The experimental monoclonal antibody ocrelizumab (Genentech), given intravenously, significantly reduced disease activity as measured by MRI (magnetic resonance imaging) scans in a phase II study of 218 people with relapsing-remitting MS. One person on the higher dose died due to brain edema; the relation of this death to the study medication is unclear. Since this is a phase II study, additional research will be needed to further determine this therapy’s safety and benefits. The results were originally announced in a press release in 2009 and have now been published in the Lancet (published online November 1).
Background: Ocrelizumab binds to a molecule (CD20) on the surface of B cells and depletes them from the circulation. B cells are immune cells that make antibodies and may play a role in the immune attack on brain and spinal cord tissues in multiple sclerosis. The drug is a humanized version of rituximab, a mouse antibody to CD20 that has previously shown benefit in people with relapsing-remitting MS.
The Study: Participants were randomly assigned to receive intravenous low-dose ocrelizumab (600 mg), high-dose ocrelizumab (2000 mg), or inactive placebo, or intramuscular injections of Avonex® (interferon beta-1a, Biogen Idec). The main objective of this study was to determine whether ocrelizumab was effective in reducing MS disease activity (number of gadolinium-enhancing lesions) compared with placebo, as observed on MRI at 12, 16, 20, and 24 weeks. Other secondary objectives included assessing relapses. After 24 weeks, participants were switched to ocrelizumab and followed out to 48 weeks. (An uncontrolled extension of this study evaluated safety in participants for up to 96 weeks; results were not included in this published paper.)
Results: The results show that disease activity on MRI scans was 89% lower than placebo in the low-dose ocrelizumab group, and 96% lower in the high-dose group. Among secondary endpoints, the average number of relapses per year was reduced by 80% over placebo in the low-dose group and by 73% in the high-dose group. Comparisons to Avonex (which were done as tertiary, or third endpoints) showed benefit for the ocrelizumab groups.
One person in the high-dose group died due to brain edema (swelling), after the occurrence of systemic inflammatory response syndrome with multi-organ failure. The association of this event to the study medication is unclear. At first infusion, more people in the ocrelizumab groups (35%, 44%) had infusion-related adverse events than did those in the placebo group (9%). In phase-III rheumatoid arthritis trials of ocrelizumab, high rates of opportunistic infections were seen with ocrelizumab treatment, but none were noted in this study.
At a recent medical meeting (ECTRIMS), results of the 96-week open-label extension study from this trial were announced. The benefits and safety of ocrelizumab were maintained out to 96 weeks, according to a Genentech press release.
Comment: Since this is a phase II study, additional research will be needed to further determine this drug’s safety and benefits. Two Phase III studies have begun in people with relapsing-remitting MS, and one involving people with primary-progressive MS.