Ocrelizumab: a new milestone in multiple sclerosis therapy

Abstract

B cells play a central role in the pathogenesis of multiple sclerosis (MS): they are involved in the activation of pro-inflammatory T cells, secretion of pro-inflammatory cytokines and production of autoantibodies directed against myelin. Hence, the use of B cell-depleting monoclonal antibodies as therapy for autoimmune diseases, including MS, has increased in recent years. Previous results with rituximab, the first therapeutic B cell-depleting chimeric monoclonal antibody that showed efficacy in MS clinical trials, encouraged researchers to evaluate the efficacy of a humanized anti-CD20 antibody, ocrelizumab, in MS. A large phase II clinical trial in patients with relapsing-remitting MS (RRMS) designed to explore the effects of two doses of ocrelizumab (600 mg and 2000 mg) compared with placebo showed a pronounced effect on radiological and relapse-related outcomes. These results were confirmed in two phase III trials (OPERA I and II) that compared the efficacies of ocrelizumab with interferon beta-1a in patients with relapsing MS, and showed decreased annualized relapse rates (46% in OPERA I and 47% in OPERA II), as well as fewer numbers of gadolinium-enhanced lesions on magnetic resonance imaging (MRI) scans (94% in OPERA I and 95% in OPERA II). Notably, ocrelizumab is the first drug to lower rates of clinical and MRI-evidenced progression in patients with primary progressive MS (PPMS). The phase III trial (ORATORIO) in patients with PPMS met its primary efficacy endpoint: the percentage of patients with 12-week confirmed disability progression was significantly lower in the active treatment group (32.9%) than in patients receiving placebo (39.3%). In March 2017, this evidence led the US Food and Drug Administration to approve the licence for ocrelizumab (Ocrevus®) as a treatment for MS, as the first treatment approved for PPMS and as the first monoclonal antibody for secondary progressive MS.