Assess siponimod efficacy/safety in patients with active SPMS with MS duration (time since first symptom onset) of <16 or ≥16 years (median value) at baseline.

Siponimod is a selective S1P receptor modulator, approved in the USA for treatment of RMS, including CIS, RRMS, and active SPMS. In the EXPAND trial in SPMS, siponimod significantly reduced 3- and 6-month confirmed disability progression (CDP) risk by 21% and 26%, respectively.

Post hoc analyses included patients with active SPMS, defined as relapse in 2 years before screening and/or ≥1 T1 Gd+ lesion at baseline, randomized to siponimod 2mg daily or placebo. Efficacy endpoints: time to 3- and 6-month CDP (per EDSS scores). AEs, serious AEs, and AEs leading to treatment discontinuation were assessed. Analyses for hypothesis generation, without adjustment for multiple comparisons.

There were 779 patients with active SPMS: 427 with MS duration <16 years (siponimod, n=285; placebo, n=142) and 352 with ≥16 years duration (n=231; n=121). For MS duration <16 years, siponimod reduced 3- and 6-month CDP risk by 32.4% and 42.7%, respectively, versus placebo (3-month: siponimod, n=68 [23.9%]; placebo, n=48 [33.8%]; HR, [95% CI]: 0.68, [0.47, 0.98]; p=0.0378; 6-month: n=48 [16.8%]; n=40 [28.2%]; 0.57, [0.38, 0.87]; p=0.0093). For MS duration ≥16 years, siponimod trended towards reduced CDP risk of 31.9% and 27.1%, respectively, versus placebo (3-month: n=61 [26.4%]; n=43 [35.5%]; 0.68, [0.46, 1.01]; p=0.0540; 6-month, n=51 [22.1%]; n=34 [28.1%]; 0.73, [0.47, 1.13]; p=0.1544). Siponimod was generally well tolerated. Any AE rates were: <16 years, 84.9% (siponimod), 75.4% (placebo); ≥16 years, 89.2%, 81.8%.

In patients with active SPMS and MS duration <16 years, siponimod significantly reduced 3- and 6-month CDP risk versus placebo. Siponimod showed a trend towards reduced CDP versus placebo in those with duration ≥16 years. This may reflect the smaller size or more advanced disease in this subgroup.