Objectives: To evaluate the long-term safety and tolerability of fingolimod using data from extension phases of the phase 2 study and the pivotal phase 3 FREEDOMS and TRANSFORMS studies.
Methods: The phase 2 study was conducted in patients (pts) with relapsing MS, and the FREEDOMS and TRANSFORMS studies were conducted in patients with relapsing-remitting MS. Pts were randomized to fingolimod 1.25 mg, 5.0 mg, or PBO QD for 6 mo (phase 2); fingolimod 0.5 mg, 1.25 mg, or PBO QD for 24 mo (FREEDOMS); or fingolimod 0.5 mg, 1.25 mg QD, or IFNβ-1a IM 30 μg weekly for 12 mo (TRANSFORMS). In the study extensions, pts continued their core phase dose (continuous fingolimod) or were rerandomized from PBO to fingolimod (phase 2 extension: 1.25 or 5.0 mg; FREEDOMS extension: 1.25 or 0.5 mg) or from IFNβ-1a IM to fingolimod (TRANSFORMS extension: 1.25 or 0.5 mg). Subsequently, all pts were transitioned to open-label fingolimod 0.5 mg following discontinuation of the 5.0-mg and 1.25-mg doses from further clinical development.
Results: 122 of 281 pts completed the phase 2 extension and entered the long-term follow up study; 94 pts completed at least 7 y. AEs were reported in 95.7–98.9% of pts across treatment groups; most common AEs were nasopharyngitis (36.6-44.7%), headache (26.6-37.2%), and fatigue (17.0-24.5%). Incidence of AEs leading to discontinuation was 23.7-28.7% and incidence of serious AEs (SAEs) was 20.2-34.0%. 16 (5.7%) cases of herpes zoster infection and 14 (5.0%) cases of skin malignancies were reported. In FREEDOMS and its extension, 773 of 1272 pts completed up to 4 y. AEs were reported in 91.7–95.5%; of pts, with nasopharyngitis (25.4-28.4%), lymphopenia (11.0-18.0%) and upper respiratory tract infection (13.5-17.5%) being most common. Incidence of AEs leading to discontinuation was 4.5-9.7% and SAE incidence was 7.1-11.7%. Basal cell carcinoma was reported in 7 patients (0-1.4%) and elevated alanine aminotransferase was reported in 36 (3.3-11.0%) pts. In TRANSFORMS and its extension, 772 of 1292 pts completed up to 4.5 y. AE rates were 92.2-96.6% across treatment groups; nasopharyngitis (30.5-31.8%), lymphopenia (14.6-22.4%), and headache (15.5-22.8%) were most common. Incidence of AEs leading to discontinuation was 7.8-16.7% and SAE incidence was 12.1-21.3%. There were 35 total cases (2.7-4.8% across treatment groups) of herpes zoster infection. Macular edema occurred in 4 pts; breast cancer occurred in 3 pts. There were no chronic effects on heart rate or atrioventricular conduction across the 3 studies.
Conclusions: With long-term dosing of up to 7 y, fingolimod was well tolerated with no new safety concerns in pts with relapsing MS.