First Data From Ocrelizumab Phase 3 Studies in MS

Genentech has released the first data from its three positive phase 3 studies of ocrelizumab in multiple sclerosis (MS). The press release was issued today ahead of the presentations of the OPERA I and II studies in relapsing-remitting MS and the ORATORIO study in primary progressive MS.

The full data are being presented in the next few days in Barcelona at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015 meeting.

At first glance, the data appear very impressive in all three trials with regard to efficacy and safety, and ocrelizumab becomes the first agent to have shown positive results in pivotal studies in both relapsing and primary progressive forms of MS.

Chair of the OPERA studies, Stephen Hauser, MD, University of California San Francisco School of Medicine, commented to Medscape Medical News: "These results are a big deal. The efficacy results in relapsing-remitting MS are equivalent to the best effects seen with any other MS drug so far, but unlike the other very effective drugs, ocrelizumab appears to have a much more benign safety profile."

He added: "While the therapeutic arena has seen a magnificent explosion in recent years, in general the less effective drugs are the safest and the most effective drugs are the least safe. We need therapies that are both highly effective and very safe. These results suggest that ocrelizumab could be such an agent."

He also suggested that, because of this profile, in the future ocrelizumab may be suitable for patients with very early disease. "The findings may encourage the MS community to look more closely at more aggressive earlier treatment of the disease. Currently, many doctors reserve what are considered highly effective MS medicines until a patient's disease becomes more advanced."

ORATORIO investigator Jerry Wolinsky, MD, University of Texas, told Medscape Medical News: "There have been four or five studies in primary progressive MS over last 20 years, but this is the first one to have met its primary endpoint. All the others have failed. At least now we have a crack in the wall — we can finally do something for primary progressive MS."

Genentech says plans to file approval applications for ocrelizumab — a humanized monoclonal antibody targeted against CD20-expressing B cells — in relapsing and primary progressive MS based on these data in early 2016.  

The OPERA Data

OPERA I and OPERA II are identical studies comparing ocrelizumab (600 mg given by intravenous infusion every 6 months) with interferon β-1a (44 μg given by subcutaneous injection three times per week) in a total of 1656 people with relapsing forms of MS for 2 years.

Key results are reported in the press release as follows:

• A 46% and 47% reduction in the annual relapse rate compared with interferon β-1a over the 2-year period in OPERA I and OPERA II, respectively (P < .0001 and P < .0001).

• A 43% and 37% risk reduction in confirmed disability progression sustained for 12 weeks compared with interferon β-1a in OPERA I and OPERA II, respectively (P = .0139 and P = .0169).

• A 43% and 37% risk reduction in confirmed disability progression sustained for 24 weeks compared with interferon β-1a in OPERA I and OPERA II, respectively (P = .0278 and P = .0370).

• A 94% and 95% reduction in the total number of T1 gadolinium-enhancing lesions compared with interferon β-1a in OPERA I and OPERA II, respectively (P < .0001 and P < .0001).

• A 77% and 83% reduction in the total number of new and/or enlarging hyperintense T2 lesions compared with interferon β-1a in OPERA I and OPERA II, respectively (P < .0001 and P < .0001).

Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to that in the interferon β-1a group in a pooled analysis of both studies (83.3% in each group); the most common adverse event associated with ocrelizumab was infusion-related reactions (34.3% of ocrelizumab recipients experienced at least one infusion-related reaction vs. 9.7% for interferon β-1a).

The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to that in the interferon β-1a group (6.9% vs 8.7%, respectively).

The ORATORIO Data

In ORATORIO, ocrelizumab (600 mg given by intravenous infusion every 6 months; two 300-mg infusions 2 weeks apart) was compared with placebo in 732 people with primary progressive MS. The blinded treatment continued for at least 120 weeks, and a predefined number of confirmed disability progression events was reached overall in the study.

Dr Wolinsky explained that because primary progressive MS is not characterized by relapses or lesions but a steady progression in disability, studies of this condition have to focus on disability as the primary endpoint.

The Genentech press release notes that ocrelizumab significantly reduced the risk for progression of clinical disability sustained for at least 12 weeks by 24% compared with placebo, as measured by the Expanded Disability Status Scale (P = .0321).

Additionally, ocrelizumab was superior to placebo in significantly reducing the risk for progression of clinical disability for at least 24 weeks by 25% (P = .0365) and the time required to walk 25 feet by 29% (P = .0404).

Ocrelizumab decreased the volume of hyperintense T2 lesions by 3.4% over 120 weeks compared with placebo, which increased T2 volume by 7.4% (P < .0001). Ocrelizumab reduced the rate of whole brain volume loss over 120 weeks by 17.5% compared with placebo (P = .0206). 

Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to that in the placebo group (95.1% vs 90.0%, respectively); the most common adverse event associated with ocrelizumab was infusion-related reactions (39.9% vs 25.5% for placebo).

The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to that in placebo recipients (20.4% vs 22.2%, respectively).

Results from the OPERA I and OPERA II studies will be presented at the ECTRIMS meeting on October 9 at 2:40 pm Central European time.

Results from the ORATORIO study will be presented in the late-breaking clinical trial session on October 10 at 8:50 am Central European time.

All three studies will be more fully reported by Medscape Medical News after the presentations.

Asked for comment on the findings, Jeffrey Cohen, MD, Cleveland Clinic, Ohio, called them "of great interest."

"In the case of relapsing-remitting MS, the potential availability of a highly effective therapy with good tolerability and safety will force the field to confront the issue of whether our current treatment strategy (to start with a safe but not very potent therapy and change therapy if there is an inadequate treatment response) needs to be re-examined," Dr Cohen said. 

"In the case of progressive MS, the potential availability of a therapy shown to be effective in a pivotal trial will be a major advance," he added.

The studies were funded by Genentech.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015. Abstracts 246 and 2368.

Medscape Medical News © 2015  WebMD, LLC

Send comments and news tips to news@medscape.net.

Cite this: First Data From Ocrelizumab Phase 3 Studies in MS - Medscape - Oct 08, 2015.