Efficacy and Safety of Ocrelizumab in Primary Progressive Multiple Sclerosis: Results of the Phase III Double-Blind, Placebo-Controlled ORATORIO Study (S49.001)

Objective: To evaluate the efficacy and safety of ocrelizumab in a Phase III, randomized, double-blind, placebo-controlled study in primary progressive MS (PPMS). Background: B cells are central to MS pathogenesis, including PPMS. Currently, no disease-modifying therapies are approved for PPMS. Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20+ B cells. Methods: A total of 732 patients were randomized (2:1) to receive ocrelizumab 600mg as two 300mg intravenous infusions 14 days apart, or placebo every 24 weeks for ≥120 weeks until a pre-specified number of 12-week confirmed disability progression (CDP) events occurred. Key eligibility criteria included: age 18-55 years; diagnosis of PPMS (2005 revised McDonald criteria); Expanded Disability Status Scale score of 3.0-6.5; and documented history of elevated immunoglobulin index and/or presence of oligoclonal bands within the cerebrospinal fluid. The primary endpoint was time to onset of 12-week CDP. Secondary endpoints included time to onset of 24-week CDP; change in timed 25-foot walk (T25FW) and T2 lesion volume from baseline to week 120; change in whole brain volume from week 24-120; and overall safety. Results: Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week CDP by 24[percnt] (HR=0.76; p=0.0321) and 24-week CDP by 25[percnt] (HR= 0.75; p=0.0365); the T25FW progression rate by 29[percnt] (39[percnt] vs 55[percnt] increase for ocrelizumab vs placebo, respectively [ranked ANCOVA, p=0.0404]); T2 lesion volume (-3.4[percnt] with ocrelizumab vs +7.4[percnt] with placebo [p<0.0001]); and the rate of brain volume loss by 17.5[percnt] (-0.9[percnt] with ocrelizumab vs -1.1[percnt] with placebo [p=0.0206]). Overall, adverse events and serious adverse events were similar in both groups. Conclusions: Ocrelizumab is the first investigational treatment to meet primary and key secondary efficacy outcomes in a Phase III PPMS study. Supported by F.