TY - JOUR
T1 - Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy
T2 - A randomised controlled phase 3 trial
AU - CARE-MS II investigators
AU - Coles, Alasdair J.
AU - Twyman, Cary L.
AU - Arnold, Douglas L.
AU - Cohen, Jeffrey A.
AU - Confavreux, Christian
AU - Fox, Edward J.
AU - Hartung, Hans Peter
AU - Havrdova, Eva
AU - Selmaj, Krzysztof W.
AU - Weiner, Howard L.
AU - Miller, Tamara
AU - Fisher, Elizabeth
AU - Sandbrink, Rupert
AU - Lake, Stephen L.
AU - Margolin, David H.
AU - Oyuela, Pedro
AU - Panzara, Michael A.
AU - Compston, D. Alastair S.
N1 - Funding Information:
Individuals with relapsing-remitting multiple sclerosis that remains active after first-line disease-modifying therapy have a poor prognosis for future disability. 2,3,25 Switching to a more potent therapy is logical in the face of aggressive disease; but considerable uncertainty and variation in practice exists in terms of how best to manage patients who relapse on first-line therapy. In our phase 3 trial, which exclusively enrolled patients who remained clinically active despite interferon beta or glatiramer treatment, escalation to alemtuzumab significantly reduced the relapse rate and risk of 6 month sustained accumulation of disability by more than 40% compared with treatment with interferon beta 1a. No phase 3 monotherapy trial has previously shown superior efficacy on EDSS disability measures against an active comparator. Although mean disability deteriorated after interferon beta 1a, it improved with alemtuzumab 12 mg; and more patients had a sustained reduction in disability after alemtuzumab. The clinical evidence for efficacy is supported by alemtuzumab's significantly greater effects on several MRI measures compared with interferon beta 1a. Adjustment for specific previous treatments, participant withdrawals before treatment, and anti-interferon antibodies present at baseline or study end, did not change the evidence for improved efficacy of alemtuzumab. Previous therapy or the presence of anti-interferon antibodies did not affect the results, although the study was not powered to detect an interaction. These results extend the experience of alemtuzumab from the phase 2 trial 12 and accompanying phase 3 trial 13 in previously untreated patients to those with disease activity on first-line therapy and increased disease duration and disability at baseline; however, compared with phase 3 trials of other compounds, this population is still at the lower end of disease duration and has typical relapse rates and disability at entry ( panel ). We regard subcutaneous high-dose, high-frequency interferon beta 1a as an appropriate comparator for this study because it is a common escalation choice for patients with disease activity during treatment with another first-line disease modifying therapy both in the USA and Europe. 29,30 Our trial supports previous experience of the safety profile of alemtuzumab accumulated for 3–5 years; 8,11,12 our cohort and others are under extended review to collect long-term safety data. In our study, infusion-associated reactions were effectively managed with methylprednisolone, antipyretics, and antihistamines. Incidence of mild-to-moderate infections and superficial herpetic infections were more common after alemtuzumab than interferon beta 1a, but were treatable with aciclovir. We did not note any serious opportunistic infections, perhaps because of intact innate immunity, sequestered lymphocytes, and maintained levels of serum immunoglobulins 9 or tissue-resident effector memory T cells. 31 We identified secondary autoimmune diseases promptly by monitoring, allowing effective therapy. At 2 years, 16% of patients treated with alemtuzumab 12 mg had autoimmune thyroid disease; our previous experience suggests that this figure might rise to about 33%, with annual incidence reducing after the third year. 32 Alemtuzumab is the first treatment for multiple sclerosis to show improved efficacy on clinical endpoints against an active comparator in one phase 2 and two phase 3 trials. 12,13 Significant effects on clinical and MRI indicators of inflammatory disease activity were accompanied in this study by slowing of cerebral atrophy and accumulation of physical disability and, for many patients, by improvements in disability. We conclude that, with appropriate monitoring to reduce the risk of potentially serious but nonetheless treatable adverse effects, alemtuzumab offers the prospect for effective immunotherapy in patients with relapsing-remitting multiple sclerosis whose disease has advanced despite use of a first-line treatment. Contributors AJC wrote the first draft of the manuscript and coordinated all reviews and submissions. The writing committee (AJC, DLA, JAC, CC, EJF, H-PH, EH, KS, HLW, DHM, MP, and DASC) met to review data outputs, suggest additional analyses, edit, and approve manuscript drafts. Statistical support was led by SLL. Final versions of the manuscript were edited and approved by representatives of the investigators (CLT, TM, and EF) and sponsors (RS and PO). Conflicts of interest AJC reports receiving consulting fees from Genzyme, lecture fees from Merck Serono, and research support paid to his institution from Genzyme. CLT reports receiving compensation from clinical trials with Genzyme, Sanofi-Aventis, Eli Lilly, Opexa Therapeutics, Biogen Idec, Teva, Roche, Novartis, Xenoport, Acorda, and Pfizer Pharmaceuticals and compensation for speaker activities and consultation activities from Acorda, Biogen Idec, Novartis, Forrest, and Teva. DLA served on advisory boards, received speaker honoraria, and served as a consultant or received research support from Bayer, Biogen Idec, Coronado Biosciences, Consortium of Multiple Sclerosis Centers, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MS Forum, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, SA Serono Symposia International Foundation, Teva, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada; and holds stock in NeuroRx Research. JAC reports receiving consulting fees from Biogen Idec, Elan, Five Prime Therapeutics, Eli Lilly, Novartis, Teva, Vaccinex, lecture fees from Novartis and Waterfront Media, and research support paid to his institution from Biogen Idec, Genzyme, Novartis, and Teva. CC reports receiving consulting fees from Biogen Idec, Gemacbio, Genzyme, Novartis, Sanofi-Aventis, Teva, UCB; lecture fees from Bayer-Schering, Biogen Idec, Genzyme, Merck-Serono, Novartis, Octopharma, Sanofi-Aventis, Teva; research support paid to his institution from Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Sanofi-Aventis, Teva. EJF reports receiving consulting fees, honoraria, travel, and research support from Acorda, Bayer, Biogen Idec, Eli Lilly, EMD Serono, Genzyme, GlaxoSmithKline, Novartis, Ono, Opexa, Pfizer, Roche, Sanofi, and Teva. H-PH reports receiving honoraria for consulting and speaking, with approval by the rector of Heinrich-Heine-University from Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi, and Teva. EH reports receiving consulting fees, honoraria, travel, and research support from Bayer, Biogen Idec, Genzyme, GSK, Merck Serono, Novartis, Roche, and Teva. KJ reports receiving consulting fees from Genzyme, Novartis, Biogen Idec, and Roche; he has received lecture fees from Novartis, Merck-Serono, Biogen Idec, and Bayer; and received financial compensation including travel from Genzyme for presentation at ECTRIMS 2010. HLW reports receiving consulting fees from Biogen Idec, EMD Serono, Nasvax, Novartis, Teva, and research support paid to his institution from Biogen Idec and EMD Serono. TM has received compensation for speaker activities for Acorda, Allergan, Bayer, Biogen Idec, Eli Lilly, Forest, Novartis, Pfizer, Questcor, Teva and National MS Society; until clinical trial closure, TM was an independent contractor for Allergan, Biogen Idec, Genzyme, Elan, Teva, Ono, Pfizer, Novartis, Sanofi-Aventis, EMD Serono, and Roche/Genentech. EF reports receiving consulting fees from Biogen Idec, Genzyme, Pfizer, and Wyeth, lecture fees from Biogen Idec and Teva, and research support paid to her institution from Biogen Idec, Genzyme, and Wyeth. RS receives personal compensation as an employee of Bayer HealthCare, Berlin, Germany. ASC reports receiving consulting fees, lecture fees and grant support from Genzyme and lecture fees from Bayer Schering Pharma, on behalf of the University of Cambridge. DHM, SLL, PO, and MP receive personal compensation as employees of Genzyme (a Sanofi company). Acknowledgments This trial was supported by Genzyme, a Sanofi company, and Bayer Schering Pharma. EH has been supported by Czech Ministry of Education, Research program MSM 0021620849. AJC and DASC are supported by the Cambridge National Institute for Health Research Biomedical Research Centre. Shelton Smith (Genzyme) provided editorial assistance.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Background The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. Findings 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. Interpretation For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.
AB - Background The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. Findings 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. Interpretation For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.
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U2 - 10.1016/S0140-6736(12)61768-1
DO - 10.1016/S0140-6736(12)61768-1
M3 - Article
C2 - 23122650
AN - SCOPUS:84869507357
VL - 380
SP - 1829
EP - 1839
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9856
ER -