Siponimod (BAF312) for the Treatment of Secondary Progressive Multiple Sclerosis: Design of the Phase 3 EXPAND Trial (P07.126)

OBJECTIVE: To present the design of a phase 3 study intended to demonstrate the efficacy, safety and tolerability of siponimod as compared with placebo in individuals with secondary progressive multiple sclerosis (SPMS). BACKGROUND: Siponimod (BAF312) is a next generation selective sphingosine 1-phosphate (S1P)-1 and -5 receptor modulator administered once-daily orally. Siponimod reduces lymphocyte infiltration into the CNS and may have direct CNS effects. Experimental studies indicate that siponimod readily crosses the blood-brain-barrier and may modulate neurobiological processes via S1P 1 and S1P 5 receptors on astrocytes and oligodendrocytes. In relapsing MS, S1P receptor modulation reduces accumulation of neurological impairment and slows progression of brain atrophy. These clinical and radiographic effects suggest that S1P receptor modulation might be effective in SPMS. DESIGN/METHODS: EXPAND ( Ex ploring the efficacy and safety of siponimod in pa tients with Seco nd ary Progressive Multiple Sclerosis, CBAF312A2304) is a multicenter, randomized, double-blind, parallel-group, placebo-controlled variable treatment duration study (anticipated range 23–42 months). Approximately 1530 individuals, aged 18–60 years with SPMS (EDSS score of 3.0–6.5) will be randomized. Treatment will start with a 6-day dose titration (0.25, 0.25, 0.5, 0.75, 1.25, 2mg) and continue at a dose of 2mg or placebo (2:1). The primary objective of the study is to demonstrate the efficacy of siponimod relative to placebo in delaying the time to 3-month confirmed disability progression as measured by EDSS. The study has 90% power to detect a 30% reduction in the risk of 3-month confirmed disability progression (hazard ratio 0.70). Study will be stopped when 374 events (patients with progression) are observed. RESULTS: Details of study design will be presented at the congress. CONCLUSIONS: New therapies, that are effective in delaying disability progression in patients with SPMS, are an important unmet medical need. The EXPAND study will explore the potential of siponimod in SPMS and help advance the knowledge of SPMS pathophysiology. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Kappos has receied personal compensation for activities with Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA and GlaxoSmithKline. Dr. Kappos has received research support from has received research support from Acorda, Actelion, Allozyne, BaroFold, Bayer HealthCare, Bayer Schering, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim, Eisai, Elan, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova and Nova. Dr. Bar-Or has received personal compensation for activities with Amplimmune, Aventis Pharmaceuticals Inc., Bayhill Therapeutics, Berlex, Bayer, Biogen Idec, BioMS, Diogenix, Eli Lilly & Company, Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, Inc., Guthy-Jackson/GGF, EMD Serono, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and Wyeth Pharmaceuticals. Dr. Bar-Or has received research support Aventis Pharmaceuticals Inc., Bayhill Therapeutics, Biogen Idec, Berlex, Eli Lilly & Company, Genentech, Inc. GlaxoSmithKline, Inc., Ono Pharma, Diogenix, Roche Diagnostics,, Merck Serono, Novartis, and Teva Neuroscience. Dr. Cree has received personal compensation for activities with Biogen Idec, EMD Serono, Genzyme Corporation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Fox has received personal compensation for activities with Avanir, Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received research support from Biogen Idec and Genentech. Dr. Giovannoni has received personal compensation for activities with Merck Serono, Biogen Idec, Vertex Pharmaceuticals, Bayer Schering Pharma, Pfizer Inc, Teva Pharmaceutical Industries Ltd, and Sanofi. Dr. Giovannoni has received research support from Biogen Idec, Merck Serono, Novartis, and Ironwood. Dr. Gold has received personal compensation for activities with Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received a license fee from Biogen Idec. Dr. Gold has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Vermersch has received personal compensation for activities with Biogen Idec, Sanofi-Aventis Pharmaceuticals, Inc., Bayer, Novartis, Merck Serono, GlaxoSmithKline, Inc., and Almirall. Dr. Vermersch has received research support from Biogen Idec, Sanofi-Aventis Pharmaceuticals, Inc., Bayer, and Merck Serono. Dr. Lam is an employee of Novartis...... Dr. Pohlmann has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Zhang-Auberson has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Dandekar has received personal compensation for activities with Novartis Pharma AG. Mr. Wallstroem has received personal compensation for activities with Novartis Pharma AG as an employee.