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Progress Made in Developing Treatments for Progressive MS in Recently Completed MS Trials (ACTRIMS 2016)
A presentation at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, held February 18-20 in New Orleans highlighted recently completed clinical trials in patients with progressive MS.
“Progressive MS has badly lagged behind relapsing forms of MS in choices of therapeutic options for disease-modifying therapies,” stated Fred Lublin, MD, from the Icahn School of Medicine at Mount Sinai, New York, USA. Recent trials have begun making headway into understanding progressive MS.
Dr. Lublin discussed the recently completed studies in progressive MS such as ORATORIO, MS-SPI, and Simvastatin. There are several challenges in study design such as what mechanism to target (inflammation or degeneration), optimal study participants (age, sex, duration of disease), activity (prior and during), the best endpoint (confirmed versus sustained and event rates), and the overall study duration. Next Dr. Lublin also discussed how to target unmet needs in progressive MS based on prior trials. He cautioned that researchers should not only looks at subgroups that did better but also “consider the subset that did worse,” when performing subset analyses of failed trials.
In the INFORMS trial in primary progressive MS patients, the average time to diagnosis of progressive disease was 2.9 years. Enrolled patients had early-stage progressive disease and received fingolimod or placebo. At the end of the 3-year study, there was no effect of treatment on confirmed disability progression (CDP) scores. Secondary outcomes suggest that there was an anti-inflammatory effect on the number of new lesions (significantly reduced with fingolimod), but not on brain volume loss.
Next Dr. Lublin described the ASCEND in SPMS trial, which looked at the efficacy of natalizumab on reducing CDP score in patients with secondary progressive MS. The primary outcome measure, the composite disability score, was not changed by treatment. However, there was a significant improvement in one component, the 9-hole peg test in the treated group. The clinical benefit of this finding is unknown.
The ORATORIO study in patients with primary progressive MS administered ocrelizumab compared to placebo and the effect on CDP. A subgroup analysis comparing patients with or without T1 gadolinium-enhancing lesions demonstrated that patients with T1 gadolinium-enhancing lesions had a 24% reduction in CDP, but this was not statistically significant due to being underpowered.
MS-SPI was a randomized trial in patients with primary progressive MS that administered biotin (MD1003) or placebo and used EDSS score as the primary endpoint. Results suggested 13% improvement in treated patients compared with placebo. The proportion of responders was higher in patients with more advanced disease. Dr. Lublin commented that this was small study and further research is needed to confirm these results as well as the mechanism of action of the agent.
Dr. Lublin stated that the breaking news is that we progress has occurred in developing agents for the treatment of progressive disease. Each clinical trial provides valuable information, and should be analyzed in detail. Dr. Lublin concluded that “we are developing a clearer understanding of how to more effectively approach progression.”