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


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.
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    • "Moreover, they may not be well tolerated due to side effects or frequent injections, which sometimes preclude adequate adherence.10 The advent of second-line drugs, such as natalizumab,11 fingolimod,12 teriflunomide,13 and dimethyl fumarate,14 as well as alemtuzumab15 in some countries, is promising both for possible higher anti-inflammatory efficacy and a more convenient way of administration (ie, either intravenous injections or oral). These advantages have, however, the price of a variable but overall less favorable safety and side-effect profile.16 "
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    • "Given the growing therapeutic armamentarium in MS, the role of Nat needs to be carefully re-evaluated taking into account several alternative strategies. Here, especially, Tecfidera (DEFINE and CONFIRM: relative reduction of annualized relapse rate, 44–53%92,93) and Alemtuzumab (CARE-MS 1 and 2: relapse free after two years, 65–78%,94,95) could be possible therapeutic options in patients with initial high disease activity or after treatment failure of interferon and glatiramer acetate. "
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    ABSTRACT: Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08-3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.
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