FDA approves ocrelizumab in RRMS, PPMS


The U.S. Food and Drug Administration has approved ocrelizumab (Ocrevus) for the treatment of adult patients with relapsing forms of multiple sclerosis, and for primary-progressive MS. Ocrelizumab is a humanized monoclonal antibody that targets CD20+ B cells. It is the first disease-modifying therapy to be approved for PPMS. The FDA had given ocrelizumab breakthrough therapy and fast track designations, and granted it a priority review.

Approval was based on the results of two clinical trials in relapsing MS (OPERA I and OPERA II), and one trial in PPMS (ORATORIO).  (Hauser et al. N Engl J Med 2017;376:221-234). For OPERA I/II, 1,656 subjects with relapsing MS were randomized to ocrelizumab 600 mg by infusion every 24 weeks, or subcutaneous interferon-beta-1a 44 mcg three times per week, for 96 weeks. The annualized relapse rate was 0.16 with ocrelizumab versus 0.29 with the interferon (47% reduction). The mean number of enhancing lesions was 94-95% lower with ocrelizumab. In a pooled analysis, the proportion of patients with 12-week confirmed disability progression was significantly lower with ocrelizumab versus interferon (9.1% vs. 13.6%; the proportion with 24-week confirmed progression was 6.9% vs. 10.5%, respectively. For change from baseline in Multiple Sclerosis Functional Composite (MSFC) scores, which combines walking speed, upper-limb movements, and cognition, ocrelizumab was superior to interferon in OPERA II but not in OPERA I.

In the phase III ORATORIO trial, 732 subjects with PPMS were randomized to ocrelizumab 600 mg q24wks or placebo for at least 120 weeks and until a prespecified number of disability events had occurred (Montalban et al. N Engl J Med 2017;376:209-220). The proportion with 12-week disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio 0.76); the proportion with 24-week disability progression was 29.6% vs. 35.7%, respectively. Timed 25-foot walk performance worsened by 38.9% with ocrelizumab, and 55.1% with placebo. Percent brain volume change was -0.90% with ocrelizumab versus -1.09% with placebo.

The most common adverse event was infusion-related reactions: 34.3% in the OPERA studies, and 39.9% in ORATORIO. Other adverse events of interest were herpes infections (OPERA: 5.9 vs. 3.4% with interferon), and upper respiratory tract infections (ORATORIO: 10.9% vs. 5.9% with placebo).

Treatment may be associated with an increased risk of neoplasms (OPERA: 0.5% vs. 0.2% with interferon; ORATORIO: 2.3% vs. 0.8% with placebo); 5 additional malignancies have been reported to date in the OPERA extension.

The full U.S. product monograph was not available at the time of writing. The FDA stated in a press release that Ocrevus must be dispensed with a patient medication guide. Ocrelizumab should not be used in patients with hepatitis B. The drug may increase the risk of malignancies, particularly breast cancer. Vaccination with live or live attenuated vaccines is not recommended during treatment with ocrelizumab.

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