March 26, 2019
The US Food and Drug Administration (FDA) has approved siponimod (Mayzent, Novartis) to treat adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive (SP) disease, the agency announced.
"Multiple sclerosis can have a profound impact on a person's life," Billy Dunn, MD, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research, said in a statement. "We are committed to continuing to work with companies that are developing additional treatment options for patients with multiple sclerosis."
Approval was based on results of the phase 3 EXPAND trial, which 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% confidence interval [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 in 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 drug must be dispensed with a patient Medication Guide that describes "important information about the drug's uses and risks," the statement notes. Treatment was shown to increase the risk for infections, so patients should have a complete blood count taken before treatment is initiated. It may cause macular edema, "so patients should contact their physician if they experience a change in vision, the FDA adds.
It may cause transient bradycardia or decline in lung function. Liver enzymes should be checked before starting the drug, "and health care professionals should closely monitor patients with severe liver impairment," as well as blood pressure during treatment, the statement notes.
Women of childbearing potential should use effective contraception during and for 10 days after stopping the drug because of potential risk for fetal harm, the agency said. "Health care professionals should monitor patients for posterior reversible encephalopathy syndrome and monitor patients that had treatment with immunosuppressive/immune-modulating therapies because there may be unintended additive immunosuppression with" siponimod.