BAF312, a Selective Sphingosine-1-Phosphate Receptor Modulator Improves MRI and Clinical Outcomes in Relapsing-Remitting Multiple Sclerosis (RRMS) (S30.001)

Abstract

Objective: To report relapse data and MRI findings from a double-blind, placebo-controlled, adaptive design phase II dose-finding study of BAF312 in patients with RRMS. Background BAF312, a next generation selective sphingosine-1-phosphate receptor (S1PR-1/5) modulator, significantly reduces MRI lesion activity in RRMS, and has demonstrated a 3-month dose-MRI response curve 1 . Here we report 6-month relapse data. Design/Methods: Patients were randomized to two sequential cohorts: Cohort 1 (n=188), received once-daily BAF312 10mg, 2mg, 0.5mg or placebo for 6mo; Cohort 2 (n=109), 1.25mg, 0.25mg (doses selected following Cohort 1 interim analysis) or placebo for 3mo. Brain MRI was performed monthly. Patients completing the core study were eligible for the extension study. Annualized relapse rate (ARR), calculated from confirmed relapses in 6mo, was analyzed post-hoc: Cohort 1 (6mo core data), Cohort 2 (3mo core plus 3mo extension data). Results: At 6mo, adjusted proportion of relapse-free patients (Cohort 1 only), was 84%, 92% and 77% for BAF312 10mg, 2mg and 0.5mg, respectively, vs 72% for placebo (p=0.014 for BAF312 2mg vs placebo). In the 6mo post-hoc analysis, ARR was lower with BAF312 10mg, 2mg, and 1.25mg (0.30, 0.20, 0.23, respectively) compared to BAF312 0.5mg, 0.25mg and placebo (0.61, 0.55, and 0.58, respectively). BAF312 three highest doses resulted in 48%-66% ARR reduction over placebo (p=0.044 for 2mg vs placebo). A significant dose-response relationship at 3mo was previously demonstrated (p=0.0001) 1 . The MRI dose-response curve estimated at 3mo indicated near-maximal efficacy at 2mg and submaximal efficacy at 0.5mg (∼50% reduction vs placebo). BAF312 reduced brain MRI lesion numbers up to 80% vs placebo. Most frequent adverse events were headache, bradycardia, dizziness and nasopharyngitis; highest in BAF312 10mg. Conclusions: BAF312 1.25-10mg reduces relapses in RRMS, correlating with MRI efficacy estimated from the 3mo dose-response curve. Overall safety and tolerability was favorable. Reference 1. Selmaj et al. ECTRIMS 2011. Supported by: Novartis-sponsored. Disclosure: Dr. Stuve has received personal compensation for activities with Teva Neuroscience, Novartis, Roche, Genzyme, EMD Serono, and Sanofi-Aventis. Dr. Stuve has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Li has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant.Dr. Li has receved research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences,Sanofi-Aventis, Transition Therapeutics, and Novartis. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Genzyme Corporation, EMD Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Freedman has received research support from Genzyme Corporation and Bayer Healthcare. Dr. Rieckmann has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Boehringer-Ingelheim, Novartis, Merck-Serono, TEVA, and Sanofi-Aventis as a speaker. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. Pohlmann has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Mercier has received personal compensation for activities with Novartis as an employee. Dr. Dahlke has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Wallstrom has received personal compensation for activities with Novartis as an employee. Dr. Wallstrom holds stock and/or stock options in Novartis.