Ocrelizumab is a humanised monoclonal antibody that selectively targets CD20-expressing B cells. Although its mechanism of action in MS has not been fully elucidated, it is presumed to involve immunomodulation via a reduction in the number and function of these B-cells. Innate immunity and total T-cell numbers are not affected.
Lower relapse rates with ocrelizumab
The OPERA I and OPERA II trials were identical double-dummy, active-controlled, parallel-group studies comparing ocrelizumab with interferon beta-1a in 1,656 patients aged 18 to 55 years with relapsing MS.
Patients were randomised to receive ocrelizumab (600mg every 24 weeks given as two 300mg iv infusions on days 1 and 15 for the first dose and as a single 600mg iv infusion thereafter), or interferon beta-1a (44 microgram by sc injection three times a week).
In both studies, ocrelizumab was associated with a significant reduction in annualised relapse rate at 96 weeks (the primary endpoint) compared with interferon beta-1a (0.16 vs 0.29 in both studies, indicating a 46% lower relapse rate for ocrelizumab in OPERA I and a 47% lower rate in OPERA II; p < 0.001 for both comparisons).
In addition, the prespecified pooled analysis showed the risk of disability progression at 12 weeks to be 40% lower in the ocrelizumab group than in the interferon beta-1a group (9.1% vs 13.6%; hazard ratio 0.60 [95% CI 0.45-0.81], p<0.001). Similar results were seen at 24 weeks.
Number of lesions reduced
Ocrelizumab was also shown to be superior to interferon beta-1a in terms of mean number of gadolinium-enhancing lesions per T1-weighted MRI scan (94% and 95% fewer lesions in the OPERA I and OPERA II trials, respectively; p < 0.001 for both).
Significantly greater improvement in the MS Functional Composite score (a measure of walking speed, upper limb coordinated movements and cognition) was also seen for patients in the ocrelizumab group compared with those in the interferon beta-1a group in OPERA II but not in OPERA I (p=0.004 and p=0.33, respectively).
Lower progression rates in primary progressive MS
In another study 732 patients aged 18 to 55 years with primary progressive MS were randomised to receive ocrelizumab (600mg administered as two 300mg infusions 14 days apart) or matching placebo every 24 weeks. Treatment was continued for at least 120 weeks and until a prespecified number of disability progression events had occurred.
The percentage of patients with confirmed disability progression was significantly lower in the ocrelizumab group than in the placebo group at 12 weeks (32.9% vs 39.3%; relative risk reduction 24%, p=0.03) and 24 weeks (29.6% vs 35.7%; relative risk reduction 25%, p=0.04).
In addition, worsening of performance on the timed 25-foot walk from baseline to week 120 was significantly lower in the ocrelizumab group than in the placebo group (38.9% vs 55.1%, p=0.04).
Ocrelizumab was also associated with a reduction in the total volume of hyperintense lesions on T2-weighted MRI images from baseline to week 120 compared with an increase with placebo (mean change -3.4% vs 7.4%; p < 0.001).
The most commonly reported adverse events in clinical studies were infusion-related reactions and infections. The reported incidence of neoplasms was greater in the patients treated with ocrelizumab than in those who received interferon beta-1a (0.5% vs 0.2%) or placebo (2.3% vs 0.8%).
No cases of progressive multifocal leukoencephalopathy have been reported so far with ocrelizumab, but the authors of the study in primary progressive MS state that further assessment is required to characterise the risk of uncommon adverse events.