Early switch to fingolimod reduces rates of severe relapses over the long term: Post hoc analysis from the FREEDOMS, FREEDOMS II, and TRANSFORMS studies

Abstract Background : Relapse frequency is often correlated with the prognosis of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), relapses vary in severity and may affect activities of daily living, require steroid intervention, or warrant hospitalization. Incomplete recovery from relapses results in increasing disability. In 3 pivotal phase III studies of fingolimod (FREEDOMS, FREEDOMS II, and TRANSFORMS), the frequency of overall and severe relapses was significantly reduced in patients with RRMS treated with fingolimod compared with placebo or intramuscular interferon β-1a (IFN β-1a). The objective of this study was to report the effect of fingolimod on relapse severity and associated healthcare utilization in patients with RRMS. Methods : This is a post hoc descriptive analysis of data from the pooled placebo-controlled FREEDOMS/FREEDOMS II studies and from the active-comparator TRANSFORMS study. Patients were analyzed under 2 groups: those initially randomized to receive fingolimod 0.5 mg and who continued fingolimod throughout the core and extension study (continuous group), and those who initially received placebo or IFN β-1a during the core phase and switched to fingolimod during the extension phase (switch group). Annualized relapse rate (ARR) was estimated for severe relapses (defined as Expanded Disability Status Scale increase of >1 point, or >2-point change in 1 or 2 Functional Systems, respectively, or >1-point change in >4 Functional Systems). ARR was also estimated for relapses that affected activities of daily living, required steroid use, or hospitalization. Results : In the pooled FREEDOMS/FREEDOMS II extensions, the continuous group showed sustained reductions in the proportion (core: 15.8% and extension: 9.3%) and in ARR over 4 years (0.032 and 0.015) for severe relapses, in relapses requiring steroids (0.149 and 0.123), hospitalization (0.049 and 0.039) and relapses affecting activities of daily living (0.155 and 0.112). In the TRANSFORMS extension, similar reductions were observed in the continuous group for the proportion of severe relapses (core: 11.8% and extension: 9.8%). ARR remained low over 2 years for severe relapses (0.024 and 0.018), relapses affecting activities of daily living (0.112 and 0.109), relapses requiring steroids (0.156 and 0.161) and hospitalization (0.027 and 0.033). Results in the FREEDOMS/FREEDOMS II and TRANSFORMS extensions for the switch group were similar. In the TRANSFORMS extension, the proportion of severe relapses were 18.0% (core) and 11.1% (extension); there were significant reductions in ARR for severe relapses (core: 0.079 and extension: 0.029), relapses requiring steroids (0.366 and 0.232), hospitalization (0.092 and 0.055), and relapses affecting activities of daily living (0.285 and 0.144) (all p Complete recovery was reported for the majority of relapses during the core and extension phases in both the continuous and switch groups (pooled FREEDOMS/ FREEDOMS II: continuous 59.7%–65.5% and switch 64.9%–67.7%; TRANSFORMS: 72.1%–80.0% and 65.4%–70.8%). Conclusions : In patients with RRMS, the frequency of severe relapses and relapse severity remained low in the continuous fingolimod group over a period of 4 years. Reductions in the proportion of severe relapses post switch from IFN β-1a or placebo to fingolimod underscore the clinical benefit and the relevance of an early switch to fingolimod.