Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis
N Engl J Med. 2016 Dec 21. doi: 10.1056/NEJMoa1601277. [Epub ahead of print]
|Authors/Editors:||Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators.|
Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles.
B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation, autoantibody production, cytokine regulation, and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration. Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed on pre-B cells, mature B cells, and memory B cells but not on lymphoid stem cells and plasma cells. Humanized anti-CD20 antibody was designed to reduce immunogenicity, which was shown in a phase 2 study. Ocrelizumab binds to the large extracellular loop of CD20 with high affinity, selectively depleting CD20-expressing B cells while preserving the capacity for B-cell reconstitution and preexisting humoral immunity. B-cell depletion is achieved by means of several mechanisms, including antibody-dependent cell-mediated phagocytosis, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and induction of apoptosis.
On the basis of results from previous phase 2 studies of the chimeric anti-CD20 antibody rituximab and ocrelizumab, we undertook two phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group trials (OPERA I and OPERA II) to investigate the efficacy and safety of ocrelizumab, as compared with subcutaneous interferon beta-1a, in patients with relapsing multiple sclerosis. The two trials used identical protocols but were conducted independently at nonoverlapping trial sites.