Siponimod Slows Disability in SPMS: EXPAND Published

March 29, 2018

The first trial to show a slowing in the progression of disability in secondary progressive multiple sclerosis (SPMS) has now been published online in The Lancet.

The results of the EXPAND trial with siponimod (Novartis) were first presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016, and reported by Medscape Medical News at that time.

"The siponimod EXPAND study is, to our knowledge, the first large trial of any disease-modifying therapy to show superiority over placebo in terms of disability progression in a representative population of patients with SPMS, including a large proportion of patients who had reached the non-relapsing stage of SPMS and had a high level of established disability," state the authors, led by Ludwig Kappos, MD, University of Basel, Switzerland.

But, writing in a Comment accompanying the publication, Luanne Metz, MD, and Wei-Qiao Liu, MD, University of Calgary, Alberta, Canada, express caution because of the small size of the treatment effect and the absence of an effect on some of the secondary outcomes. 

"Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial," they suggest. 

Transition to SPMS

In their publication, Kappos and colleagues note that more than half of patients with relapsing-remitting multiple sclerosis (RRMS) transition to SPMS within 15 to 20 years. Relapses are absent or infrequent in SPMS, yet disability continues to worsen gradually.

Most disease-modifying treatments for multiple sclerosis are indicated for relapsing forms of the disease, but none of these therapies have shown consistent efficacy in slowing disability progression in patients with SPMS, they report.

The EXPAND trial randomly assigned 1651 patients with SPMS and an Expanded Disability Status Scale score of 3.0 to 6.5 to oral siponimod 2 mg once daily (1105 patients) or placebo (546 patients) for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression events.

At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years, and the mean time since conversion to SPMS was 3.8 years; 64% of patients had not relapsed in the previous 2 years, and 56% needed walking assistance.

The primary endpoint was time to 3-month confirmed disability progression. This occurred in 26% of the siponimod group and 32% of those receiving placebo (hazard ratio, 0.79, 95% CI, 0.65 - 0.95; relative risk reduction, 21%; P = .013).

Serious adverse events were reported for 18% of those receiving siponimod vs 15% in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo.   

Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.

In addition, secondary outcomes of the trial suggest that reduction in brain volume was less severe for people given the drug compared with those receiving placebo (adjusted mean percentage brain volume change, −0.50% vs −0.65%; between-group difference, 0.15 percentage points [95% CI, 0.07 - 0.23 percentage points]; P = .0002).

But siponimod was not associated with any significant effect on patients' walking speed in the timed 25-foot walking test. 

Subgroup analyses favored siponimod over placebo across the entire bracket of previous disease duration, disability status, and age, although the treatment effect became less pronounced with increasing age, disability, baseline disease duration, and diminishing signs of disease activity.

The authors point out that the study's design allowed some patients to transition to active, open-label treatment as rescue medication as early as 6 months after randomization. "This protocol-defined rescue option was more frequently chosen by patients in the placebo group than in the siponimod group (17% vs 11%), and will have reduced the power of the study to show effects on secondary outcomes since patients were analysed as randomly assigned," they note.

In their commentary, Metz and Liu point out that the significant outcomes in the EXPAND trial "might all reflect an effect on the inflammatory disease activity that characterises RRMS and this trial does not, in our opinion, provide convincing evidence that we have found a treatment that exerts its clinical effect through other mechanisms."

They point out that "Findings from the reported subgroup analysis were driven largely by benefit on the more inflammatory phase of SPMS because greater benefit was noted in participants who were younger, female, and earlier in their disease, and who had more recent relapses."

"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," they add. "Trials of other novel treatments that target non-inflammatory mechanisms are still needed."

This study was funded by Novartis. The funder of the study participated in the design and conduct of the study, data analysis, data interpretation, and the writing of the report. Kappos reports that in the last 3 years, his institution (University Hospital Basel) has received funding used exclusively for research support and educational activities from Actelion, Alkermes, Allergan, Almirall, Bayer, Biogen, Celgene, CSL Behring, df-mp, the European Union, Excemed, GeNeuro, Genzyme, Merck, Mitsubishi Pharma, Novartis, Pfizer, Receptos/Celgene, Roche, Roche Research Foundations, Sanofi-Aventis, Santhera, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation, Teva, UCB Pharma, and Vianex

Lancet.  Published online March 22, 2018. Full text, Comment

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