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 (S8.005)

Objective: Using multiple statistical methods, we aimed at assessing the impact of siponimod on disability progression in non-relapsing SPMS patients and at uncoupling the treatment effect on disability progression from the effect of relapses. 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. 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 29–33% 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. Study Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Cree has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Biogen, EMD Serono, GeNEuro, Novartis, Sanofi Genzyme. Dr. Cree has received research support from Acorda, Hoffman La Roche, MedImmune, Novartis, Receptos and Teva. Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for serving as consultant or speaker from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva Pharmaceutical Industries. Dr. Fox has received research support from Biogen (clinical trial contracts) and Novartis (research study support).. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Almirall, Atara Bio, Biogen, Sanofi-Genzyme, Genentech, GSK, Merck, Novartis. Dr. Giovannoni has received personal compensation in an editorial capacity for Elsevier as Editor of MSARDs. Dr. Giovannoni has received research support from Takeda. Dr. Vermersch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Almirall, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, Servier, and Teva. Dr. Vermersch has received research support from Almirall, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, Servier, and Teva. Dr. Bar-Or has nothing to disclose. Dr. Gold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Diseases, Experimental Neurology and the Journal of Neuroimmunology. Dr. Gold has received research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Dr. Magnusson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis. Dr. Rouyrre has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis. Dr. Piani Meier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Tomic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Karlsson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis. Dr. Dahlke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis. Dr. Kappos has received research support from Bayer HealthCare Pharmaceuticals, Biogen, F. Hoffmann-La Roche Ltd and Genentech,Novartis, Research grants from: the European Union, Roche Research Foundation, Swiss Multiple Sclerosis Society and Swiss National Research Foundation.