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BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND.Endpoints3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p

BackgroundSiponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study.ObjectiveThe aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years.MethodsIn the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group).ResultsContinuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term.ConclusionThe sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation.Trial registration numberNCT01665144.

BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

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 progression (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. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study" that was published in the March 5, 2016 issue is presented.

Background: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study., Objective: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years., Methods: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group)., Results: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p  = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p  = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term., Conclusion: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation., Trial Registration Number: NCT01665144.

Background: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses., Objective: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial., Methods: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses., Results: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively., Conclusion: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.