Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial

Mellen Center, Cleveland Clinic, Cleveland, OH, USA. Electronic address: .
The Lancet (Impact Factor: 45.22). 10/2012; 380(9856). DOI: 10.1016/S0140-6736(12)61769-3
Source: PubMed

ABSTRACT BACKGROUND: The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with, number NCT00530348. FINDINGS: 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION: Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING: Genzyme (Sanofi) and Bayer Schering Pharma.

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Available from: Elizabeth Fisher, Jun 16, 2014
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    • "Alemtuzumab is specific for CD52, an antigen present at high levels on the surface of T and B lymphocytes and at lower levels on other immune cells (Hale et al., 1990; Rao et al., 2012). Pivotal phase 3 trials conducted in treatment-naïve relapsing–remitting (RRMS) patients (CARE-MS I) and in RRMS patients who relapsed on prior therapy (CARE-MS II) indicated that alemtuzumab administered as two annual courses of treatment (12 mg intravenously on 5 consecutive days at study start and 3 days a year later) provided superior efficacy compared to interferon-β1a (IFN-β1a) administered three times per week (44 μg subcutaneously) (Cohen et al., 2012; Coles et al., 2012a). In addition, long-term follow-up of patients from a phase 2 study (CAMMS223) suggested that alemtuzumab provides a durable "
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    ABSTRACT: Alemtuzumab, a monoclonal antibody directed against human CD52, is used in the treatment of MS. To characterize the impact of anti-CD52 administration, a monoclonal antibody to mouse CD52 (anti-muCD52) was generated and evaluated in EAE mouse models of MS. A single course of anti-muCD52 provided a therapeutic benefit accompanied by a reduction in the frequency of autoreactive T lymphocytes and production of pro-inflammatory cytokines. Examination of the CNS revealed a decrease in infiltrating lymphocytes, demyelination and axonal loss. Electrophysiological assessment showed preservation of axonal conductance in the spinal cord. These findings suggest that anti-CD52 therapy may help preserve CNS integrity. Copyright © 2015. Published by Elsevier B.V.
    Journal of Neuroimmunology 05/2015; 83. DOI:10.1016/j.jneuroim.2015.05.018 · 2.79 Impact Factor
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    • "Acyclovir prophylaxis was implemented during that period to decrease the incidence of herpes infection. Importantly, infection rates did not increase after the second or, in some cases, third course of alemtuzumab (Coles et al., 2008; Cohen et al., 2012; Coles et al., 2012a, 2012b). "
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    ABSTRACT: Alemtuzumab is a monoclonal antibody against the CD52 antigen present at high levels on the surface of lymphocytes. While treatment of multiple sclerosis patients with alemtuzumab results in marked depletion of lymphocytes from the circulation, it has not been associated with a high incidence of serious infections. In a human CD52 transgenic mouse, alemtuzumab treatment showed minimal impact on the number and function of innate immune cells. A transient decrease in primary adaptive immune responses was observed post-alemtuzumab but there was little effect on memory responses. These results potentially help explain the level of immunocompetence observed in alemtuzumab-treated MS patients.
    Journal of neuroimmunology 06/2013; 261(1-2). DOI:10.1016/j.jneuroim.2013.04.018 · 2.79 Impact Factor
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    • "IJCM month following that course. However, no association has been determined for the appearance of the antibodies and effects on alemtuzumab clinical efficacy, safety, or lymphocyte effects [49] [50] [51] "
    International Journal of Clinical Medicine 01/2013; 04(10):459-471. DOI:10.4236/ijcm.2013.410082
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