Long-Term Safety of Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: Results from Phase 3 FREEDOMS II Extension Study (P01.165)

OBJECTIVE: To presents the long-term (48 months) safety results of fingolimod from the FREEDOMS II extension study. BACKGROUND: In the 24-month, FREEDOMS II study, once daily, oral fingolimod (0.5mg or 1.25mg) was generally well tolerated in patients with relapsing-remitting multiple sclerosis. DESIGN/METHODS: In the extension phase, fingolimod-treated patients continued with their assigned dose while placebo patients were re-randomized (1:1) to fingolimod 0.5mg/1.25mg (switch group: placebo-0.5mg and placebo-1.25mg). After protocol amendment, all patients received fingolimod 0.5 mg. Safety assessments included adverse events (AEs), serious AEs (SAEs), and laboratory evaluations; events occurring in the extension are presented. RESULTS: 529/632 patients completed the extension study (83.7%). Withdrawal of consent and AEs were the main reasons for discontinuations (4.7% each). In both continuous and switch groups, AEs were reported in 85.3%-87.9% of patients. Placebo-1.25mg patients (11.4%) reported highest incidence of SAEs versus others (7.4%, 7.8% and 3.7% in the 1.25mg, 0.5mg and placebo-0.5mg). The 1.25mg (8.4%) patients reported highest AEs leading to study discontinuations versus others (4.8-7.5%). Across all groups serious infections were comparable (0.9-2%). One patient on 1.25mg reported severe herpes zoster. After first dose of fingolimod, placebo-0.5mg patients reported hypotension (n=1; SAE) and symptomatic bradycardia (n=2) and placebo-1.25mg patients reported first degree atrioventricular (AV) block, bradycardia and Mobitz type I second degree AV block (all SAEs and n=1). One patient each on placebo-1.25mg and placebo-0.5mg reported confirmed macular edema. Patients on 1.25mg (n=2) and 0.5mg (n=1) reported squamous cell carcinoma. One patient on 0.5mg reported basal cell carcinoma. Placebo-1.25mg patients reported highest (6.7%) increase in alanine aminotransferase enzyme (>3xULN) versus others (1.5%, 4.6% and 4.7% in the 1.25mg, 0.5mg and placebo-0.5mg). CONCLUSIONS: The long-term safety results of FREEDOMS II extension study were generally consistent with previous fingolimod studies. Switching therapy from placebo to fingolimod after 24 months identified no unexpected safety concerns. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Vollmer has received personal compensation for activities with Genzyme Corporation, Acorda Therapeutics, Accelerated Cure Projects for MS, Bristol-Myers Squibb Company, Teva Neuroscience, Biogen Idec, Novartis, and Hoffman-LaRoche. Dr. Vollmer has received research support from Teva Neuroscience, Genzyme Corporation, Ono Pharmaceutical, Biogen Idec, Janssen, and the National Institutes of Health. Dr. Jeffery has received personal compensation for activities with Berlex Laboratories, Inc., GlaxoSmithKline, Inc., Pfizer Inc, Serono, Inc., and Teva Neuroscience. Dr. Jeffrey has received research support from Berlex, Pfizer Inc, Serono, Inc., and Teva Neuroscience. Dr. Goodin has received personal compensation for activities with Ares-Serono, Merck Serono, Novartis, Berlex Laboratories, Bayer Schering HealthCare, Biogen Idec, Schering AG and Teva Neuroscience. Dr. Goodin has received research support from Novartis. 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. Lublin has received personal compensation for consulting from Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono Inc., Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Celgene, Abbott, Johnson & Johnson, Revalesio, Coronado Bioscience, and GenFL. Dr. Lublin has received compensation from Elsevier for serving as Co-Chief Editor of Multiple Sclerosis and Related Diseases. Dr. Radue has received personal compensation for activities with AIM, Biogen Idec, and Novartis as a consultant. Dr. Radue has received research support from Actelion, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, and Novartis. Dr. Rammohan has received personal compensation for activities with BIOGEN IDEC, TEVA, NOVARTIS, EMD SERONO, PFIZER, ROCHE GENENTECH, QUESTCOR AND ACORDA as a speaker and consultant. Dr. Rammohan has received research support from BIOGEN IDEC, TEVA, EMD SERONO, NOVARTIS, GSK, NIH, ACORDA. Dr. Reder has received personal compensation for activities with Bayer, Genentek, Genzyme, Merck, Novartis, Questcor, Serono, Teva Neuroscience, Caremark, Canadian MSS, NMSS, State of IL, State of IN. Dr. Reder received personal compensation in an editoral capacity for Medlink/Neurobase electronic journal. Dr. Agius has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Berlex Labs and Serono as a speaker and consultant. Dr. Agius has received research support from Novartis, Teva, Biogen, Genzyme, Roche, Immune Tolerance Network, Actelion, and Acorda. Dr. Stites has received personal compensation for activities with Novartis Pharmaceuticals Corporation as an employee. Dr. Li has received personal compensation for activities with Novartis as an employee. Dr. Cappiello has received personal compensation for activities with Novartis. Dr. Von Rosenstiel has received personal compensation for activities with Novartis. Dr. Calabresi has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Genzyme Corporation, Vaccinex, Vertex, and Novartis. Dr. Calabresi has received research support from the National Institutes of Health, the National Multiple Sclerosis Society, Nancy Davis Foundation, Biogen Idec, Vertex, Genentech, Inc., Abbott, and Bayer.