Ocrelizumab: promising results in relapsing and progressive MS
European Committee for Treatment and Research in MS (ECTRIMS) – 31st Congress – Barcelona, Spain, October 7-10, 2015 – A new medication with a novel way of treating multiple sclerosis was the top story at this year’s ECTRIMS congress, the largest meeting of MS researchers and physicians held annually.
Ocrelizumab is a biological therapy that is given by infusion (like Tysabri and Lemtrada), and is administered every six months. Most MS medications primarily target T cells, part of the immune system that recognizes Stranger (e.g. bacteria) or Danger (e.g. abnormal cells) signals and works to control the problem. In contrast, ocrelizumab targets B cells, a different part of the immune response responsible for producing antibodies and activating T cells. MS has traditionally been seen as a T cell disease. That view began to change after the early success of Rituxan (rituximab), a B cell-directed therapy that was shown to reduce inflammatory lesions in the brain (Hauser and colleagues. N Engl J Med 2008;358:676-688).
Ocrelizumab is a retooled version of Rituxan and was shown to reduce inflammatory lesions by about 90% in a phase II trial (Kappos and colleagues. Lancet 2011;378:1779-1787). So more rigorous phase III trials, called OPERA I and OPERA II, were launched and results for those studies are now available.
The OPERA studies were run at the same time and compared ocrelizumab with Rebif in 1,656 people with relapsing MS over a two-year period (Hauser and colleagues. ECTRIMS 2015; abstract 246). At the end of the study, the annualized relapse rate was about 45% lower among people taking ocrelizumab compared to those on Rebif (0.156 relapses per year for the group compared to 0.29/year). Progression of disability was 37-43% lower with ocrelizumab versus Rebif. The greatest effects were seen on magnetic resonance imaging (MRI). The number of new lesions was 95% lower with ocrelizumab compared to Rebif – which was even better than what was seen in the phase II trial against a placebo. Overall, up to 48% of people taking ocrelizumab had no evidence of disease activity, which means they had no relapses, no short-term worsening of disability, and no new inflammation visible on their MRI.
The most common side effect was reactions at the time of infusion, which affected about 1 in 3 people. The risk of infections with ocrelizumab was lower than what was seen with Rebif. A potential concern with B cell therapies is progressive multifocal leukoencephalopathy (PML), a potentially fatal infection that has dampened enthusiasm for Tysabri. PML has occurred with Rituxan when it is used at higher doses to treat cancer. However, no PML cases have been seen with ocrelizumab in phase II or III studies of MS. There was one death in phase II testing due to a rare condition called systemic inflammatory reaction syndrome (SIRS), but additional cases haven’t been seen.
The OPERA I/IOPERA II results indicate that ocrelizumab will be a highly effective treatment for relapsing MS when it becomes available in a year or so. But even more hotly anticipated was how well ocrelizumab would do in the arena where nothing has been shown to work – primary-progressive MS (PPMS).
In ORATORIO, a select group of 725 people with PPMS received ocrelizumab or placebo for at least 120 weeks (Montalban and colleagues. ECTRIMS 2015; abstract LB228). Overall, ocrelizumab significantly reduced the risk of worsening disability by 24%. There was also less impairment in walking ability, and a modest reduction in inflammatory lesions seen on MRI.
ORATORIO is the first study to show that an MS medication can have a significant impact on disability in people with PPMS. However, it’s important to note that the effect was somewhat modest, and the people enrolled in the trial didn’t really represent the population of people living with PPMS. People had to be younger than age 55 years, had a broad range of disability at the start (from mild to severe), and had been living with PPMS for 10 years or less. One issue is how much inflammatory activity there was at the start – MS medications primarily reduce inflammation and have less effect on the neurodegeneration that causes disability in PPMS. This point was illustrated in the PPMS trial of Rituxan (Hawker and colleagues. Ann Neurol 2009;66:460-471). In that study, Rituxan did not significantly impact disability. But it did have a significant effect in people with new inflammatory lesions, and in the subgroup of younger people (aged 50 or less). So ORATORIO may simply have included the types of people known from the Rituxan trial to be likely responders to a B cell drug.
As a result, some of the enthusiasm for ocrelizumab in PPMS has been rather muted. The ORATORIO trial provides some hope that treatment can slow the rapidly progressing disability that occurs in PPMS. More will be known about how effective ocrelizumab will be in PPMS once the full results have been published.
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