Siponimod reduces progression with or without relapses
http://web.b.ebscohost.com/abstract?sit ... d144209775
Background: Siponimod (Mayzent) is a selective sphingosine 1-phosphate receptor (S1P1, S1P5) modulator, approved in the United States for the treatment of relapsing forms of multiple sclerosis (MS), including active secondary progressive MS (SPMS). In the phase 3, randomized, double-blind, placebo-controlled EXPAND trial, siponimod reduced the risk of 3- and 6-month confirmed disability proression (CDP) by 21% and 26%, respectively, compared with placebo, in patients with SPMS. Subgroup analyses of EXPAND data suggest that a proportion of the effect of siponimod on CDP was attributable to effects on relapse-independent disability progression.
Objectives: Assess the impact of siponimod on CDP in patients with/without relapses to uncouple treatment effects on CDP from those on relapses. Methods: In EXPAND, patients (aged 18-60 years) with SPMS and Expanded Disability Status Scale score of 3.0-6.5 were included in the study and received once-daily oral siponimod 2 mg or placebo for up to 3 years. We analyzed the impact of siponimod on CDP by subgroup analysis using the Cox model on time to 3- and 6-month CDP in patients with or without relapses in the 1 and 2 years before study; principal stratum analysis to estimate the effect in patients who would not have relapsed on-study at the month 12, month 18, and month 24 timepoints, regardless of treatment; and Cox model on time to 3-/6- month CDP in the overall population, censoring at time of first relapse.
Results: For nonrelapsing patients in the 1 and 2 years before study, risk reductions were 18% (hazard ratio [HR], 0.82 [CI: 0.66, 1.02]) and 13% (0.87 [0.68, 1.11]), respectively, for 3-month CDP, and 25% (0.75 [0.59, 0.96]) and 18% (0.82 [0.62, 1.08]), respectively, for 6-month CDP; for relapsing patients, risk reductions were 33% and 33% (3-month CDP), and 30% and 37% (6-month CDP), respectively. In principal stratum estimates, siponimod reduced 3-month CDP by 14%-20% and 6-month CDP by 29%-33% in nonrelapsing patients across the 3 timepoints, suggesting that these patients achieved a large proportion of the effect in the overall population. Cox model censoring at relapse confirmed beneficial effects, reaching nominal statistical significance (6-month CDP: HR 0.77 [0.62, 0.96]).
Conclusions: Siponimod reduces risk of CDP in patients with SPMS with or without relapses, indicating that the effects on disability are largely independent from those on relapses. Patients with or without relapses may thus benefit from treatment with siponimod.