Background: In the EXPAND Core study, siponimod significantly reduced the risk of 3-/6-months(m) confirmed disability progression (3m/6mCDP) and 6m confirmed ?4-points clinically meaningful worsening on Symbol Digit Modalities Test (6mCWSDMT) vs placebo in the active SPMS subgroup (aSPMS, presence of relapses 2 years before screening and/or ?1 T1 gadolinium-enhancing lesion at baseline) and overall SPMS population. Objectives: Assess long-term efficacy and safety of siponimod in aSPMS and overall SPMS population from the Core and Extension parts of EXPAND. Methods: This analysis included Core and 36m extension data from all study participants who received ?1 dose of siponimod 2 mg or placebo (cut-off 06Apr2019; total study duration of ?5 years). Time-to-6mCDP by Expanded Disability Status Scale, time-to-6mCWSDMT and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in Core+Extension) and Switch (placebo in Core and open-label siponimod in Extension) groups. Safety was also evaluated. Results: Of 1651 SPMS patients randomized in the EXPAND Core part, 1224 (74%) patients entered Extension (878 [72%] ongoing). Of 779 patients with aSPMS randomized in the Core part, 582 entered Extension. In the Continuous vs Switch group, 6mCDP risk was reduced by 29% (p=0.0044) and 22.3% (p=0.0026) in aSPMS and the overall population; time to reach the 25th 6mCDP percentile was delayed by 78% and 54%, respectively. Time for 50% of patients to reach 6mCDP in aSPMS and the overall population was 48m and 51.7m respectively for Switch group. For the Continuous group, less than 50% reached 6mCDP. In the Continuous vs Switch group, 6mCWSDMT risk was reduced by 33% (p=0.0018) and 23% (p=0.0047) in aSPMS and the overall population; time to reach the 25th 6mCW percentile was delayed by 45% and 62%, respectively. Median time-to-6mCWSDMT (55.5m) was reached only for the Switch group in the aSPMS cohort. ARR reduction was significant in the Continuous vs Switch group across aSPMS (39.7%; p=0.0023) and overall (52%; p<0.0001) populations. Incidence rates of adverse events/100 patient-years in both populations were consistent over the long-term period with no new safety findings observed. Conclusions: The differences in sustained treatment effects (disability, relapse and cognitive processing speed) over the long-term period between Continuous siponimod and placebo-Switch groups highlight the benefit of early siponimod treatment initiation in SPMS. The safety profile remained favorable and consistent with previous reports.