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. 2021 Apr 23:14:1756286420982134.
doi: 10.1177/1756286420982134. eCollection 2021.

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial

Alasdair J Coles  1 , Douglas L Arnold  2 , Ann D Bass  3 , Aaron L Boster  4 , D Alastair S Compston  5 , Óscar Fernández  6 , Eva Kubala Havrdová  7 , Kunio Nakamura  8 , Anthony Traboulsee  9 , Tjalf Ziemssen  10 , Alan Jacobs  11 , David H Margolin  12 , Xiaobi Huang  13 , Nadia Daizadeh  13 , Madalina C Chirieac  14 , Krzysztof W Selmaj  15
Affiliations

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial

Alasdair J Coles et al. Ther Adv Neurol Disord. .

Abstract

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline.

Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab.

Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups.

Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups.

Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553.

Keywords: CD52; MRI; alemtuzumab; brain volume; disability; disease activity; efficacy; extension; multiple sclerosis; relapse; safety.

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Conflict of interest statement

Conflict of interest statement: AJC reports receiving consulting fees, lecture fees, and institutional grant support from Sanofi prior to 2017. DLA reports receiving consulting fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffmann-La Roche, Immune Tolerance Network, Immunotec, MedDay, Merck Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, International Progressive MS Alliance, and an equity interest in NeuroRx Research. ADB reports receiving research funding, compensation for medical advisory boards, and compensation for speakers bureaus from Actelion, Biogen, EMD Serono, Genentech-Roche, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics. ALB reports receiving consulting fees and/or speaking fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. DASC reports receiving consulting fees, grant, and research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi, prior to 2017. ÓF reports receiving speaking and/or consulting fees for Allergan, Almirall, Bayer-Schering Pharma, Biogen, Merck Serono, Novartis, Sanofi, and Teva, and research support from the Hospital Foundation FIMABIS; he also serves as editor of the Revista Española de Esclerosis Múltiple. EKH reports receiving honoraria and grant support from Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva, and is supported by the Ministry of Education of the Czech Republic, project PROGRES Q27/LF1. KN reports speaking fees and research support from Biogen and Sanofi, along with royalty fees for licenses with Biogen. AT reports receiving consulting and/or speaking fees, along with grant and research support, from Biogen, Chugai, Roche, Sanofi, and Teva. TZ reports receiving consulting and/or speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, along with grant and research support from Biogen, Novartis, Sanofi, and Teva. AJ, DHM, XH, and MCC report being employees of Sanofi during the time of the analysis. ND reports receiving personal compensation as an employee of Sanofi. KWS reports receiving consulting and/or speaking fees from Biogen, Merck, Novartis, Roche, Sanofi, and Synthon.

Figures

Figure 1.
Figure 1.
CARE-MS I and II patient disposition. Schematic of the as-randomized patient population from the core CARE-MS studies through the extension study, CAMMS03409. Patients randomized to SC IFNB-1a 44 μg who received treatment in the core studies discontinued SC IFNB-1a before initiating alemtuzumab 12 mg in the extension. (A) CARE-MS I patients who were randomized to either alemtuzumab or SC IFNB-1a at core study start. (B) CARE-MS II patients who were randomized to either alemtuzumab or SC IFNB-1a at core study start. CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; IFN, interferon; SC IFNB-1a, subcutaneous interferon beta-1a.
Figure 2.
Figure 2.
Efficacy outcomes in CARE-MS I patients through year 6. Results are shown for the CARE-MS I alemtuzumab-only and IFN–alemtuzumab groups. (A) Yearly ARR from year 2 of the core study to the end of the CAMMS03409 extension study, and cumulative ARR from core study baseline through year 6. Core study ARR values are presented for year 2 only in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 0.18; SC IFNB-1a: 0.39). (B) Change in mean (SE) EDSS score from core study baseline through year 6. (C) Percentages of patients with improved, stable, and worsened EDSS scores at year 2 and year 6 from core study baseline. Percentages may not sum to 100% due to rounding. (D) Kaplan–Meier estimates of the percentages of patients free of 6-month CDW. (E) Kaplan–Meier estimates of the percentages of patients with 6-month CDI. (F) Percentages of patients free of MRI disease activity each year from core study baseline through year 6. For IFN–alemtuzumab patients, MRI disease activity values for year 1 and year 2 are presented only for patients who entered the extension only. (G) Percentages of patients free of new Gd-enhancing lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new Gd-enhancing lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for year 2 only (alemtuzumab: 93%; SC IFNB-1a: 81%). (H) Percentages of patients free of new/enlarging T2 hyperintense lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new/enlarging T2 hyperintense lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 52%; SC IFNB-1a: 42%). For IFN–alemtuzumab patients, values for proportions free of Gd-enhancing lesions and new/enlarging T2 lesions for year 1 and year 2 are presented for patients who entered the extension only, and were reported previously for all patients who received SC IFNB-1a in the core study. (I) Median cumulative percentage BVL from core study baseline to the end of CAMMS03409. (J) Median annual percentage BVL. Alemtuzumab-only group versus IFN–alemtuzumab group: *p < 0.05 indicates significant between-treatment group differences in favor of the alemtuzumab-only group and †p < 0.05 indicates significant between-treatment group differences in favor of the IFN–alemtuzumab group. Year 2 of SC IFNB-1a treatment versus each year (years 3–6) after initiating alemtuzumab treatment: ‡p < 0.05. ARR, annualized relapse rate; BPF, brain parenchymal fraction; BVL, brain volume loss; 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; IFN, interferon; MRI, magnetic resonance imaging; SC IFNB-1a, subcutaneous interferon beta 1-a; SE, standard error; Y, year.
Figure 3.
Figure 3.
Efficacy outcomes in CARE-MS II patients through year 6. Results are shown for the CARE-MS II alemtuzumab-only and IFN–alemtuzumab groups. (A) Yearly ARR from year 2 of the core study to the end of the CAMMS03409 extension study, and cumulative ARR from core study baseline through year 6. Core study ARR values are presented for year 2 only in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 0.26; SC IFNB-1a: 0.52). (B) Change in mean (SE) EDSS score from core study baseline through year 6. (C) Percentages of patients with improved, stable, and worsened EDSS scores at year 2 and year 6 from core study baseline. Percentages may not sum to 100% due to rounding. (D) Kaplan–Meier estimates of the percentages of patients free of 6-month CDW. (E) Kaplan–Meier estimates of the percentages of patients with 6-month CDI. (F) Percentages of patients free of MRI disease activity each year from core study baseline through year 6. For IFN–alemtuzumab patients, MRI disease activity values for year 1 and year 2 are presented for patients who entered the extension only. (G) Percentages of patients free of new Gd-enhancing lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new Gd-enhancing lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for year 2 only (alemtuzumab: 91%; SC IFNB-1a: 77%). (H) Percentages of patients free of new/enlarging T2 hyperintense lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new/enlarging T2 hyperintense lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 54%; SC IFNB-1a: 32%). For IFN–alemtuzumab patients, values for proportions free of Gd-enhancing lesions and new/enlarging T2 lesions for year 1 and year 2 are presented for patients who entered the extension only, and were reported previously for all patients who received SC IFNB-1a in the core study. (I) Median cumulative percentage BVL from core study baseline to the end of CAMMS03409. (J) Median annual percentage BVL. Alemtuzumab-only group versus IFN–alemtuzumab group: *p < 0.05 indicates significant between-treatment group differences in favor of the alemtuzumab-only group and †p < 0.05 indicates significant between-treatment group differences in favor of the IFN–alemtuzumab group. Year 2 of SC IFNB-1a treatment versus each year (years 3–6) after initiating alemtuzumab treatment: ‡p<0.0001, §p<0.001, and p<0.05. ARR, annualized relapse rate; BPF, brain parenchymal fraction; BVL, brain volume loss; 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; IFN, interferon; MRI, magnetic resonance imaging; SC IFNB-1a, subcutaneous interferon beta 1-a; SE, standard error; Y, year.
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