3.1.1. FREEDOMS

FREEDOMS was a phase III double-blind, placebo-controlled trial with 1272 patients that demonstrated superior efficacy of FGM in RMS when compared to placebo [93]. Inclusion criteria included a diagnosis of RMS, Expanded Disability Status Scale (EDSS) score ≤5.5, and evidence of active disease over the previous 2 years. The median disease duration was 6.7 years, and median EDSS at baseline was 2.0. Patients were randomized in a 1:1:1 ratio to receive placebo, FGM 0.5 mg, or 1.25 mg once daily. The primary endpoint was annualized relapse rate (ARR) and the main secondary endpoint was time to three-month confirmed disability progression (CDP). Other secondary endpoints included: time to first relapse, change in EDSS score and the MS Functional Composite (MSFC) z-score at baseline compared to 24-months, conventional MRI measurements, drug tolerability, and safety. Because the 1.25 mg dose of FGM did not demonstrate therapeutic superiority to the 0.5 mg dose, it was the latter that received regulatory approval, and for that reason only the data for the 0.5 mg dose are presented.

The ARR was 0.18 for 0.5 mg FGM, and 0.40 for placebo-treated patients (*p* < 0.0001), a relative reduction of 54% in favor of FGM. Time to first relapse was significantly longer in FGM than in placebo-treated patients and more FGM patients remained relapse free over 24-months. Cumulative probability of three months of CDP was 17.7% for FGM and 24.1% for placebo (Hazard ratio 0.70). During the 24-month study period, EDSS score and MSFC z-scores remained stable in the FGM-treated group and minimally worsened in the placebo group. FGM treatment was associated with a significant relative decrease in the number of new or enlarging T2 lesions (74%), gadolinium-enhancing (Gd+) lesions (79%) and a relative reduction in brain volume loss (36%), all MRI comparisons being significant at 24 months (*p* < 0.001).
