Full results from three phase 3 trials show that the humanized monoclonal antibody ocrelizumab (Ocrevus, Roche) provides "consistent and clinically meaningful reductions in major markers of disease activity and progression" in patients with relapsing multiple sclerosis (MS) or primary progressive MS, report investigators.
Although initial results and subgroup analyses have been presented over the past year at various meetings, full data from the OPERA 1, OPERA 2, and ORATORIO randomized controlled trials were published online December 21 in the New England Journal of Medicine.
The almost identical OPERA 1 and OPERA 2 trials each included about 800 patients with relapsing MS. Results showed that participants in each trial who received 600 mg of intravenous (IV) ocrelizumab every 6 months for 96 weeks had a 46% and 47% lower annualized relapse rate, respectively, compared with those who received 44 μg of subcutaneous interferon β-1a (Rebif, EMD Serono) three times weekly (the primary endpoint).
Lead author, Stephen L. Hauser, MD, chair of the Department of Neurology at the University of California, San Francisco (UCSF), and director of the UCSF Weill Institute for Neuroscience, told Medscape Medical News that these studies "have been a very exciting 'bench to bedside to bench to bedside' exercise" over many years.
"The take-home message is that the effect size in relapsing MS was truly extraordinary," he said. "And this was a highly effective therapy against plaques."
Dr Hauser also participated in the ORATORIO trial, which included 732 patients with primary progressive MS. It showed that 33% of the treatment group had confirmed disability progression at 12 weeks vs 39% of the matching placebo group; the percentages were 30% vs 36%, respectively, at 24 weeks.
The results from all three trials have been submitted to the US Food and Drug Administration (FDA).
Although the Prescription Drug User Fee Act (PDUFA) date to review the Biologics License Application for the treatment was originally scheduled for December 28, Roche recently reported that the FDA has extended its review until March 28, 2017.
Peter A. Calabresi, MD, Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland, writes in an accompanying editorial that B-cell depletion, as shown in these trials, signifies a "frontier in monoclonal antibodies" for MS.
He adds that the OPERA studies showed significant benefits but the ORATORIO results were remarkable because the study involved "a previously untreatable subtype" of the disorder.
"This is the first drug to show a significant effect in slowing disability progression in a phase 3 trial in primary progressive multiple sclerosis, and therefore the trial represents a landmark study in the field," writes Dr Calabresi.
As reported by Medscape Medical News, preliminary results from the trials were presented at the 2015 Congress of the European Committee for Treatment and Research in MS (ECTRIMS).
This was followed by subgroup analysis from ORATORIO presented at the Americas Committee for Treatment and Research in MS (ACTRIMS) Forum 2016 and a presentation of OPERA 1 and OPERA 2 analyses on NEDA (no evidence of disease activity) at the American Academy of Neurology (AAN) 2016 Annual Meeting.
Dr Hauser noted that the new journal articles contain fuller data and represent first publication of the results.
Hitting the Right Notes: OPERA 1 and 2
OPERA 1 included 821 patients with relapsing MS who were enrolled at 141 trial sites in 32 countries. All were randomly assigned to receive IV ocrelizumab (n = 410) or interferon β-1a (control group, n = 411).
OPERA 2 was conducted in 24 countries, with 417 and 418 patients assigned to each treatment group, respectively. The mean age for all participants was 37 years.
In each trial, the annualized relapse rate at 96 weeks was 0.16 for patients receiving ocrelizumab and 0.29 for those receiving interferon β-1a (both trial comparisons, P < .001).
In pooled analyses, just 9.1% of the treatment group vs 13.6% of the control group had confirmed disability progression at 12 weeks (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45 - 0.81; P < .001). At 24 weeks, the rates were 6.9% vs 10.5%, respectively (HR, 0.60; 95% CI, 0.43 - 0.84; P = .003).
Disability improvement at 12 weeks was achieved by 20.7% of the ocrelizumab group and by 15.6% of the control group (P = .02).
In addition, the number of gadolinium-enhancing lesions per T1-weighted MRI exam was significantly lower for patients receiving ocrelizumab in OPERA 1 (0.02 vs 0.29; P < .001) and in OPERA 2 (0.02 vs 0.42; P < .001).
"Ocrelizumab, given every 6 months, was 95% more effective than high-dose β-interferon in preventing new areas of inflammation in the white matter and new plaque formation," added Dr Hauser.
A case of any adverse event (AE) was reported by a similar 80.1% and 80.9% of the treatment and control groups, respectively, in OPERA 1 and by 86.3% and 85.6% in OPERA 2. Serious AEs were reported by more members of the control group than the treatment group in each trial (7.8% vs 6.9% and 9.6% vs 7%, respectively).
However, infusion-related reactions were more common in the total group of ocrelizumab-receiving patients (34.3% vs 9.7%).
More troubling, four neoplasms occurred in the overall treatment group (0.5%; two cases of invasive breast carcinoma and one case each of renal cell carcinoma and of malignant melanoma) vs two occurrences in the control group (0.2%; one case each of mantle cell lymphoma and of squamous cell carcinoma).
Two additional cases of breast cancer, two cases of basal cell skin carcinoma, and one case of malignant melanoma were also detected during the open-label extension phase.
Still, among most of the participants, "there was a high degree of tolerability and apparent safety over the 2-year period of the trial," said Dr Hauser. "But long-term follow-up with larger numbers of patients will be necessary to assess the risks for the very rare side effects and the long-term safety of this treatment."
In ORATORIO, patients with primary progressive MS (mean age, 45 years) were randomly assigned 2:1 to receive ocrelizumab (n = 488) every 24 weeks for at least 120 weeks or matching placebo (control group, n = 244).
The HR for disability progression at 12 weeks was 0.76 for the ocrelizumab vs placebo groups (95% CI, 0.59 - 0.98; P = .03). At 24 weeks, the HR was 0.75 (95% CI, 0.58 - 0.98; P = .04).
Significant outcomes at 120 weeks for the ocrelizumab vs placebo groups included the following:
A 3.4% decrease in total volume of brain lesions vs a 7.4% increase, respectively (P < .001);
Less brain volume loss (0.9% vs 1.9%; P = .02); and
Less worsening on a timed 25-foot walk test (38.9% vs 55.1%; P = .04).
Scores on the 36-Item Short-Form Health Survey's Physical Component Summary did not differ significantly between the groups. There were also no significant differences in AEs, serious AEs, and serious infection rates.
However, 39.9% of those receiving ocrelizumab reported at least one infusion-related reaction vs 25.5% of the participants receiving placebo. Cases of upper respiratory tract infection were also greater in the ocrelizumab group (10.9% vs 5.9%), as were cases of oral herpes infection (2.3% vs 0.4%).
Neoplasms were also seen in this trial, occurring in 2.3% vs 0.8% of the treated and placebo groups, respectively.
"When we searched, to better understand this possible signal, it appeared that the prevalence of malignancies seen in ocrelizumab-treated patients was in accord with the expected numbers for this population with multiple sclerosis. So this was consistent with epidemiologic expectations," said Dr Hauser.
"Nevertheless, this needs to be followed up very closely."
He noted in a release that, overall, "the consistency of the pioneering data, the effect seen in these clinical studies, and the favorable safety profile may support treating MS earlier with a high-efficacy disease-modifying medicine."
"This is a very exciting time for people with MS. And it's an optimistic moment for those with all forms of the disease," he told Medscape Medical News.
In his editorial, Dr Calabresi notes cautious optimism about the results.
"Although ocrelizumab offers promise for patients with primary progressive [MS], who are desperately in need of a therapy, side effects must also be considered," he writes.
"Agents that target the immune system often result in some degree of immune suppression, potentially rendering the host susceptible to infections and impaired immune surveillance of new cancer cells, which could increase the risk of neoplasms."
Dr Calabresi added to Medscape Medical News that more and longer-term studies are needed to look into these events, and he stressed the need for early monitoring for any side effect.
"Right now, in these trials, the drug looks generally favorable. But there are things we don't know coming out of these trials that may become more evident when we have 4 or 5 years of experience and get it into the market," he said.
A marketing application for the drug is under review by the European Medicines Agency. The FDA's PDUFA review date extension for the treatment was based on the submission of additional data on commercial manufacturing processing, Roche noted in a statement — and was not due to safety or efficacy concerns.
Still, Dr Hauser said he was "quite disappointed" that the date has been pushed back. "I'm hopeful that the FDA will be able to act on this drug, which did receive breakthrough designation for primary progressive MS, expeditiously," he said.
When Dr Calabresi, who was not involved with any of this research, was asked whether he believes the FDA will approve ocrelizumab for both types of MS, he said, "I really do."
He followed up by noting that although the ORATORIO trial showed a modest slowing of disease progression in the patients with primary progressive MS, "it didn't make anyone better or arrest progression."
Nevertheless, "it was a significant difference between the treated and placebo groups. And that was the first time there's ever been a drug that's achieved that outcome in these patients," he said.
"This has been almost an orphan disease in the sense that it's so rare and has been hard to treat. If the FDA goes ahead with approving this drug, it would be really nice to have an option for that form of the disease," said Dr Calabresi.
"But again, I think we need to get more experience about the risk-to-benefit analysis."
The studies were funded by F. Hoffman-La Roche. Dr Hauser reports having received personal fees as a scientific advisory board member for Bionure, Symbiotix, Annexon, Molecular Stethoscope, and Neurona,and he has received nonfinancial support from F. Hoffman-La Roche. Disclosures for the other study authors are listed in the original articles. Dr Calabresi reports having received grant support from MedImmune, Teva Pharmaceuticals, and Novartis; personal fees from Vertex Pharmaceuticals; and grant support and personal fees from Biogen Idec.
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Cite this: Ocrelizumab Reduces MS Progression: OPERA, ORATORIO Trials Published - Medscape - Dec 22, 2016.