first 2 years, 87% were free from 6-month SAD over Years 0–2 on alemtuzumab

− Improvement in preexisting disability, as measured by 6-month SRD, was achieved by an additional 15% of patients after switching to alemtuzumab

− EDSS scores 2 years after switching to alemtuzumab were improved or stable in 69% of patients (Figure 2)

Title


Disability

• Disability-related results at the end of Year 2 of the extension study, following alemtuzumab treatment at Months 0 and 12, included the following:

• Of those patients whose EDSS score had worsened over the 2 years on SC IFNB-1a (n=56), EDSS scores after 2 alemtuzumab courses were improved or stable in 71% of patients (Figure 2)

• Patients who worsened on SC IFNB-1a, then improved after switching (36% [n=20]), had a 0.88-point mean reduction in EDSS score

Safety

• The safety profile of alemtuzumab after switching from SC IFNB-1a was similar to that seen for alemtuzumab-treated patients in the core study (Tables 2 and 3)1

− Most AEs were mild to moderate in severity

− Infections were more frequent after switching to alemtuzumab than while receiving SC IFNB-1a (73% vs 66%, respectively), and of a similar incidence to that in alemtuzumab-treated patients in the core study (77%) 1

• The annual incidence of thyroid AEs was 2.1% during the first year after switching to alemtuzumab and increased to 11.4% during the second year, following a similar time course to that observed in alemtuzumab-treated patients in the core study

− No ITP, nephropathy, or death occurred over the 2-year extension study among SC IFNB-1a patients who switched to alemtuzumab

Title

AAN 2015: Poster presentation on April 23, 2015 (afternoon session) (P7.278) 1. Coles AJ, Twyman CL, Arnold DL, et al. Lancet 2012;380:1829-39.

CONCLUSIONS:

• In active RRMS patients with an inadequate response to a prior therapy (core CARE-MS II patients), switching from SC IFNB-1a to 2 annual courses of alemtuzumab in the extension study further improved both relapse and disability outcomes

• The efficacy and safety profile of alemtuzumab in patients who switched from SC IFNB-1a was similar to that observed in patients treated with alemtuzumab in the core study

• These findings support the favorable benefit-risk profile of alemtuzumab in patients who received more than 2 years of prior disease-modifying therapy.


Title


EVALUATION OF COMPREHENSIVE ALEMTUZUMAB INFUSION GUIDANCE IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS: EMERALD STUDY DESIGN

Patrick Vermersch,1 Ludo J Vanopdenbosch,2 Rafael Arroyo González,3 Oscar Fernandez,4 Francesca Baldinetti,5 Stanley Krolczyk,5 Leah Martell,5 Thibault Moreau6; on behalf of the EMERALD Study Investigators

1University of Lille, Lille, France; 2Department of Neurology, AZ Sint Jan Brugge Oostende, Brugge, Belgium; 3Hospital Clinico San Carlos, Madrid, Spain; 4Fundacion IMABIS, Hospital Universitario Carlos Haya, Malaga, Spain; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6Burgundy University, Dijon University Hospital, Dijon, France

OBJECTIVE:

• To describe Evaluation of the Management of Infusion Reactions in Alemtuzumab-treated Patients (EMERALD), a study evaluating comprehensive alemtuzumab infusion guidance to optimize management of infusion-associated reactions (IARs).

BACKGROUND:

• Most patients receiving alemtuzumab in multiple sclerosis clinical trials experienced mild/moderate IARs during infusion (most commonly headache, rash, pyrexia, nausea); 3% had serious events. IAR treatment was administered at the investigator's discretion, but treatment algorithms may improve patient management

DESIGN/METHODS:

• EMERALD is a phase 4, single-arm, open-label study being conducted at 22 sites in Belgium, France, the Netherlands, and Spain

• Eligible patients have a diagnosis of RRMS and are planning to initiate treatment with alemtuzumab according to the local approved label – Exclusion criteria include prior treatment with alemtuzumab, contraindications to alemtuzumab or symptomatic medication for IARs, and current participation in another interventional study

• Planned enrollment is 56 patients

Title


OBJECTIVE:

• To describe Evaluation of the Management of Infusion Reactions in Alemtuzumab-treated Patients (EMERALD), a study evaluating comprehensive alemtuzumab infusion guidance to optimize management of infusion-associated reactions (IARs).

BACKGROUND:

• Most patients receiving alemtuzumab in multiple sclerosis clinical trials experienced mild/moderate IARs during infusion (most commonly headache, rash, pyrexia, nausea); 3% had serious events. IAR treatment was administered at the investigator's discretion, but treatment algorithms may improve patient management

DESIGN/METHODS:

• EMERALD is a phase 4, single-arm, open-label study being conducted at 22 sites in Belgium, France, the Netherlands, and Spain

• Eligible patients have a diagnosis of RRMS and are planning to initiate treatment with alemtuzumab according to the local approved label – Exclusion criteria include prior treatment with alemtuzumab, contraindications to alemtuzumab or symptomatic medication for IARs, and current participation in another interventional study

• Planned enrollment is 56 patients

Title


METHODS:

• Study duration is approximately 13.5 months over 2 study periods, corresponding with 2 alemtuzumab treatment courses, each with a 1-month follow-up (Figure 1)

− Period 1: Alemtuzumab 12 mg/day intravenous (IV) on 5 consecutive days at baseline

− Period 2: Alemtuzumab 12 mg/day IV on 3 consecutive days 12 months later

• After the end of Period 2, patients will be followed up by their physician in a regular healthcare setting for required safety monitoring for 48 months following the last infusion in accordance with approved labeling

Title


METHODS:

• Pre-infusion medication will be administered to all patients on the day before infusion (Day 0), and on the day of each infusion (1 hour prior; Figure 2)

− Includes methylprednisolone given at a dose that tapers from Day 0 to the last infusion day of each course

Title


METHODS:

• During infusion, antihistamine, antipyretic, saline, antiemetic, and/or proton pump inhibitor may be administered as needed (Table 1)

Title


Study Objectives and Endpoints

• The primary objective is to assess the distribution of IARs by severity grade when alemtuzumab and infusion-associated medications are administered following comprehensive infusion guidance

− IARs are defined as any AE occurring during infusion, the 2-hour period after infusion, and up to 24 hours after infusion

− Study endpoints are shown in Table 2

RESULTS:

• Patient recruitment began in October 2014. Results of the first period are anticipated in 2015

Title


Health & Medicine

AAN 2015 alemtuzumab