Elsevier

The Lancet

Volume 378, Issue 9805, 19–25 November 2011, Pages 1779-1787
The Lancet

Articles
Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial

https://doi.org/10.1016/S0140-6736(11)61649-8Get rights and content

Summary

Background

B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis.

Methods

We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18–55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00676715.

Findings

218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68–97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89–99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0–4·4) patients in the placebo group, one of 55 (2%; 1·3–2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6–6·3) in the 2000 mg group, and two of 54 (4%; 3·0–4·4) in the interferon beta-1a group.

Interpretation

The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials.

Funding

F Hoffmann-La Roche Ltd, Biogen Idec Inc.

Introduction

Inflammation in multiple sclerosis was previously thought to be mainly mediated by proinflammatory CD4 T cells (Th1, ThIL-17).1 However, B cells might also contribute to multiple sclerosis through antibody-dependent and antibody-independent mechanisms. B cells might differentiate into plasma cells and produce CNS-directed autoantibodies, triggering cellular and complement-dependent cytotoxic effects.2 These cells can also function as antigen-presenting cells and thereby modulate priming of effector T cells.3 Secretion of proinflammatory and anti-inflammatory cytokines by B cells is a function that seems to be abnormal in patients with multiple sclerosis.4, 5, 6 Production of cytokines and chemokines by B cells could also contribute to formation of ectopic lymphoid-like structures, resulting in CNS-compartmentalised presentation of autoantigens and further immune activation.7, 8 B cells could also be the reservoir for Epstein-Barr virus, which has been associated with risk of multiple sclerosis. Therefore, targeting of these cells might disrupt processes in multiple sclerosis pathogenesis.

Studies of rituximab—a chimeric monoclonal antibody against CD20—have shown that B-cell depletion is of clinical benefit as treatment for some lymphoma types, chronic lymphocytic leukaemia,9 and rheumatoid arthritis10, 11, 12 and as a potential treatment for multiple sclerosis.13 Ocrelizumab is a recombinant humanised antibody designed to selectively target CD20 B cells. Compared with rituximab, ocrelizumab is associated with increased antibody-dependent cell-mediated cytotoxic effects, and reduced complement-dependent cytotoxic effects in vitro.14, 15 By increasing antibody-dependent cell-mediated cytotoxic effects, ocrelizumab might modulate tissue-dependent mechanisms of pathogenic response more effectively than does rituximab. As a humanised molecule, ocrelizumab is expected to be less immunogenic with repeated infusions and might thus have a more favourable benefit–risk profile than rituximab.

We did this phase-2, placebo-controlled trial to assess efficacy and safety of two dose regimens of ocrelizumab in patients with relapsing-remitting multiple sclerosis. We also compared ocrelizumab with once a week interferon beta-1a (avonex) as open-label treatment.

Section snippets

Patients

We recruited patients from 79 centres in 20 countries, and did an international multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding study with ocrelizumab. 58 patients were from centres in North America, 120 from centres in east-central Europe and Asia, 34 from centres in western Europe, and eight from centres in Latin America. Eligible patients were aged 18–55 years with a diagnosis of relapsing-remitting multiple sclerosis,16 had had two or more documented

Results

Baseline characteristics were similar in all groups (table 1). Of the 220 randomly assigned patients, 204 (93%) completed the 24-week study period (figure 2). Completion rates for week 48 were similar to those for week 24. We noted highly significant differences in both ocrelizumab groups (p<0·0001) for total number of gadolinium-enhancing T1 lesions at weeks 12, 16, 20, and 24, versus placebo. Overall, the relative reductions were 89% (95% CI 68–97) for the 600 mg ocrelizumab group, and 96%

Discussion

The total number of gadolinium-enhancing MRI lesions at weeks 12, 16, 20, and 24 was lower in both ocrelizumab dose groups than in patients given placebo. Annualised relapse rates were also lower in the ocrelizumab treatment groups than in the placebo group. Both ocrelizumab doses seemed to be equivalent because we recorded no clear dose separation in key endpoints for the intention-to-treat population. The low level of clinical disease activity in the original ocrelizumab groups at week 48

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