Recently published data from three Phase 3 trials of Ocrevus (ocrelizumab) show that the investigational drug does what no other therapy has achieved so far — working to prevent disease in both relapsing and primary progressive (PP) forms of multiple sclerosis (MS).
Publications in the New England Journal of Medicine show that all three studies reached their main goals. In the case of relapsing MS, that meant effectively lowering relapse rates, and for PPMS, slowing the progression of disability.
The two identical OPERA I and OPERA II trials (NCT01247324 and NCT01412333) in relapsing MS were covered in the article “Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis,” and the ORATORIO (NCT01194570) study in PPMS was described in the article “Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.”
In relapsing MS, the trials showed that treatment with Ocrevus, a B-cell depleting drug, was superior to treatment with Rebif (interferon beta-1a), with a 46% and 47% relative reduction in the annualized relapse rate in the two trials. In the PPMS trial, the drug was compared to placebo.
All three trials also met key secondary goals. Among the 1,656 relapsing MS patients who participated in the OPERA trials, this included 94% to 95% fewer new brain lesions over 96 weeks of treatment. One of the trials also indicated that a composite score of how well a patient walked and moved, and taking the impact on cognition into account, was better among those treated with Ocrevus.
In the two OPERA trials, 64% and 89% more of the patients receiving Ocrevus reached “No Evidence of Disease Activity (NEDA)” than those treated with Rebif. NEDA is defined as no relapses, no confirmed disability progression, and no new brain lesions detected on brain scans.
“These publications that indicate that B cells play a central role in MS are the result of a longstanding collaboration between the scientific community and industry for the benefit of people with MS,” Stephen Hauser, MD, chair of the Scientific Steering Committee of the OPERA studies, director of the Weill Institute for Neurosciences and chair of the Department of Neurology at the University of California, San Francisco, said in a press release.
“The consistency of these 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,” he added.
The PPMS trial included 732 patients. For every patient receiving placebo, two were treated with Ocrevus. Patients were treated for at least 120 weeks, with an option to continue treatment in an open-label extension study, or until they had a prespecified number of disability progression events.
Its main endpoint was a reduced risk of disease progression over 12 weeks, but the study also showed lower risk of progression at 24 weeks. The relative risk of disability progression was 25% lower with Ocrevus treatment compared to placebo — an impressive feat given that no previous drug has managed to slow disability progression in these patients.
The time required to walk 25 feet, the volume of chronic brain lesions, and total brain volume loss were also improved in Ocrevus-treated patients compared to placebo. In fact, while the brain lesion load steadily increased among placebo-treated participants, those receiving Ocrevus showed fewer brain lesions at the trial’s end than when the study started.
“Ocrevus is the first and only investigational medicine to significantly reduce the progression of physical disability in primary progressive MS in a large Phase 3 study,” said Xavier Montalban, MD, PhD, chair of the Scientific Steering Committee of the ORATORIO study and a professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital and Research Institute in Spain.
“Over the last decade, other molecules have tried and failed to demonstrate efficacy for PPMS, so the positive results for Ocrevus mark an important step in our understanding of this highly disabling form of the disease.”
But while the treatment was considered safe it is by no means free of side effects. The depletion of B-cells makes patients more vulnerable to certain infections and cancer development — a point noted in an accompanying editorial by Peter Calabresi with the Johns Hopkins University School of Medicine.
“Clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early,” he wrote.
Among PPMS patients, serious adverse events and serious infections were similar among Ocrevus-treated patients and those receiving placebo. Among Ocrevus-treated patients, serious adverse events were reported in 20.4% and serious infections in 6.2%. Similarly, in the placebo group, serious adverse events were reported in 22.2% and serious infections in 5.9% of the patients.
Tumors were, however, more common in those receiving Ocrevus. These patients developed tumors in 2.3 percent of cases. When adjusted for the total time of exposure to the treatment, the rate was twice as high compared to the 0.8 percent of placebo group patients who developed tumors.
Infection rates were also similar in relapsing MS patients treated with Rebif and Ocrevus, and tumors were again twice as common after Ocrevus treatment.
So far, infection with the JC virus, causing the dreaded disease progressive multifocal leukoencephalopathy, has not been seen in patients treated with Ocrevus or other B-cell depleting drugs.
Approval by the U.S. Food and Drug Administration (FDA) is expected in a few months’ time, but all involved researchers agree that larger and longer studies are needed to better understand the impact Ocrevus treatment has on infections and tumors.
More studies are also needed to better understand how getting rid of B-cells prevents the progression of PPMS.
Editor’s Note: An earlier version of this article incorrectly reported serious adverse events as higher than trial data found them to be. The article now correctly reports that tumors were found to be twice as high in Ocrevus-treated PPMS patients, and rates of serious adverse events and serious infections were similar between treated patients in this group and placebo patients.