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Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

N Engl J Med. 2016 Dec 21. doi: 10.1056/NEJMoa1606468. [Epub ahead of print]

Authors/Editors: Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators.
Publication Date: 2016



Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis. The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur. Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful, and no disease-modifying treatments have been approved.

B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form. Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis through antigen presentation, autoantibody production, or cytokine secretion. B cells are present in meningeal inflammation, which is characteristic of chronic multiple sclerosis and may cause adjacent cortical demyelinating and neurodegenerative pathologic features. CD20 is a cell-surface antigen found on pre-B cells and mature and memory B cells but not on the earliest B-cell precursors or on plasma cells. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20-expressing B cells while preserving the capacity for B-cell reconstitution and preexisting humoral immunity.

A previous phase 2–3 trial of the chimeric monoclonal anti-CD20 antibody rituximab (OLYMPUS trial) in primary progressive multiple sclerosis did not meet its primary efficacy end point, but a subgroup analysis showed delayed progression of disability in younger patients (<51 years of age) with evidence of increased inflammatory disease activity. Those results provided the rationale and in part informed the trial design for this investigation of ocrelizumab in patients with primary progressive multiple sclerosis. Here, we report results from a phase 3, randomized, parallel-group, double-blind, placebo-controlled trial (ORATORIO) that investigated the efficacy and safety of ocrelizumab in patients with primary progressive multiple sclerosis.

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