Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies

Giancarlo Comi, Raed Alroughani, Aaron L Boster, Ann D Bass, Regina Berkovich, Óscar Fernández, Ho Jin Kim, Volker Limmroth, Jan Lycke, Richard Al Macdonell, Basil Sharrack, Barry A Singer, Patrick Vermersch, Heinz Wiendl, Tjalf Ziemssen, Alan Jacobs, Nadia Daizadeh, Claudio E Rodriguez, Anthony Traboulsee, CARE-MS I, CARE-MS II, CAMMS03409, and TOPAZ Investigators, Darren P Baker, Ericka M Bueno, Colin Mitchell, Rebecca L Orndorff, Valerie P Zediak, Giancarlo Comi, Raed Alroughani, Aaron L Boster, Ann D Bass, Regina Berkovich, Óscar Fernández, Ho Jin Kim, Volker Limmroth, Jan Lycke, Richard Al Macdonell, Basil Sharrack, Barry A Singer, Patrick Vermersch, Heinz Wiendl, Tjalf Ziemssen, Alan Jacobs, Nadia Daizadeh, Claudio E Rodriguez, Anthony Traboulsee, CARE-MS I, CARE-MS II, CAMMS03409, and TOPAZ Investigators, Darren P Baker, Ericka M Bueno, Colin Mitchell, Rebecca L Orndorff, Valerie P Zediak

Abstract

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses.

Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions.

Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course.

Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses.

Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.

Trial registration: ClinicalTrials.gov NCT00530348 NCT00548405 NCT00930553 NCT02255656.

Keywords: Alemtuzumab; efficacy; multiple sclerosis; relapse; retreatment; safety.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.C. reports receiving consulting fees from Actelion, Bayer, Merck Serono, Novartis, Sanofi, and Teva; lecture fees from Bayer, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono Symposia International Foundation, and Teva. R.A. reports receiving speaker honoraria and research grants from and serving on scientific advisory boards for Bayer, Biogen, GSK, Lundbeck, Merck Serono, Novartis, Roche, and Sanofi. A.L.B. reports receiving consulting fees and/or speaking fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. A.D.B. reports receiving research funding, compensation for medical advisory boards, and fees from speaker’s bureaus for Actelion, Biogen, EMD Serono, Genentech-Roche, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics. R.B. reports participating in advisory boards and receiving consulting fees from Acorda, Avanir, Bayer, Biogen, Novartis, Questcor, Sanofi, and Teva. Ó.F. reports receiving speaking and/or consulting fees from Allergan, Almirall, Bayer-Schering, Biogen, Merck Serono, Novartis, Sanofi, and Teva; compensation for serving as a journal editor, associate editor, or member of an editorial advisory board for Revista Española de Esclerosis Múltiple; and research support from the Hospital Foundation FIMABIS. H.J.K. reports receiving consulting and/or speaking fees from Bayer, Biogen, Celltrion, Eisai, Genzyme, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok, and UCB, and research support from Genzyme, Merck Serono, the Ministry of Science & ICT of the Republic of Korea, Teva-Handok, and UCB; he also reports being a member of a steering committee for MedImmune, being co-editor for Multiple Sclerosis Journal—Experimental, Translational, and Clinical, and being an associate editor for the Journal of Clinical Neurology. V.L. reports receiving honoraria for consulting and speaking at symposia for Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva, with approval by the HR Department of Cologne General Hospital and the University of Cologne. J.L. reports receiving travel support and/or lecture honoraria from Biogen, Merck, Novartis, Sanofi, and Teva; he also reports serving on advisory boards for Almirall, Biogen, Merck, Novartis, Sanofi, and Teva, serving on the editorial board for Acta Neurologica Scandinavica, and receiving unconditional research support from Biogen, Novartis, and Teva. R.A.L.M. reports receiving compensation for advisory boards and/or speaking fees from Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, and receiving research support from Biogen, Merck, Novartis, Sanofi, and Teva. B.S. reports research and travel grants, honoraria for expert advice on MS, and speaking fees from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. B.A.S. reports receiving speaking and/or consulting fees from AbbVie, Acorda, Alexion, Biogen, EMD Serono, Genentech, Novartis, Roche, Sanofi, Teva, and TG Therapeutics, and receiving research support from AbbVie, Alkermes, Biogen, MedImmune, Novartis, Roche, and Sanofi. P.V. reports receiving consulting and/or speaking fees, and research support, from Almirall, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, Servier, and Teva. H.W. reports receiving consulting and/or speaking fees from Bayer, Behring, Biogen, EMD Serono, Fresenius Medical Care, Merck Serono, Novartis, Roche, Sanofi, and Teva; he also reports receiving license fee payments from Huber-Verlag, and grant/research support from Neotope Bioscience, Novartis, and PML Consortium. T.Z. 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. A.J. and N.D. report receiving personal compensation as employees of Sanofi. C.E.R. reports personal compensation as an employee of Sanofi at the time of the analysis and is currently affiliated with Sunovion Pharmaceuticals, Marlborough, MA, USA. A.T. reports receiving consulting and/or speaking fees, and grant/research support from Biogen, Chugai, Roche, Sanofi, and Teva.

Figures

Figure 1.
Figure 1.
Percentages of patients receiving additional courses of alemtuzumab through Year 8. (a) Percentages of all patients who entered the CARE-MS extension (N = 742) and received additional courses of alemtuzumab 12 mg/day through Year 8. (b) Timing of administration of Courses 3, 4, 5, 6, 7, and 8 through Year 8. Percentages are based on all patients who entered the CARE-MS extension (N = 742). (c) Proportions of patients included and excluded from the analysis based on inclusion criteria for the 2-, 3-, 4-, and ⩾5-courses groups. (d) Proportional makeup of the analyzed patient population belonging to the 2-, 3-, 4-, or ⩾5-courses groups. C: course; CARE-MS: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; Y: year. aIn the CARE-MS studies, seven patients received only one course of alemtuzumab. bTen patients received Course 3 < 12 months after Course 2 (Days 336, 350, 351, 352, 353, 358 (two patients), 359 (two patients), and 365). cSeven patients received Course 4 < 12 months after Course 3 (Days 337, 351, 357, 358, 364, and 365 (two patients)). dFive patients received Course 5 < 12 months after Course 4 (Days 330, 344, 351, and 365 (2 patients)).
Figure 2.
Figure 2.
Efficacy outcomes in the 2-courses group. Results for patients who received exactly two courses and no other DMT through Year 8. (a) Yearly ARR from Year 1 of the core study through Year 8. (b) Mean (SE) EDSS scores from CARE-MS core study baseline through Year 8. EDSS scores were assessed every 3 months during the core studies and the CARE-MS extension, and every 6 months during TOPAZ. (c) Kaplan–Meier analyses of the percentages of patients free of 6-month CDW, and percentages of patients with 6-month CDI from Year 1 through Year 8. (d) Percentages of patients free of MRI disease activity, new Gd-enhancing T1 lesions, new/enlarging T2 hyperintense lesions, and new T1 hypointense lesions from Year 1 through Year 8. 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; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; Gd: gadolinium; SE: standard error; TOPAZ: 5-year long-Term follow-up study for multiple sclerOsis Patients who have completed the AlemtuZumab extension study; Y: year.
Figure 3.
Figure 3.
Efficacy outcomes in the 3-courses group. Results for patients who received exactly three courses within 85 months and no other DMT through Year 8. Through 24 and 36 months, respectively, 111 and 87 patients in the 3-courses group were available for follow-up after receiving Course 3. (a) ARR at 12 months before CARE-MS core study enrollment, at 12 months before Course 3, and at 12, 24, and 36 months after Course 3. (b) Mean (SE) EDSS scores from 12 months before Course 3 to 36 months after Course 3. (c) Kaplan–Meier analyses of the percentages of patients free of 6-month CDW, and percentages of patients with 6-month CDI from the time of Course 3 administration to 36 months after Course 3. (d) Percentages of patients free of MRI disease activity, new Gd-enhancing T1 lesions, new/enlarging T2 hyperintense lesions, and new T1 hypointense lesions from 12 months before Course 3 to 36 months after Course 3. p-values for ARR analyses are based on repeated negative binomial regression with robust variance estimation. p-values for MRI analyses are based on McNemar’s test. The MRI scan immediately before the start date for receiving Course 3 is considered to be “before Course 3,” and the MRI scan ⩾ 3 months after receiving Course 3 is considered to be “after Course 3.” 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; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; Gd: gadolinium; M: month; SE: standard error.
Figure 4.
Figure 4.
Efficacy outcomes in the 4-courses group. Results for patients who received exactly four courses within 85 months and no other DMT through Year 8. Through 24 and 36 months, respectively, 40 and 20 patients in the 4-courses group were available for follow-up after receiving Course 4. (a) ARR at 12 months before CARE-MS core study enrollment, at 12 months before Course 4, and at 12, 24, and 36 months after Course 4. (b) Mean (SE) EDSS scores from 12 months before Course 4 to 36 months after Course 4. (c) Kaplan–Meier analyses of the percentages of patients free of 6-month CDW, and percentages of patients with 6-month CDI from the time of Course 4 administration to 36 months after Course 4. (d) Percentages of patients free of MRI disease activity, new Gd-enhancing T1 lesions, new/enlarging T2 hyperintense lesions, and new T1 hypointense lesions from 12 months before Course 4 to 36 months after Course 4. p-values for ARR analyses are based on repeated negative binomial regression with robust variance estimation. p-values for MRI analyses are based on McNemar’s test. The MRI scan immediately before the start date for receiving Course 4 is considered to be “before Course 4,” and the MRI scan ⩾3 months after receiving Course 4 is considered to be “after Course 4.” 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; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; Gd: gadolinium; M: month; NE: not evaluable; NS: not significant; SE: standard error.

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