Safety and Tolerability of Siponimod in Patients with Secondary Progressive Multiple Sclerosis (S33.007)

Objective: To present safety and tolerability results of the randomized, double-blind, placebo-controlled, Phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Background: Siponimod, a selective sphingosine 1-phosphate (S1P) receptor-1/-5 modulator with peripheral and central effects was investigated in SPMS, a condition driven by neurodegeneration and inflammation in the central nervous system, where treatment options are limited. Efficacy results are reported separately. Design/Methods: In EXPAND siponimod significantly reduced the risk of 3-month confirmed disability progression. Safety and tolerability based on the safety analysis set for the double blind treatment period are reported. Patients were randomized (2:1) to receive once-daily siponimod 2mg or placebo (with a 6-day initial dose titration). Results: Of 1651 randomized patients, 1645 comprised the safety population (siponimod, N=1099; placebo, N=546). Mean age was 48 years (SD 7.87), median EDSS 6.0. At least one treatment-emergent adverse event (TEAE) was reported for 88.7% and 81.5% of siponimod and placebo patients; in 7.6% and 5.1% of patients, these led to treatment discontinuation. Most common TEAEs (u003e10% in any group) were headache, nasopharyngitis, urinary tract infection, falls and hypertension. Serious TEAEs were reported in 17.9% and 15.2%, including four deaths in each treatment group (0.4% and 0.7%). Incidence of infections and malignancies were similar (49.0% vs. 49.1%, 1.9% vs. 2.6%, respectively). Lymphopenia below 0.2×10^9/uL was observed in 2.7% vs. 0.2% of patients and Liver Function Test elevations ≥3xULN – in 5.6% vs. 1.5%. The incidence of other AEs of interest were: bradyarrhythmias, 3.5% vs. 2.4%; hypertension, 12.6% vs. 9.3%; and macular edema, 1.8% vs. 0.2%, respectively. With dose titration (during treatment initiation) there were only few bradyarrhythmic events. No cases of Mobitz II or higher degree AV-blocks were reported. Conclusions: The safety profile of siponimod appears to be in line with other S1P receptor modulators. Study Supported by: This study was funded by Novartis Pharma AG, Basel, Switzerland Disclosure: Dr. Fox has received personal compensation for activities with Actelion, Biogen, Genentech, Mallinckrodt, MedDay, Novartis, and Teva Neuroscience as a consultant. Dr. Fox has received research support from Novartis. Dr. Kappos has reveived personal compensation for activities with University Hospital Basel as an advisory board member. Dr. Kappos has received research support from Swiss Multiple Sclerosis Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis Research Foundation, and Roche Research Foundation. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, and Eli Lilly for consulting, serving on scientific advisory boards and/or as a speaker. Dr. Cree has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Novartis and Shire as a consultant. Dr. Giovannoni has received personal compensation for activities with AbbVie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex for honoraria. Dr. Giovannoni has received personal compensation from Elsevier in a co-chief editor capacity of MS and Related Disorders. Dr. Giovannoni has received research support from Biogen, Ironwood, Merck Serono, Merz, and Novartis. Dr. Gold has received personal compensation for activities with Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience as a speaker. Dr. Gold has received personal compensation in an editorial capacity for Sage. Dr. Gold has received research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience. Dr. Vermersch has received personal compensation for activities with Biogen, Roche, Merck, Teva, Sanofi Genzyme, and Almirall. Dr. Vermersch has received research support from Roche, Biogen and Sanofi Genzyme. Dr. Pohlmann has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Wolf has received personal compensation for activities with Desitin, Synthon, Mylan, and Novartis as a consultant. Dr. Dahlke has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Wallstrom has nothing to disclose. Dr. Sidorenko has received personal compensation for activities with Novartis Pharma AG as an employee.