Ocrelizumab Demonstrates Efficacy in Relapsing MS
A phase II trial demonstrated impressive results in reducing magnetic resonance imaging lesions and clinical relapses in patients with multiple sclerosis.
Ocrelizumab is an investigational humanized antibody that selectively targets CD20 B cells. For this phase II, industry-sponsored trial, researchers randomized 220 patients with relapsing-remitting multiple sclerosis (MS) to receive placebo, 600 mg of ocrelizumab, 2000 mg of ocrelizumab, or weekly interferon beta-1a for 24 weeks. After the week-24 visit, all participants received open-label ocrelizumab (at different doses) and were followed through 48 weeks. The primary endpoint was the reduction of gadolinium-enhancing (GdE) lesions on magnetic resonance imaging (MRI). Secondary endpoints included relapse rates and freedom from relapse. Ocrelizumab was administered as two infusions, spaced 2 weeks apart, repeated every 6 months.
Of those randomized, 93% remained in the trial at 24 weeks; 89% were followed up at 48 weeks. Compared with the placebo group, the 600-mg ocrelizumab group had 89% fewer GdE lesions, and the 2000-mg group had 96% fewer lesions. Compared with placebo rates, annualized relapse rates were 80% lower over the 24 weeks with 600 mg of ocrelizumab and 73% lower with 2000 mg of ocrelizumab. Both ocrelizumab groups had significant improvements over interferon for these endpoints; interferon was not significantly better than placebo, as expected in this short-duration trial and relatively small comparator arm.
Adverse events included one death in the ocrelizumab group due to status epilepticus, disseminated intravascular coagulopathy, multiorgan failure, and brain herniation. Blood cultures for this fatality were lost, and so sepsis could not be confirmed. Overall, adverse events led to withdrawal in 2% to 4% of the ocrelizumab groups; the most common adverse events were no different from those with placebo. Mild-to-moderate reactions to the first infusion occurred in 35% to 44% of ocrelizumab recipients.
Comment: This phase II study demonstrates rapid efficacy for ocrelizumab, which represents the next-generation B-cell depleting therapy after rituximab. Although opportunistic infections were not observed in this preliminary MS trial, in trials of ocrelizumab for rheumatoid arthritis (RA), serious opportunistic infections occurred in nine patients, and two other participants died of pneumonia. Although the dosing was lower in the RA trials, participants had prior and concomitant immunosuppression with other agents.
Ongoing phase III studies aim to randomize 800 patients with relapsing-remitting MS to ocrelizumab or interferon beta-1a three times weekly and to randomize 630 primary-progressive MS patients to ocrelizumab or placebo. The trials are expected to be completed by 2015 and 2017, respectively. Ocrelizumab may offer an additional treatment option for MS, with a different mechanism of action compared with the other available and forthcoming agents.
Robert T. Naismith, MD
Dr. Naismith is a consultant and is on the speaker’s bureau for one of the manufacturers that funded this study.
Published in Journal Watch Neurology November 15, 2011
Kappos L et al. Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet2011 Nov 1; [e-pub ahead of print]. [Medline ® Abstract] Chataway J and Miller DH. Multiple sclerosis Quenching the flames of inflammation. Lancet 2011 Nov 1