Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

BACKGROUND

Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS.

METHODS

This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation.

RESULTS

Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND.

CONCLUSIONS

In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Informations de copyright

Copyright © 2023. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Le H Hua has received personal fees for speaking, consulting and advisory board activities from Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Novartis, TG Therapeutics, Horizon, Greenwich and Alexion, and research support from Biogen paid to her institution. Amit Bar-Or participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi Genzyme, and has received grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono and Novartis. Stanley L Cohan has received speaker fees from Biogen, Bristol Myers Squibb, Novartis, Roche Genentech and Sanofi Genzyme, and serves on advisory boards or as a consultant to AbbVie, Biogen, Bristol Myers Squibb, EMD Serono, Novartis and Sanofi Genzyme. Institutional research support (the Providence Brain and Spine Institute) was received from AbbVie, Adamas, Biogen, EMD Serono, MedDay, Novartis, Roche Genentech, Sage Bionetworks and Sanofi Genzyme. Fred D Lublin has participated in consulting agreements, advisory boards and Data and Safety Monitoring Board activities for Actelion/Janssen, Acorda, Apitope, Atara Biotherapeutics, Avotres, Banner Life Sciences, Biogen, Brainstorm Cell Therapeutics, EMD Serono, GW Pharma, Immunic, Jazz Pharmaceuticals, Labcorp Entelexo Biotherapeutics, Mapi Pharma, Medday, MedImmune/Viela Bio/Horizon Therapeutics, Mylan, Neuralight, Neurogene, Novartis, Orion Biotechnology, Population Council, Receptos/Celgene/Bristol Myers Squibb, Roche/Genentech, Sanofi/Genzyme, Teva and TG Therapeutics, acted as a speaker (non-promotional) for Sanofi, reports research funding from Actelion, Biogen, Brainstorm Cell Therapeutics, National Institutes of Health, Novartis, National Multiple Sclerosis Society and Sanofi, and has stock options with Avotres and Neuralight. Patricia K Coyle has received consulting fees from Accordant, Alexion, Bayer, Biogen, Celgene, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Mylan, Novartis, Serono and TG Therapeutics, and research grants from Actelion, Alkermes, Corrona LLC, Genentech/Roche, MedDay, NINDS, Novartis and PCORI. Bruce AC Cree has received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics and Therini and received research support from Genentech. Xiangyi Meng, Wendy Su and Gina M Cox are employees of Novartis Pharmaceuticals Corporation. Robert J Fox has received personal fees from Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis and Teva, grants from Novartis and other support from Biogen and Novartis (clinical trial contracts).