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Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes.
Lancet Neurol. 2011 Apr; 10(4):338-48.LN

Abstract

BACKGROUND

Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability.

METHODS

334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS.

FINDINGS

322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab.

INTERPRETATION

Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis.

FUNDING

Genzyme and Bayer Schering Pharma.

Authors+Show Affiliations

Department of Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. ajc1020@medschl.cam.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21397567

Citation

Coles, Alasdair J., et al. "Alemtuzumab Versus Interferon Β-1a in Early Relapsing-remitting Multiple Sclerosis: Post-hoc and Subset Analyses of Clinical Efficacy Outcomes." The Lancet. Neurology, vol. 10, no. 4, 2011, pp. 338-48.
Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011;10(4):338-48.
Coles, A. J., Fox, E., Vladic, A., Gazda, S. K., Brinar, V., Selmaj, K. W., Bass, A. D., Wynn, D. R., Margolin, D. H., Lake, S. L., Moran, S., Palmer, J., Smith, M. S., & Compston, D. A. (2011). Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. The Lancet. Neurology, 10(4), 338-48. https://doi.org/10.1016/S1474-4422(11)70020-5
Coles AJ, et al. Alemtuzumab Versus Interferon Β-1a in Early Relapsing-remitting Multiple Sclerosis: Post-hoc and Subset Analyses of Clinical Efficacy Outcomes. Lancet Neurol. 2011;10(4):338-48. PubMed PMID: 21397567.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. AU - Coles,Alasdair J, AU - Fox,Edward, AU - Vladic,Anton, AU - Gazda,Suzanne K, AU - Brinar,Vesna, AU - Selmaj,Krzysztof W, AU - Bass,Ann Doan-Do, AU - Wynn,Daniel R, AU - Margolin,David H, AU - Lake,Stephen L, AU - Moran,Susan, AU - Palmer,Jeffrey, AU - Smith,M Shelton, AU - Compston,D Alastair S, PY - 2011/3/15/entrez PY - 2011/3/15/pubmed PY - 2011/6/16/medline SP - 338 EP - 48 JF - The Lancet. Neurology JO - Lancet Neurol VL - 10 IS - 4 N2 - BACKGROUND: Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. METHODS: 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. FINDINGS: 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. INTERPRETATION: Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. FUNDING: Genzyme and Bayer Schering Pharma. SN - 1474-4465 UR - https://www.unboundmedicine.com/medline/citation/21397567/Alemtuzumab_versus_interferon_β_1a_in_early_relapsing_remitting_multiple_sclerosis:_post_hoc_and_subset_analyses_of_clinical_efficacy_outcomes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1474-4422(11)70020-5 DB - PRIME DP - Unbound Medicine ER -