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