Background: Siponimod is a selective S1P receptor (S1P1 and S1P5) modulator, approved in the USA for treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting MS and active secondary progressive MS (SPMS). In the phase 3 EXPAND trial, for patients with active SPMS, siponimod significantly reduced risk of 3-month (primary endpoint) and 6-month confirmed disability progression (CDP) by 31% and 37% versus placebo, respectively. Objectives: Assess efficacy and safety of siponimod in patients with active SPMS in subgroups of patients aged <50 and ?50 years at Baseline from the EXPAND study. Methods: Post hoc analyses were performed in subgroups of patients aged <50 and ?50 years at Baseline with active SPMS, defined as having at least one relapse in the 2 years before Baseline and/or ?1 T1 gadolinium-enhancing lesion at Baseline, randomized to siponimod 2 mg daily or placebo. Proportional hazard model was used in the analysis of time to 3- and 6-month CDP (as per EDSS scores). Number and percentage of patients with adverse events (AEs) were reported. Analyses for hypothesis generation only. Results: There were 779 patients with active SPMS: 471 patients aged <50 years (siponimod, n=326; placebo, n=145) and 308 patients aged ?50 years (siponimod, n=190; placebo, n=118). In those <50 years, siponimod reduced risk of 3-month CDP by 30.5% compared with placebo (siponimod, n=87 (26.7%); placebo, n=52 (35.9%); hazard ratio (HR) (95% confidence interval (CI)): 0.70 (0.49 0.98); p=0.0383), and reduced 6-month CDP risk by 37.9% (siponimod, n=69 (21.2%); placebo, n=46 (31.7%); HR (95% CI): 0.62 (0.43 0.90); p=0.0126). In the subgroup of patients ?50 years, siponimod reduced the risk of 3-month and 6-month CDP by 37.7% and 37.4%, respectively, versus placebo (3-month: siponimod, n=42 (22.1%); placebo, n=39 (33.1%); HR (95% CI): 0.62 (0.40 0.96); p=0.0332; 6-month: siponimod, n=30 (15.8%); placebo, n=28 (23.7%); HR (95% CI): 0.63 (0.37 1.0); p=0.0749). Siponimod was generally well tolerated in both subgroups. Rates of any AE were similar for siponimod and placebo in patients <50 years (85.6% vs 80.0%), and slightly higher for siponimod in those ?50 years (88.9% vs 76.3%). Rates of serious AEs and AEs leading to discontinuation were similar between groups. Conclusions: Siponimod provided similar clinical benefits in reducing CDP risk in patients aged <50 years and ?50 years with active SPMS. In addition, these results are consistent with the overall active SPMS cohort in EXPAND.