Impact of Siponimod on Cognition in Patients With Secondary Progressive Multiple Sclerosis: Results From Phase 3 EXPAND Study (S44.004)

Objective: To evaluate the effect of siponimod on cognition in secondary progressive multiple sclerosis (SPMS) patients. Background: Cognitive impairment impacts 50–70% of MS patients and is more severe in progressive than relapsing MS. Cognitive processing speed (CPS) is the most frequently affected cognitive domain. Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) are often used to assess CPS in clinical trials, although SDMT requires less working memory, and is more reliable and sensitive. A responder definition of 10% or 4 points change on SDMT is also becoming the standard. The Brief Visuospatial Memory Test-Revised (BVMT-R) evaluates visual/spatial memory. Design/Methods: SPMS patients in siponimod (N=1099) and placebo (N=546) arms of EXPAND study underwent SDMT, PASAT and BVMT-R at baseline, and at Months (M) 6, 12, 18, and 24. Between-group comparisons for change from baseline were performed on the full analysis set using a repeated measures model (visit as a categorical factor), adjusted for treatment and baseline scores. Subgroup analysis included patients with relapses (rSPMS) and without (nrSPMS) in the 2 years before baseline. Time to 6-months sustained 3 and 4 points change on SDMT was assessed by Cox proportional hazards model. Results: At baseline, mean SDMT and PASAT scores were 39.09 and 39.10. At M24, SDMT scores improved with siponimod versus placebo (2.47 point difference in adjusted means, p=0.0004), with no significant difference in PASAT or BVMT-R scores. In rSPMS patients, M24-SDMT and M24-PASAT favored siponimod (difference: 2.57[p=0.0151] and 2.42[p=0.0275] respectively) while in nrSPMS patients, the difference was significant only for SDMT (2.44, p=0.0099). Risk of sustained SDMT score change by 3 and 4 points was reduced by 28.6% (p=0.0002) and 21.3% (p=0.0157) with siponimod versus placebo. Conclusions: In rSPMS and nrSPMS subgroups, siponimod demonstrated a significant and clinically meaningful positive effect on CPS as measured by SDMT. Study Supported by: This study was funded by Novartis Pharma AG, Basel, Switzerland Disclosure: Dr. Benedict has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with has received personal compensation for activities with Actelion, Biogen Idec, Bayer, and Novartis as a consultant. 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. Tomic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. 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. 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. 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. Pohlmann 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.