Drug delays disability in secondary progressive MS

A new drug, called siponimod, is said to slow the progression of disability in secondary progressive multiple sclerosis (MS), according to a double-blind, randomised, phase III trial published in The Lancet.

MS is a condition that affects the central nervous system and involves the nerves losing their protective coating of myelin. Most cases of MS present as relapsing-remitting MS, and more than half of these patients later develop secondary progressive MS within 15–20 years.

The Novartis EXPAND study of BAF312 (siponimod) is a placebo-controlled Phase III trial, comparing the efficacy and safety of siponimod versus placebo in people with secondary progressive multiple sclerosis (SPMS). The study was funded by Novartis and conducted by researchers from University of Basel, University of Pennsylvania, McGill University, University of California San Francisco, Cleveland Clinic, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, St Josef-Hospital/Ruhr-University Bochum, University of Lille, NeuroRx Research and Novartis Pharma AG, Lycalis.

The trial involved 1645 patients aged 18–60 who had moderate or advanced disability from 292 centres in 31 countries. They were either given 2 mg of siponimod once a day (1099 patients) or a placebo (546 patients) for up to three years or until their disability had progressed after six months. Patients whose disease progressed were offered open-label siponimod.

Progression to higher levels of disability was more common in people given a placebo, compared to those given siponimod. After three months, a quarter of patients saw their disability progress on the drug compared to a third of those given a placebo. Further research into the long-term use of the drug is ongoing. The authors also note that the drug had some side effects.

The drug may directly prevent degeneration of the nerve fibres, suppress the autoimmune attack causing the damage and promote recoating of the nerves in the central nervous system. The patients had assessments of their disability levels every three months in the trial, as well as MRI scans at the start of the trial, and after 12, 24 and 36 months.

At the start of the trial, on average, patients had had MS for 17 years and had had secondary progressive MS for 4 years. More than half of the group needed walking assistance (55%, 918/1651 people). 1327 people completed the study (including 903 given siponimod and 424 people given placebo). On average participants of the study took the study drug for 18 months. Of the 424 people given placebo, 11% switched to open-label siponimod after their disability progressed as confirmed after six months.

The risk of a patient’s disability getting worse was 21% lower for people given siponimod, compared to people given placebo — around a quarter of people given the drug saw their level of disability increase after three months (26%, 288/1096 people), compared with a third of people on placebo (32%, 173/545 people).

In addition, secondary outcomes of the trial suggest that, from the start of the trial to 24 months, the reduction in brain volume was less severe for people given the drug, compared to placebo. Loss of brain volume is a marker for tissue damage in MS.

The drug had no effect on maintaining patients’ walking speed, and both the group taking the drug and the placebo group became slower after three months when doing a timed walk of 25 feet. However, the authors note that most of these patients already relied on walking aids, and this might have affected the test.

More patients given the drug than the placebo experienced adverse events (89% vs 82% patients), such as a slower heart rate (4% vs 3%), high blood pressure (12% vs 9%), reduced white blood cell count (1% vs 0%), macular oedema (2% vs less than 1%), increased liver enzymes (6% vs 4%) and increased numbers of convulsions (2% vs less than 1%).

The authors say that this safety profile is similar to other drugs in the same class and conclude that siponimod could be a useful treatment for secondary progressive MS.

“So far, no drug has consistently reduced disability progression in people with secondary progressive multiple sclerosis. These patients often have a high level of disability, and preventing further progression is important for their quality of life,” said lead author Professor Ludwig Kappos, University of Basel, Switzerland.

“Although the effects of the drug on disability progression after three and six months are impressive, our study does not yet look at the long-term effects of siponimod, which we are investigating in the long-term follow-up of the study patients.”

The authors acknowledged some limitations, including that results for people who were originally given a placebo and chose to have open-label siponimod after their disability progressed were still included in the study. This may have reduced the effect size of siponimod for some secondary outcomes of the study.

Although the authors attempted to analyse it, the treatments people were given before the study may have affected their response to siponimod.

Dr Luanne Metz, University of Calgary, Canada, expressed caution because the drug did not have an effect on all of the secondary outcomes. She said, “Relapsing-remitting multiple sclerosis (RRMS) has been treatable for over 20 years and increasingly effective therapies continue to be developed. Unfortunately, therapies that convincingly affect the progressive phase of MS have yet to be identified… Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small. In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for SPMS. Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target non-inflammatory mechanisms are still needed.”

Novartis plans to file for regulatory approval of siponimod for SPMS with the US Food and Drug Administration (FDA) in early 2018. Novartis has initiated a scientific advice consultation with the European Medicines Agency (EMA) and, pending its outcome, plans to file in Q3 2018. The EXPAND results have previously been presented at scientific congresses.

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