Is Ocrelizumab The Next Game-Changer in MS Treatments?
The 31st annual ECTRIMS Congress, the largest conference focused on multiple sclerosis in the world, occured last week with over 9,000 people in attendance in Barcelona. It was the place for researchers to present their work and for pharmaceutical companies to release new information regarding approved and investigational products. Many of the conference abstracts and posters can be accessed directly through the ECTRIMS 2015 app.
After lots of hype and buildup ahead of the conference, the pharmaceutical company Roche-Genentech finally revealed a bit more than simply “positive results” from three pivotal Phase III studies of the experimental MS therapy ocrelizumab in relapsing MS and primary progressive MS (PPMS). While relapsing MS has 13 approved therapies and other treatments which are used off-label, such as rituximab, effective treatment for PPMS has continued to be elusive.
What is ocrelizumab?
Ocrelizumab is a humanized (10 percent mouse, 90 percent human-derived) monoclonal antibody designed to target a selective group of immune cells - CD20+ B-cells - which have been implicated in the damage of myelin, the fatty substance that protects nerve cells and helps to speed the transmission of nerve signals throughout the body. In clinical trials, ocrelizumab 600 mg was administered by intravenous (IV) infusion every six months, given as two 300 mg infusions spaced two weeks apart in the ORATORIO trial, while repeat rounds in the OPERA I and II trials were given as a single 600 mg dose infusion.
Ocrelizumab works in the same way as rituximab (Rituxan), a chimeric (100 percent mouse-derived) monoclonal antibody that attaches to CD20 cell surface proteins and causes certain B-cells (but not stem cells or plasma cells) to self-destruct. Rituxan is used to treat rheumatoid arthritis (RA), non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), granulomatosis with polyangitis (GPA) and microscopic polyangitis (MPA). Rituxan is also used off-label for a number of other autoimmune diseases including MS and neuromyelitis optica (NMO). Patents protecting Rituxan (jointly marketed by Genentech and Biogen) from generic competition begin to expire in 2015.
Ocrelizumab was tested in three major clinical trials: OPERA I, OPERA II, and ORATORIO.
The OPERA I and OPERA II studies were conducted by Roche-Genentech in 1,656 people with relapsing MS, including those with secondary progressive MS who still experience relapses, and showed that ocrelizumab was more effective in reducing annualized relapse rates (by 46 and 47 percent), confirmed disability progression at 12 and 24 weeks (by 43 and 37 percent), and number of T1 gadolinium-enhancing lesions (by 94 and 95 percent), and total number of new and/or enhancing hyperintense T2 lesions (by 77 and 83 percent) compared to treatment with interferon beta-1a (Rebif).
A pooled analysis showed that the rate of adverse events (83.3 percent) was similar in each treatment group. The most common adverse event associated with ocrelizumab was infusion-related reactions (34.3 percent vs. 9.7 percent for interferon beta-1a). The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to interferon beta-1a (6.9 percent vs. 8.7 percent, respectively).
The ORATORIO study which focused on patients with PPMS (n=732) showed that ocrelizumab significantly reduced risk of sustained disability progression for at least 12 weeks (by 24 percent) and 24 weeks (by 25 percent) compared to placebo, as measured by EDSS. Over 120 weeks, ocrelizumab also showed reductions in time to walk 25 feet (by 29 percent), volume of hyperintense T2 lesions (by 3.4 percent), and brain atrophy (by 17.5 percent) compared to placebo.
Overall, the proportion of patients in the ocrelizumab group with adverse events was similar to placebo (95.1 percent vs. 90.0 percent, respectively); the most common adverse event associated with ocrelizumab was infusion-related reactions (39.9 percent vs. 25.5 percent for placebo). The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to placebo (20.4 percent vs. 22.2 percent, respectively).
“This is an important moment for the MS community. For decades, trial after trial has failed to show the benefit of any medicine for people with primary progressive MS. Now, for the first time, we have a positive Phase III study result for people with this debilitating form of the disease,” said Xavier Montalban, M.D., Ph.D., Chair of the Scientific Steering Committee of the ORATORIO study and Professor of Neurology and Neuroimmunology at Vall d’Hebron University Hospital and Research Institute, Barcelona, Spain.
While some neurologists and many patients were excited to hear these trial results, others were less than enthusiastic. The patients included in the ORATORIO study were younger and less disabled than those included in previous PPMS trials. Researchers will need to dig deeper into the trial data to analyze the results from subgroups of patients to better determined which patients would be best helped by treatment with ocrelizumab.
Next steps for Roche-Genentech will be to seek marketing authorization for ocrelizumab in both relapsing MS and PPMS from the FDA and other regulatory agencies.
While it is exciting to have an effective disease-modifying therapy to fight PPMS, ocrelizumab is not the first nor only CD20+ B-cell depleting therapy on the market. Rituximab was previously in trials for RRMS and PPMS with positive and mixed results, but Genentech stopped that program to turn their attention to ocrelizumab, perhaps more carefully selecting trial participants to increase the chance of showing positive results.
As a patient who has been using Rituxan for 6 years (officially prescribed for RA, but effective against MS in my case), I do hope that more patients will be able to access any therapy that may prove effective for them.
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Roche’s ocrelizumab first investigational medicine to show positive pivotal study results in both relapsing and primary progressive forms of multiple sclerosis [press release]. October 8, 2015.