The Effect of Fingolimod on Four Measures of Disease Activity in Patients with Relapsing–Remitting Multiple Sclerosis: A Meta-Analysis of the Phase 3 Freedoms Trials

Background: In individual trials significant benefits of fingolimod 0.5 mg versus (vs) placebo were reported for annualized relapse rate (ARR), MRI lesion activity and brain volume loss (BVL) in patients with relapsing–remitting multiple sclerosis (RRMS), with significant improvements in confirmed disability progression (CDP) in FREEDOMS and numerical improvements in FREEDOMS II. A meta-analysis can test the homogeneity of the treatment effect across trials.

Objectives: To determine the consistency of the treatment effect of fingolimod across the 2-year, randomized, placebo-controlled FREEDOMS and FREEDOMS II trials in patients with RRMS.

Methods: The post-hoc analysis included the intent-to-treat populations from FREEDOMS and FREEDOMS II; results are reported for fingolimod 0.5 mg (approved dose (N=783) vs placebo (N=773). Both ARR and new/enlarging T2 lesions were analyzed using negative binomial regression, BVL in an analysis of covariance, and CDP (confirmed at 6 months) with a Cox proportional hazards model; CDP was an increase in EDSS score of ≥1.5 if score at baseline (BL)=0, of ≥1.0 if BL=0.5–5.0, and of ≥0.5 if BL≥5.5. All statistical models included a treatment-by-study interaction.

Results: Compared with placebo in the pooled population, fingolimod 0.5 mg was associated with a 52% reduction in ARR (ratio [95%CI]: 0.48 [0.41–0.56]; p<0.0001), 76% reduction in new/enlarging T2 lesions (ratio [95%CI]: 0.24 [0.20–0.29]; p<0.0001), 33% reduction in the rate of BVL (respectively, 0.71 vs 0.48%/year; least-squares mean difference [95%CI]: 0.23 [0.13–0.33]; p<0.0001), and 39% reduction in the risk of CDP (hazard ratio [95%CI]: 0.61 [0.46–0.81]; p=0.0006). For all four endpoints, the treatment effect was consistent between the two studies (no significant treatment-by-study interaction).

Conclusions: Fingolimod was associated with a consistent, significant reduction in disease activity across key measures of inflammatory processes and disease worsening in patients with RRMS.