Roche's Genentech unit said Thursday that results from the late-stage OPERA I and OPRERA II studies showed that its experimental drug ocrelizumab was superior to Merck KGaA's Rebif (interferon beta-1a) in patients with relapsing multiple sclerosis (RMS), and also demonstrated efficacy against placebo in the Phase III ORATORIO trial involving patients with primary progressive MS (PPMS). Chief medical officer Sandra Horning suggested the findings, which were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), "have the potential to transform the treatment of MS," adding that "ocrelizumab is the first investigational medicine to significantly reduce disability progression in people with RMS and people with PPMS." Roche indicated plans to seek marketing approval for ocrelizumab in both indications, with data from the three trials to be submitted to global regulatory authorities in early 2016.
The OPERA I and OPERA II studies enrolled 1656 patients with RMS who were randomly assigned treatment with an intravenous infusion of ocrelizumab every six months, or Rebif administered by subcutaneous injection three times weekly.
Results showed that ocrelizumab met the primary endpoint of significantly cutting the annualised relapse rate over a two-year period by 46 percent and 47 percent in the OPERA I and OPERA II, respectively. With regard to secondary endpoints, a pooled analysis of both studies found that ocrelizumab significantly delayed confirmed disability progression (CDP) by approximately 40 percent, sustained through 12 weeks and 24 weeks. The experimental therapy also significantly lowered the total number of T1-gadolinium-enhancing lesions by more than 90 percent, and reduced the emergence of more chronic or growing areas of MS-related brain injury by around 80 percent, compared with Rebif. According to Roche, the proportion of patients in the ocrelizumab group with adverse events was similar to Rebif overall, as was the relative number of patients experiencing serious adverse events, including serious infections.
In the randomised ORATORIO study, ocrelizumab was compared with placebo in 732 patients with PPMS who received Roche's drug via intravenous infusion every six months, with the dose split over two infusions given two weeks apart. The company noted that unlike the OPERA I and OPERA II studies, where the blinded treatment period was two years, ORATORIO's blinded treatment period continued until all patients received at least 120 weeks of either ocrelizumab or placebo and a pre-defined number of CDP events was reached overall in the study.
Roche said the primary endpoint was met, with ocrelizumab significantly diminishing the risk of clinical disability progression, sustained for at least 12 weeks by 24 percent, compared with placebo, as measured by the Expanded Disability Status Scale. Moreover, ocrelizumab significantly reduced the risk of progression of clinical disability for at least 24 weeks by 25 percent, and the time required to walk 25 feet over 120 weeks by 29 percent. Roche also reported that ocrelizumab was associated with a 3.4-percent decrease in the volume of hyperintense T2 lesions over 120 weeks, compared to placebo, which increased T2 volume by 7.4 percent. Further, ocrelizumab reduced the rate of whole brain volume loss over 120 weeks by 17.5 percent compared to placebo. The company noted that the proportion of patients with adverse events and serious adverse events, including serious infections, was similar between the two groups.
According to Stephen Hauser, chair of the scientific steering committee of the OPERA studies, the results for ocrelizumab, a humanised monoclonal antibody designed to selectively target CD20-positive B cells, "redefine our understanding of MS by highlighting the central role of the B cell." He added that "the findings may also encourage the MS community to look more closely at earlier treatment of the disease." Meanwhile, Roche's head of neuroscience clinical development Paulo Fontoura noted that "on relapses, we are essentially equal to the most efficacious medicines out there and on CDP we believe we are a little bit better."
Fontoura also pointed out that there are no approved treatments for PPMS, which affects about 10 percent of all patients. "This is a rare condition with really, really major medical need…we hope the regulators will see it that way as well," he said. Analyst Odile Rundquist of Baader-Helvea suggested Roche could generate peak annual sales of about $2 billion just for the PPMS subset. Last December, Novartis reported data from the Phase III INFORMS study indicating that its drug Gilenya (fingolimod) had failed to show a significant difference versus placebo on a combination of disability measures in patients with PPMS.
