Oral Fingolimod (FTY720) vs Placebo in Relapsing-Remitting Multiple Sclerosis: 24-Month Safety and Tolerability Results from a Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III Study (FREEDOMS)

OBJECTIVE:To report safety findings from FREEDOMS – a 24-month placebo-controlled phase III study of oral fingolimod (FTY720) 1.25mg and 0.5mg once daily in relapsing–remitting multiple sclerosis (RRMS). BACKGROUND:Oral fingolimod, a sphingosine 1-phosphate receptor modulator, has been studied in phase II and III studies. This study provides 2-year tolerability and safety data in RRMS. DESIGN/METHODS:RRMS patients aged 18–55 years with EDSS score 0–5.5, and ≥1 relapse in the previous year (or ≥2 in the previous 2 years) were randomized. In addition to routine safety assessments, FREEDOMS included close monitoring of vital signs and ECGs following first-dose administration, and regular pulmonary function testing and ophthalmic and dermatologic examinations. RESULTS:1033/1272 (81%) randomized patients completed the study. The proportion of patients discontinuing study drug was lower with fingolimod 0.5mg (19%) vs fingolimod 1.25mg (31%) or placebo (28%). Proportions of patients reporting any adverse events (AE) were similar for fingolimod (94% both groups) and placebo (93%) as were proportions of patients with serious AEs: 0.5mg, 10%; 1.25mg, 12%; placebo, 13%. Infectious AE were reported in 69–72% of patients. Serious infectious AE occurred in 1.6% (0.5mg), 2.6% (1.25mg) and 1.9% (placebo) of patients. Three deaths were reported (placebo, n=2; fingolimod 1.25mg, n=1); all were considered unrelated to study drug. Malignant neoplasms were reported in 10 placebo-treated patients and four patients in each fingolimod group. Seven cases of macular edema occurred, all in patients receiving fingolimod 1.25mg. A transient heart rate decrease on treatment initiation, minor increases in blood pressure and generally asymptomatic liver enzyme increases were observed. CONCLUSIONS/RELEVANCE:These results confirm that fingolimod is generally well tolerated. The 0.5mg dose was generally better tolerated than the 1.25mg dose, being associated with fewer SAE and bradycardia events and no cases of macular edema.