Abstract Details

Title Uncoupling the Impact on Relapses and Disability Progression: Siponimod in Relapsing and Non-relapsing Patients With Secondary Progressive Multiple Sclerosis in the Phase III EXPAND Study

Topic Multiple Sclerosis

Presentation(s) S8 - (-)

Poster/Presentation
Number 005

Background Siponimod reduced confirmed disability progression (CDP) in patients with SPMS (21%, p=0.013 risk for 3-month [3m] and 26%, p=0.006 for 6-month [6m] CDP). Because siponimod reduces the frequency of relapses, the impact of siponimod on disability progression independent of relapse reduction cannot be readily accounted for by standard analytic methods.

Objective

Design/Methods We applied several approaches to assess the impact of siponimod on disability progression independent of relapse activity: (a) subgroup analysis using Cox model on time to 3m/6m-CDP in subgroups of patients with (rSPMS, n=596)/without (nrSPMS, n=1055) relapses 2 years prior to study; (b) principal stratum analysis to estimate effect in patients who would not have relapsed on-study by m12, m18 and m24, regardless of treatment; (c) Cox model on time to 3m/6m-CDP in overall population, censoring at time of first relapse; (d) simulation from empirical distribution to assess effect in overall population removing the reduction on relapse rate.

Results Risk reductions of 13% and 18% in nrSPMS-subgroup were observed for 3m- and 6m-CDP [HR 0.87, (CI 0.68; 1.11); 0.82 (0.62; 1.08)], and 33%–37% in rSPMS-subgroup. In the principal stratum estimate, siponimod reduced disability in nrSPMS patients by 14–20% for 3m-CDP and 29–32% for 6m-CDP, suggesting that non-relapsing patients can achieve a large portion of the effect on the overall population. Cox model censoring at relapses (HR 0.77 [0.62; 0.96]) and simulation from empirical distribution (0.77 [0.63; 0.96]) consistently depicted more pronounced effects for 6m- than for 3m-CDP in nrSPMS patients.

Conclusions Siponimod treatment reduces the risk for CDP in both relapsing and non-relapsing SPMS patients. Our analyses suggest that siponimod’s effect on disability is largely independent from the effect on relapses.

Authors/Disclosures
Bruce A. Cree, MD, PhD, MCR, FAAN (UCSF, Multiple Sclerosis Center) PRESENTER	The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avotres. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon. Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kyverna. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. The institution of Dr. Cree has received research support from Kyverna. Dr. Cree has received publishing royalties from a publication relating to health care.
Robert J. Fox, MD, FAAN (Cleveland Clinic)	Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Science. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Janssen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Immunic. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genzyme. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for INmune Bio. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lily. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Greenwich Biosciences. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AB Science. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Fox has received research support from National Institutes of Health. The institution of Dr. Fox has received research support from National MS Society. Dr. Fox has received publishing royalties from a publication relating to health care.
Gavin Giovannoni, MD (QMUL)	Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck KGaA. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Japanese Tobacco. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aurinia Pharmaceuticals. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Oxford Health Policy Forum. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Peervoice. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Bristows .
Patrick Vermersch (CHR de Lille)	Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Science. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Imcyse. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS-Celgene. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ad Scientiam. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for La revue des microbiotes. The institution of Patrick Vermersch has received research support from Roche. The institution of Patrick Vermersch has received research support from Sanofi.
Amit Bar-Or, MD, FRCPC (University of Pennsylvania)	Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen/Actelion. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merk/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. The institution of Dr. Bar-Or has received research support from Novartis. The institution of Dr. Bar-Or has received research support from Biogen. The institution of Dr. Bar-Or has received research support from Roche/Genentech. The institution of Dr. Bar-Or has received research support from Merck/EMD Serono.
Ralf Gold, MD (Neurologische Universitaetsklinik)	Dr. Gold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen . Dr. Gold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Gold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer Vital. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharamaceuticals. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Gold has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for SAGE Publishers. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Novartis. Dr. Gold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Biogen. The institution of Dr. Gold has received research support from Novartis. The institution of Dr. Gold has received research support from Biogen.
	No disclosure on file
	No disclosure on file
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Davorka Tomic	Davorka Tomic has stock in Meck KGaA.
Goeril Karlsson, PhD	Dr. Karlsson has received personal compensation for serving as an employee of Novartis.
Frank Dahlke, MD, PhD	Dr. Dahlke has received personal compensation for serving as an employee of Novartis.
Ludwig Kappos, MD, FAAN (RC2NB, University Hospital Basel)	The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care.