Emma Hitt, PhD

May 31, 2011

May 31, 2011 (Lisbon, Portugal) — Ocrelizumab reduces relapse rates in multiple sclerosis (MS) with a manageable adverse event profile until at least 72 weeks of treatment, according to new phase 2 trial findings.

Ludwig Kappos, MD, chair of neurology at the University Hospital Basel in Switzerland, presented the findings here at the 21st Meeting of the European Neurological Society.

"The phase 2 data with ocrelizumab are quite promising," Dr. Kappos told Medscape Medical News after the presentation, "and this agent will be at the higher part of the scale of efficacy."

However, he pointed out that there are no long-term safety data yet available, although "we have data from rituximab, which unlike ocrelizumab, is not humanized, so from this point of view, the ocrelizumab data are quite reassuring."

Rheumatoid Arthritis Trial Stopped

B-lymphocytes play an important role in MS pathogenesis; in addition, other CD20-targeted therapies have had a positive effect in relapsing-remitting MS (RRMS), the study authors note.

Ocrelizumab is a humanized anti-CD20 monoclonal antibody. In March 2010, ocrelizumab development for the treatment of rheumatoid arthritis (RA) was stopped after a recommendation from the Data and Safety Monitoring Board that the safety risk outweighed the benefits observed in this specific patient population. Issues included serious infections, some fatal, and opportunistic infections.

In the current study, ocrelizumab was evaluated in 220 patients with RRMS treated for 72 weeks randomized 1:1:1:1 to receive, at days 1 and 15, placebo, intravenous ocrelizumab at a total dose of 600 mg, intravenous ocrelizumab at a total dose of 2000 mg, or weekly interferon beta-1a at a dose of 30 µg in cycle 1 for 24 weeks.

For cycles 2 and 3 until week 72, all groups received ocrelizumab at a dose of 600 mg, expect for the 2000-mg ocrelizumab group, which received a subsequent 1000-mg dose.

After 72 weeks, 86.8% of patients were still enrolled in the trial. Ocrelizumab effectiveness was maintained through week 72 as demonstrated by annual relapse rates. The proportion of relapse-free patients at week 72 was 84% for the 600-mg group and 82% for the 2000/1000-mg ocrelizumab groups.

One patient in the high-dose group died at week 12 of treatment in an earlier phase of this trial. Data to 24 weeks were presented by Dr. Kappos at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Gothenburg, Sweden, in October 2010 and reported by Medscape Medical News at that time.

At week 72, no further deaths have occurred. Serious treatment-related adverse events occurred in approximately 2% of patients across treatment groups. Rates of infection were comparable and no opportunistic infections reported. Infusion-related events were highest during the first cycle of treatments but decreased to a lower level by the third cycle. No withdrawals due to adverse events were reported.

"No participants dropped out due to adverse events from week 48 to 72 of the study," Dr. Kappos said. "In addition, ocrelizumab was generally well tolerated through week 72, and further investigation in phase 3 studies is warranted."

Longer-Term Data 'Critically Required'

"According to these phase 2 data, ocrelizumab looks promising due to its high therapeutic efficacy," said independent commentator Mathias Buttmann, MD, with the Department of Neurology at the University of Würzburg in Germany. "However, longer-term safety data in a larger cohort of MS patients are critically required," he told Medscape Medical News.

"I would be cautious to draw conclusions from rituximab on ocrelizumab," he added. "Although both are anti-CD20 antibodies, their epitopes and their modes of action differ in part. While rituximab has shown a favorable safety profile in a large cohort of patients with RA for whom it was approved by the [US Food and Drug Administration] in 2006, the extensive phase 3 ocrelizumab program in RA was discontinued in 2010 due to serious or opportunistic infections, some of them ending fatal.

"I really hope that ocrelizumab will look better in MS patients in phase 3, where it is tested as a monotherapy and not with methotrexate comedication as in RA, and that a fatal case of disseminated intravascular coagulopathy in the first 24 weeks of the phase 2 MS trial remains a single case," he said. "In my view, ocrelizumab really holds the potential to enrich the therapeutic armamentarium for MS," he added.

The study was supported by F. Hoffmann-La Roche Ltd and Biogen Idec. Dr. Kappos reports that he receives financial support from multiple commercial interests, including Genentech and Biogen Idec, the manufacturers of ocrelizumab. Independent commentator Dr. Buttmann has disclosed no relevant financial relationships.

21st Meeting of the European Neurological Society (ENS): Abstract 189. Presented May 29, 2011.

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