Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study

Abstract

Background: Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.

Objectives: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.

Methods: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.

Results: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.

Conclusions: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS.

Gov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Conflict of interest statement

TZ: Consulting and/or speaking fees (Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Biogen, Novartis, Sanofi, and Teva). ADB: Consulting fees/fees for non-CME services from commercial interests or their agents/grant and research support (Biogen, EMD Serono, Mallinckrodt, Novartis, Roche-Genentech, Sanofi, and TG Therapeutics). RB: Advisory boards and consulting (Acorda, Avanir, Bayer, Biogen, Novartis, Questcor, Sanofi, and Teva). GC: Consulting fees (Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva); lecture fees (Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). SE: Speaking and/or consulting (Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). JH: Consulting fees, honoraria, travel payment, or research support (Acorda, Bayer-Schering, Biogen, Global Blood Therapeutics, LORA Group, Merck Serono, Novartis, Oxford PharmaGenesis, Roche, Sanofi, Teva, and Vantia) and license fee/royalty payments (Plymouth University). SFH: Consulting agreements, speaker honoraria, writing support, and grant/research financial support (AbbVie, Actelion-Janssen, Adamas, Alkermes, Biogen, Genentech-Roche, Genzyme, Novartis, Osmotica, Mallinckrodt, and Sanofi-Genzyme). CL: Compensation for consulting (Acorda Therapeutics, Bayer, Biogen, Cephalon, EMD Serono, Novartis, Pfizer, Questcor, Sanofi, Strativa, Teva, and UCB). VL: Honoraria for consulting and speaking at symposia (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva, with approval by the HR Department, Cologne General Hospital, and University of Cologne). DP: Consulting and/or speaking fees and grant/research support (Biogen, Merck Serono, Novartis, Roche, and Sanofi). CP: Consulting and/or speaking fees, research, and travel grants (Actelion, Biogen, Merck, Novartis, Sanofi, and Teva). SS: Consulting and/or speaking fees (Biogen, Merck Serono, Novartis, Sanofi, and Teva) and grant/research support (Novartis and Sanofi). LS: Compensation for advisory board and speaking fees (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). AT: Consulting and/or speaking fees and grant/research support (Biogen, Chugai, Roche, Sanofi, and Teva). BMJU: Consulting fees (Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva). BVW: Research and travel grants, honoraria for MS-expert advice, and speaking fees (Actelion, Bayer-Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). ZC and ND: Employees of Sanofi. BAS: Speaking and/or consulting (AbbVie, Bayer, Biogen, Celgene, EMD Serono, Genentech, Novartis, Roche, Sanofi, Teva, and TG Therapeutics), and research support (AbbVie, Alkermes, Biogen, MedImmune, Novartis, Roche, and Sanofi).

Figures

Fig. 1

HAD definitions and HAD patient disposition: a primary and alternative definitions of HAD used in this post hoc analysis; b CARE-MS I and II alemtuzumab-treated HAD patient disposition through year 9 defined by the primary HAD definition. CARE-MS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, DMT disease-modifying therapy, Gd gadolinium, HAD highly active disease, MRI magnetic resonance imaging, SC IFNB-1a subcutaneous interferon-β-1a

Fig. 2

Clinical efficacy in CARE-MS I alemtuzumab-treated HAD patients through year 9: a ARR; b percentage of patients with improved or stable EDSS scores over time; may not sum appropriately due to rounding; c percentage of patients free of 6-month CDW; d percentage of patients achieving 6-month CDI. *p = 0.01 vs. SC IFNB-1a over years 0–2. Primary HAD definition: ≥ 2 relapses in the year prior to baseline and ≥ 1 Gd-enhancing lesion at baseline. Improved EDSS score: ≥ 1.0-point decrease from core study baseline; stable EDSS score: ≤ 0.5-point change in either direction from core study baseline. CDW: ≥ 1.0-point EDSS increase (or ≥ 1.5 points if baseline EDSS = 0) confirmed over 6 months. CDI: ≥ 1.0-point EDSS decrease from baseline confirmed over 6 months (assessed only in patients with baseline EDSS score ≥ 2.0). ARR annualized relapse rate, CARE-MS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, CDI confirmed disability improvement, CDW confirmed disability worsening, CI confidence interval, EDSS Expanded Disability Status Scale, Gd gadolinium, HAD highly active disease, SC IFNB-1a subcutaneous interferon-β-1a, Y year

Fig. 3

Clinical efficacy in CARE-MS II alemtuzumab-treated HAD patients through year 9: a ARR; b percentage of patients with improved or stable EDSS scores over time; may not sum appropriately due to rounding; c percentage of patients free of 6-month CDW; d percentage of patients achieving 6-month CDI. *p = 0.004 vs. SC IFNB-1a over years 0–2. Primary HAD definition: ≥ 2 relapses in the year prior to baseline and ≥ 1 Gd-enhancing lesion at baseline. Improved EDSS score: ≥ 1.0-point decrease from core study baseline; stable EDSS score: ≤ 0.5-point change in either direction from core study baseline. CDW: ≥ 1.0-point EDSS increase (or ≥ 1.5 points if baseline EDSS = 0) confirmed over 6 months. CDI: ≥ 1.0-point EDSS decrease from baseline confirmed over 6 months (assessed only in patients with baseline EDSS score ≥ 2.0). ARR annualized relapse rate, CARE-MS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, CDI confirmed disability improvement, CDW confirmed disability worsening, CI confidence interval, EDSS Expanded Disability Status Scale, Gd gadolinium, HAD highly active disease, SC IFNB-1a subcutaneous interferon-β-1a, Y year

Fig. 4

MRI outcomes and NEDA in CARE-MS I alemtuzumab-treated HAD patients through year 9: a percentage of patients free of MRI disease activity; b percentage of patients achieving annual NEDA; c cumulative BVL, change from baseline in median BPF over time. *p = 0.0007 vs. SC IFNB-1a in year 2. Primary HAD definition: ≥ 2 relapses in the year prior to baseline and ≥ 1 Gd-enhancing lesion at baseline. Freedom from MRI disease activity: no new Gd-enhancing T1 lesions on current MRI and no new/enlarging T2 hyperintense lesions since last MRI. NEDA: absence of relapse, 6-month CDW, and MRI disease activity. BPF brain parenchymal fraction, BVL brain volume loss, CARE-MS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, CDW confirmed disability worsening, CI confidence interval, Gd gadolinium, HAD highly active disease, MRI magnetic resonance imaging, NEDA no evidence of disease activity, SC IFNB-1a subcutaneous interferon-β-1a, Y year

Fig. 5

MRI outcomes and NEDA in CARE-MS II alemtuzumab-treated HAD patients through year 9: a percentage of patients free of MRI disease activity; b percentage of patients achieving annual NEDA; c cumulative BVL, change from baseline in median BPF over time. *p < 0.0001 vs. SC IFNB-1a in years 1 and 2. Primary HAD definition: ≥ 2 relapses in the year prior to baseline and ≥ 1 Gd-enhancing lesion at baseline. Freedom from MRI disease activity: no new Gd-enhancing T1 lesions on current MRI and no new/enlarging T2 hyperintense lesions since last MRI. NEDA: absence of relapse, 6-month CDW, and MRI disease activity. BPF brain parenchymal fraction, BVL brain volume loss, CARE-MS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, CDW confirmed disability worsening, CI confidence interval, Gd gadolinium, HAD highly active disease, MRI magnetic resonance imaging, NEDA no evidence of disease activity, SC IFNB-1a subcutaneous interferon-β-1a, Y year