Cohen et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis. The Lancet, Early Online Publication, 1 November 2012doi:10.1016/S0140-6736(12)61769-3.
Background: The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated MSers 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 MSers who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00530348 .
Findings: 187 (96%) of 195 MSers randomly allocated interferon beta-1a and 376 (97%) of 386 MSers randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) MSers in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) MSers 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 MSers in the interferon beta 1a group were relapse-free at 2 years compared with 78% of MSers in the alemtuzumab group (p<0·0001). 20 (11%) of MSers 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 MSers 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%) MSers treated with alemtuzumab versus 85 (45%) MSers treated with interferon beta 1a. 62 (16%) MSers treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) MSers treated with interferon beta 1a. By 24 months, 68 (18%) MSers 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 MSers 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 MSers 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.
"This the news that we have been waiting for and makes 2012 a momentous year in the field of MS."
"Congratulations to the team in Cambridge (Herman Waldmann, Alastair Compston. Alasdair Coles, et al.) for their perseverance in getting this far. Let's hope the EMA, FDA and NICE don't spoil the party."
"MSers with active RRMS deserve the option of receiving alemtuzumab! The option of early aggressive treatment needs to be on the table before irreversible damage has occurred."
"I would also like to take this opportunity of thanking all the study subjects at Barts for volunteering for this study and for their patience with a very demanding study protocol."
"Finally to all the staff in the Clinical Research Centre, and my colleagues, thank you for all your hard-work on this study!"
CoI: I am a co-author on this study, the principal investigator on this study at Barts Health and have received consultancy and honorarium payments from Genzyme and Sanofi, in relation to alemtzumab.