Early Effect of Fingolimod on Clinical and MRI Outcomes in Relapsing Multiple Sclerosis

Background: Fingolimod is a once-daily sphingosine 1-phosphate receptor modulator approved in the US, European Union, and other countries as first-line treatment for patients with relapsing forms of multiple sclerosis.

Objectives: To evaluate the early clinical and MRI effects of fingolimod at the approved 0.5 mg/d dose during the first 6 months of treatment in the FREEDOMS and FREEDOMS II Phase 3 studies.

Methods: FREEDOMS and FREEDOMS II were 24-month, double-blind, randomized clinical trials, comparing the efficacy and safety of fingolimod vs placebo in patients with relapsing forms of multiple sclerosis. Data from FREEDOMS and FREEDOMS II were analyzed for treatment differences between fingolimod 0.5 mg/d and placebo on relapse and MRI endpoints within the first 6 months. Analyses were conducted on the intent-to-treat population. Prespecified efficacy outcomes up to or at 6 months included: proportions of patients free of confirmed relapse; proportions free of T1 Gd-enhancing lesions, new/newly enlarged T2 lesions, and both T1 Gd-enhancing and new/newly enlarged T2 lesions; mean numbers of T1 Gd-enhancing and new/newly enlarging T2 lesions; and percentage brain volume loss.

Results: In FREEDOMS, Kaplan-Meier (KM) estimates of the percentage of patients free of confirmed relapse receiving fingolimod 0.5 mg vs placebo were 91.5% vs 86.5% at 3 months (P=0.025) and 86.5% vs 77.9% at 6 months (P=0.035). In FREEDOMS II, KM estimates of the percentage of patients free of confirmed relapse on fingolimod 0.5 mg vs placebo were 92.9% vs 87.8% at 3 months (P<0.001) and 87.4% vs 77.9% at 6 months (P<0.001). The proportion of patients receiving fingolimod that was free of T1 Gd-enhancing lesions at 6 months was similar in FREEDOMS and FREEDOMS II (89.6% and 87.6%, respectively) and significantly greater (P<0.001) than in those receiving placebo (62.2 % and 63.4%). Similarly, the proportion of patients free of new/newly enlarged T2 lesions (64.7% and 66.7% with fingolimod vs 38.1% and 42.5% with placebo, P<0.001) and of both T1 Gd-enhancing and new/newly enlarged 2 lesions (65.0% and 66.4% vs 39.4% and 42.3%, P<0.001) was significantly greater with fingolimod, compared with placebo. Fingolimod also reduced the numbers of T1 Gd-enhancing lesions and new/newly enlarged T2 lesions compared with placebo by 85% and 72%. Significant differences in mean number of T1 Gd-enhancing lesions and new/newly enlarged T2 lesions, as well as brain volume loss, were observed at Month 6 and were sustained over 2 years in both trials.

Conclusions: In FREEDOMS and FREEDOMS II, treatment with fingolimod 0.5 mg/d significantly reduced the risk of relapse within 3 months and the development of new focal MRI lesions and brain volume loss by the first study scan at 6 months. These early effects of fingolimod appeared to be sustained for the duration of the trial.