Long-term safety of fingolimod in patients with relapsing-remitting multiple sclerosis: Results from phase 3 freedoms II extension study

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.