Kappos L, Fox RJ, Burcklen M, et al. - In this multicenter, double-blind, active-comparator, superiority randomized clinical trial, researchers compared the effectiveness of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P ₁) modulator, with teriflunomide, a pyrimidine synthesis inhibitor, approved for the treatment of patients with relapsing multiple sclerosis. Study participants (n = 1,133) were randomized 1:1 to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P ₁ modulators and a follow-up period of 30 days. In this investigation, ponesimod outperformed teriflunomide in terms of annualized relapse rate reduction, fatigue, MRI activity, brain volume loss, and no evidence of disease activity status, but not confirmed disability accumulation. The safety profile was consistent with previous ponesimod safety findings as well as the established profile of other S1P receptor modulators.