Investigational S1P modulator reduces rate of disease progression in MS

At 3 months, siponimod—an investigational selective receptor modulator—reduced disability progression in patients with secondary progressive multiple sclerosis (SPMS) and had a safety profile similar to that of other S1P antagonists, according to findings from a randomized double-blind multinational phase 3 study known as EXTEND.  

EXTEND researchers, led by led by Ludwig Kappos, MD, professor and chair, Neurology, University of Basel, Switzerland, found that the rate of confirmed disease progression (CDP) was reduced by 21% at 3 months in patients assigned to siponimod compared with placebo.

“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,” they wrote in The Lancet.

Siponimod is an oral once-daily selective modulator of S1P that readily crosses the blood-brain barrier. Preclinical studies suggest that it might prevent synaptic neurodegeneration and promote remyelination in the central nervous system.

Dr. Kappos and fellow researchers compared the efficacy and safety of siponimod vs placebo in 1,651 patients with SPMS (mean age: 48 years; disease duration: 17 years) from 31 countries. Patients had received a diagnosis of SPMS and demonstrated progression of disability in the 2 years prior to study. Eligible patients had an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, with a median score of 6.0, which corresponds to the use of unilateral assistance to walk (eg, a cane or a crutch).

They were randomized 2:1 to receive either 2 mg of siponimod once daily or placebo. Eighty percent of the siponimod arm and 78% of the placebo arm completed the study. Patients continued on siponimod treatment in an open-label, long-term extension of the study.

As mentioned, the risk of 3-month CDP was reduced from 32% in the placebo group to 26% in the siponimod arm, for a significant 21% relative reduction vs placebo (P=0.013); the efficacy was consistent across many predefined sub groups.

Other outcomes with siponimod relative to placebo were as follows:

• A reduction in the risk of 6-month CDP by 26% (P=0.0058);
• A slowing in the rate of brain volume loss by 23% (-0.50% vs -0.65%; mean across 12 and 24 months; P=0.0002);
• Limited the increase of T2 lesion volume from baseline by approximately 80%; (183.9 vs 879.2 mm³, adjusted mean over 12 and 24 months; P < 0.0001);
• A reduction in the annualized relapse rate by 55% (P < 0.0001).

More patients in the siponimod arm compared with the placebo arm were free from gadolinium-enhancing lesions (89% vs 67%) and from new or enlarging T2 lesions (57% vs 37%). However, there was no significant effect of siponimod on the time to 3-month confirmed worsening of the times 25-foot walk (T25FW) (P=0.44).

The safety profile of siponimod was consistent with the known effects of S1P receptor modulation. Hypertension was reported in 10% and 8% of the siponimod and placebo groups, respectively, and herpes zoster reactivation occurred in 2% and 1%, respectively.

According to the study group “the delay in disability on EDSS (primary endpoint) and the benefits observed for several other clinical and magnetic resonance imaging-related secondary outcomes are clinically relevant.”

Additional data from EXPAND were presented at the 70th annual meeting of the American Academy of Neurology held in Los Angeles on April 21-27, 2018. Specifically, from baseline to month 24, treatment with siponimod showed a significant benefit on cognitive processing speed as measured by the Symbol Digit Modalities Test (SDMT) compared with placebo for all patients (P=0.0004).

In patients who had relapses within 2 years before starting the trial, there was a significant benefit to siponimod on the SDMT (P=0.0151) and on the Paced Auditory Serial Addition Test (PASAT) (P=0.0275). In those without relapses within the previous 2 years, the improvement on the SDMT in the siponimod arm was significant (P=0.0099) but there was no significant difference between arms on the PASAT. Treatment with siponimod did not result in significant differences in memory.

The benefits of siponimod appear to result from an anti-inflammatory effect and not from any effects on the progressive phase of MS, wrote Luanne M. Metz, MD, FRCPC, and Wei-Qiao Lu, University of Calgary, Canada, in an editorial to accompany the study. As evidence, they point to the lack of a significant effect on the T25FW, a key secondary outcome of EXPAND. The treatment effect on the primary outcome was small, with an absolute benefit of only 6%, they added.

“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,” they concluded.