VANCOUVER—Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently reduces relapses, disability progression, and new or enlarging lesions, compared with interferon beta-1a, in patients with relapsing-remitting multiple sclerosis (MS), according to two phase III trials reported at the 68th Annual Meeting of the American Academy of Neurology.

OPERA I and OPERA II

The identical trials, dubbed OPERA I and OPERA II, each included about 800 patients. Subjects were randomized one-to-one to 600 mg of IV ocrelizumab every 24 weeks or to 44 μg of subcutaneous interferon beta-1a three times weekly for 96 weeks. Patients had early disease, and a significant proportion was naive to MS treatments.

At 96 weeks, 47.9% and 47.5% of patients receiving ocrelizumab, respectively, had no evidence of disease activity (NEDA) versus 29.2% and 25.1% of patients receiving interferon. NEDA is a composite score defined as the absence of relapses, confirmed disability progression, and new or enlarging T2 or gadolinium-enhancing T1 lesions.

In both studies, relapses occurred in about 20% of patients receiving ocrelizumab versus about 35% of patients receiving interferon. About 10% of participants receiving ocrelizumab and about 15% of patients receiving interferon had clinical disease progression. Similarly, about 10% of patients receiving ocrelizumab developed new gadolinium-enhancing lesions, compared with about 35% of those receiving interferon. New or enlarging T2 lesions were found in about 40% of the ocrelizumab groups and in more than 60% of the interferon groups.

After week 24, 96% of patients receiving ocrelizumab, compared with between 60% and 70% of patients receiving interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new or enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

Ocrelizumab Appears Safe

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment, said investigator Anthony Traboulsee, MD, a neurologist at the University of British Columbia in Vancouver, Canada. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis.” Many patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis because of serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the FDA in the first half of 2016. The FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about four years. Patients had had about 1.5 relapses in the first and second years before entering the studies.

An Alternative to Natalizumab?

The positive results and the increasing buzz about ocrelizumab in the MS community raise the question of how the treatment will fit into the MS armamentarium if it is approved. A review in Therapeutic Advances in Neurological Disorders addressed the issue in January, before the OPERA results were made public.

It’s unclear whether ocrelizumab will become the preferred option when patients have progression on first-line agents such as interferon and glatiramer acetate. Phase II data suggest that ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude, compared with that of fingolimod and natalizumab,” and that the treatment will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favorable risk–benefit profile, compared with natalizumab in [John Cunningham (JC)] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody–positive, whereas natalizumab, or, alternatively, oral fingolimod, would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Per Soelberg Sorensen, MD, and Morten Blinkenberg, MD, PhD, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore postmarketing safety programs will be needed,” they said. The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, eg, every six months [as in OPERA], or if retreatment should be guided by the recovery of CD19-positive B cells.”

In any case, infusion reactions with ocrelizumab should be less common than with rituximab, another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody, they concluded.

—M. Alexander Otto

Ocrelizumab May Be More Effective for Relapsing-Remitting MS Than Interferon