UPDATED March 9, 2016
- Additional results were presented today showing that the experimental monoclonal antibody ocrelizumab slowed the progression of disability compared to placebo in a phase III trial.
- The study, known as ORATORIO, involved 732 people with primary progressive MS.
- Compared to placebo, ocrelizumab significantly reduced the risk of progression of clinical disability by 24%, and it also reduced the time required to walk 25 feet by 29%, decreased the volume of brain lesions by 3.4%, and reduced the rate of whole brain volume loss by 17.5% over 120 weeks.
- This is the first large-scale clinical trial to show positive results in people with primary progressive MS.
- Genentech, a member of the Roche Group, supported the trial. In a press release the company stated that it plans to seek marketing approval from the FDA in 2016.
Background: There are no approved disease-modifying therapies to treat primary progressive MS, which is characterized by steady worsening of neurologic functioning, without any distinct relapses or attacks, or periods of remission.
Ocrelizumab binds to a molecule (CD20) on the surface of immune cells called B cells, and depletes them from the circulation. B cells have several functions including making antibodies, and they may play a role in immune-system mediated damage to brain and spinal cord tissues in MS. Previous positive results from two phase III clinical trials of ocrelizumab in relapsing MS were announced earlier this year.
The Study: The trial, called ORATORIO, involved 732 people with primary progressive MS from many parts of the world. Participants were randomly assigned to receive ocrelizumab or placebo (IV infusions every 6 months) and were monitored for worsening of symptoms and other effects. The primary outcome measured was the time to sustained disability progression (an increase in the EDSS disability scale that is sustained for at least 12 weeks). Other outcomes measured included change in timed walk, volume of MS lesions seen on MRI scans, and safety and tolerability.
Results: At a scientific session at the European Committee for Treatment and Research in MS, Xavier Montalban, MD, PhD (Vall d’Hebron University Hospital and Research Institute, Barcelona, Spain) presented first detailed results from the trial. The ORATORIO study met its primary endpoint, showing treatment with ocrelizumab significantly reduced the risk of progression of clinical disability by 24% compared with placebo. Compared to placebo, ocrelizumab also reduced the time required to walk 25 feet by 29%, decreased the volume of brain lesions by 3.4%, and reduced the rate of whole brain volume loss by 17.5%, over 120 weeks.
Overall, both groups experienced similar rates of adverse events and similar rates of serious adverse events. The most common adverse event associated with ocrelizumab was infusion-related reactions (39.9%, compared to 25.5% for placebo). Serious infections occurred in 20.4% of those in the ocrelizumab group, compared to 22.2% in the placebo group.
In a press release, the company stated that it plans to seek marketing approval for the treatment of relapsing MS and primary progressive MS from the FDA and other regulatory authorities in early 2016.
Comment: “This is the first large-scale clinical trial to show positive results in people with primary progressive MS, and although the impact on progression was modest, this has the potential to be a real advance for people who have waited so long for an effective disease-modifying therapy,” says Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society. “These results offer hope that effective treatments will be found that can stop all forms of progressive MS.”
Frequently Asked Questions Related to the Ocrelizumab Clinical Trial Results in Primary Progressive MS
Q: How effective was ocrelizumab in primary progressive MS?
A: The impacts of treatment with ocrelizumab were modest, but significant. Results suggested that ocrelizumab significantly reduced the risk of progression of clinical disability by 24% compared with placebo. Compared to placebo, ocrelizumab also reduced the time required to walk 25 feet by 29%, decreased the volume of brain lesions by 3.4%, and reduced the rate of whole brain volume loss by 17.5% over 120 weeks.
Q: What were all of the side effects or other impacts of the treatment?
A: Overall, both groups experienced similar rates of adverse events and similar rates of serious adverse events. The most common adverse event associated with ocrelizumab was infusion-related reactions (39.9%, compared to 25.5% for placebo). Serious infections occurred in 20.4% of those in the ocrelizumab group, compared to 22.2% in the placebo group.
Q: When will ocrelizumab become available?
A: It is not possible to say if or when ocrelizumab may become available. The company has stated plans for applying for regulatory approval of ocrelizumab in early 2016. The timeline for successful marketing approval depends on many variables, such as whether the application is accepted by the FDA or whether the agency requests additional information before the application is deemed complete. Then the FDA needs time to evaluate the results and make a decision about whether the therapy can be marketed.
Q: Will ocrelizumab help people with secondary progressive MS?
A: We don’t know. So far, the clinical trials of ocrelizumab have involved people with relapsing forms of MS (relapsing-remitting MS and people with secondary progressive MS who were experiencing relapses) and primary progressive MS. Results have been announced as positive for the trials in these populations. There is no information yet on whether ocrelizumab may be effective in people with secondary progressive MS who are no longer experiencing relapses.
Q: Is ocrelizumab the same as rituximab, which is a therapy used to treat some cancers?
A: No. Based on published reports, ocrelizumab is manufactured differently than rituximab. These monoclonal antibodies bind to specific, but overlapping, areas of a molecule on immune B cells (called CD20 cells). There are also differences in the ways that rituximab and ocrelizumab induce the death of CD20 B cells. Whether these differences are meaningful in terms of potential effectiveness in MS, or in terms of safety, is difficult to say at this time.
Q: What other trials are going on to find treatments for progressive MS?
- Large clinical trials are going on right now in progressive MS, including tests of Tysabri, masitinib, laquinimod, and siponimod.
- The MS-SMART trial is testing three therapies that may have nerve-protecting properties in secondary progressive MS (with the MS Society of the U.K.)
- SPRINT-MS trial of Ibudilast, an oral anti-inflammatory agent, is ongoing in people with secondary progressive and primary progressive MS thanks to a unique collaboration between NIH's NeuroNEXT Network, MediciNova, and the National MS Society.
- The National MS Society and its sister societies around the globe take progressive MS very seriously and have come together toestablish the International Progressive MS Alliance, an unprecedented international initiative that is connecting resources and experts around the world to find answers and develop solutions to end progressive MS. The Alliance has made a nearly $25 million commitment to advancing research in progressive MS and is now supporting 33 research grants across 11 countries, including 11 grants newly awarded in September to plan collaborative, worldwide research networks. www.EndProgressiveMS.org
Q: Why aren’t there more treatments for progressive MS?
A: Virtually every therapy approved for relapsing MS has been tested, or is now in testing, in people with progressive forms of the disease. There is still a lack of complete understanding of the biological processes and pathways that lead to progression, a lack of models for progressive MS that can be used to screen molecules for potential therapeutic benefits for progressive MS, and a lack of good outcome measures that can provide good readouts for whether therapies in clinical trials for progressive MS are working. Research is underway to address these knowledge gaps.
Q: Based on these trial results, is there still a need to invest in additional research on progressive MS?
A: Yes. We need to continue our investment in research to find solutions for progressive MS. This trial is the first success after many disappointments. We welcome this development, but we must remain focused on finding more and better solutions for treating all forms of progressive MS. We will do this by our continued leadership in the International Progressive MS Alliance and by funding research on progressive MS through our own research programs, and by encouraging other companies to commit to developing treatments for progressive forms of MS.