Results Published from Trial of Siponimod in Secondary Progressive MS

• Results of a 60-month, phase III clinical trial of the experimental oral therapy siponimod (BAF312, Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS have been published. The results were originally presented in September 2016 at the ECTRIMS conference.
• The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23% lower average change in brain volume and reduced lesion volume. There was no significant difference seen between groups in the timed 25-foot walk.
• The therapy was generally well tolerated and similar to adverse events reported for similar compounds. The serious adverse events reported to be more likely for those taking siponimod included nervous system disorders and infections.
• Dr. Ludwig Kappos (University of Basel in Switzerland) and a large team of investigators report detailed results of the trial in The Lancet (online March 22, 2018). A commentary about the results by Drs. Luanne Metz and Wei-Qiau Liu (University of Calgary) is also published online.

DETAILS
Background: Siponimod (BAF312) is an experimental immune system-modulating therapy that was designed to be a more selective sphingosine 1-phosphate receptor modulator than Gilenya® (fingolimod, Novartis International AG). Gilenya, was approved in 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability. Siponimod previously demonstrated safety and efficacy on MRI scans in a phase II study in people with relapsing-remitting MS (The Lancet Neurology, 2013 Aug;12(8):756-67).

Siponimod is thought to act by retaining certain white blood cells in the body’s lymph nodes, keeping them out of circulation and from entering the central nervous system. Siponimod also distributes effectively to the central nervous system (brain and spinal cord) where it may have direct anti-inflammatory or other effects.

The Study: Participants with secondary progressive MS were randomly assigned to take siponimod or placebo capsules daily for up to 60 months. The primary endpoint of the study was reducing the risk of disability progression, as measured by the EDSS scale that was sustained for at least 3 months. Secondary endpoints included reducing the risk of disability progression as measured by the EDSS at six months, the risk of worsening mobility as measured by the timed 25-foot walk test, disease activity as observed on MRI scans, relapse rate, and safety/tolerability.

Results: The results were originally presented in September 2016 at the ECTRIMS conference. The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression (confirmed at 3 months) compared to those on placebo. Secondary endpoints suggested that those on active therapy had a 23% lower average change in brain volume, and reduced MRI-detected brain lesion volume. There was no significant difference seen between groups in the timed 25-foot walk. Relapse rates were significantly lower in those taking siponimod.

Safety: The therapy was generally well tolerated and similar to adverse events reported for related compounds. Serious adverse events occurred in 16.7% of participants. The serious adverse events reported to be more likely for those taking siponimod included nervous system disorders and infections. More of those taking siponimod than the placebo experienced adverse events (89% vs 82% patients), such as a slower heart rate, high blood pressure, reduced white blood cell counts, macular oedema (swelling at the back of the eye), increased liver enzymes, and increased numbers of convulsions.

Dr. Ludwig Kappos (University of Basel in Switzerland) and a large team of investigators report detailed results of the trial in The Lancet (online March 22, 2018). A commentary about the results by Drs. Luanne Metz and Wei-Qiau Liu (University of Calgary) is also published online.

Comment: “While the magnitude of this response is somewhat modest, it represents a milestone in our unrelenting search for treatments that will benefit people living with progressive forms of MS,” said Bruce Bebo, PhD, Executive Vice President of Research at the National MS Society.

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