Safety and Efficacy of Siponimod (BAF312) in Patients with Relapsing-remitting Multiple Sclerosis: Results from Dose-blinded Extension Phase of BOLD Study (P3.151)

OBJECTIVE: To present siponimod (BAF312) safety and efficacy results in patients with relapsing-remitting multiple sclerosis during the dose-blinded phase (up to 24 months) of BOLD extension study. BACKGROUND: In the core BOLD study, siponimod showed dose-dependent reduction in MRI-assessed inflammatory lesion activity and annualized relapse rate (ARR) with a manageable safety and tolerability profile, particularly at low doses. DESIGN/METHODS: Patients either continued on siponimod doses assigned in the core phase or were re-randomized from placebo to siponimod 10 (n=33), 2 (n=29), 1.25 (n=43), 0.5 (n=29) and 0.25 (n=50) mg. Dose titration from 0.25 mg over the first 10 days was implemented to reduce the risk of bradycardia during siponimod treatment initiation. MRI was performed at extension baseline and every 6 months thereafter. RESULTS: Of the 184 patients who entered the extension study, 159 completed the dose-blinded phase (overall average exposure, 655 days). The following data pertain to patients taking 10, 2, 1.25, 0.5 and 0.25mg doses, respectively. Mean number of Gd-enhanced T1 lesions by visit: 0.2, 0.5, 0.1, 0.6, 0.7 (Month 12) and 0.0, 0.1, 0.3, 0.6, 1.3 (Months 24) versus 1.7, 1.4, 1.8, 3.1, 1.3 (core baseline). Mean number of new/enlarged T2 lesions: 0.0, 0.5, 0.3, 2.1, 2.9 (Month 24) versus 0.5, 0.6, 0.3, 1.6, 1.7 (Month 12). Annualized confirmed relapse rate (95% CI) remained low: 0.22 (0.12, 0.40), 0.20 (0.10, 0.38), 0.14 (0.08, 0.26), 0.33 (0.19, 0.56), and 0.33 (0.21, 0.50). Seven patients withdrew from study drug due to adverse events (AE). Most common AEs (蠅12% in any dose group) were nasopharyngitis, headache, lymphopenia, decreased lymphocyte count, upper respiratory tract infection, increased alanine aminotransferase, pharyngitis, sinusitis, insomnia and depression. Serious AEs were reported in 9 patients. CONCLUSIONS: Siponimod showed sustained efficacy on MRI and clinical measures with highest effects in the 1.25mg, 2mg, and 10mg dose groups, in line with dose-finding results in the core study. No new safety signals emerged. Study Supported by: Novartis Pharma AG Disclosure: Dr. Kappos has received personal compensation for activities with the University Hospital Basel. Dr. Kappos has received research support from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, Novartis, and Roche Diagnostics Corp. Dr. Stuve has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Roche Diagnostics Corp., Genzyme Corp., Novartis, and Sanofi-Aventis Pharmaceuticals Inc.. Dr. Stuve has received personal compensation in an editorial capacity for Archives of Neurology and Therapeutic Advances in Neurological Disorders. Dr. Stuve holds stock in Teva Pharmaceuticals which sponsored research in which Dr. Stuve was involved as an investigator. Dr. Stuve has received research support from Teva Pharmaceuticals. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corp., CSL Behring, Biogen Idec, Genzyme Corp., Grifols, Merck Serono, Novartis, Roche Diagnostics Corp., Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals Inc. as a consultant and speaker. Dr. Freedman has received personal compensation for activities with Bayer Pharmaceuticals Inc., Genzyme Corp., EMD Canada, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Celgene, Glycominds, and Teva Neuroscience. Dr. Li has received personal compensation for activities with Opexa, Nuron, Genzyme Corp., Roche Diagnostics Corp., and Novartis. Dr. Li has received research support from EMD Serono, Genzyme Corp., and Roche Diagnostics Corp. Dr. Hemmer has received personal compensation for activities with Roche Diagnostics Corp., Novartis, Bayer Schering, GlaxoSmithKline, Inc., Chugai, Genzyme Corporation, Biogen Idec, Merck Serono, and Teva Neuroscience. Dr. Hemmer has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Hemmer has filed a patent for KIR4.1 antibody testing. Dr. Hemmer has received research support from Biogen Idec, Bayer Schering, Merck Serono, Metanomics and Novartis. Dr. Rieckmann has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc., Novartis, Merck Serono, Teva Neuroscience and Genzyme Corp. Dr. Montalban has received personal compensation for activities with Bayer Pharmaceuticals Corp., BIogen Idec, EMD Serono, and Genente. Dr. Ziemssen has received personal compensation for activities with Almirall, Biogen Idec, Bayer, Genzyme Corporation, GlaxoSmithKline, Inc., MSD, Merck Serono, Novartis, Sanofi, Teva Neuroscience, and Synthon. Dr. Ziemssen has received research support from Bayer, Biogen Idec, Merck Serono, Novartis, Teva, and Sanofi. Dr. Hunter has nothing to disclose. Dr. Arnould has received personal compensation for activities with Novartis 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. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Genzyme Corp., Ono Pharmaceutical, Novartis, Bayer Pharmaceuticals Corp., Hoffmann La-Roche, Merck Serono and Synthon.