For the phase III multicenter, double-blind, active-comparator, superiority randomized clinical trial «Kappos L, Fox RJ, Burcklen M, ym. Ponesimod Compar...»1 a total of 1133 patients with relapsing multiple sclerosis were randomized. Their median age was 37.0 (18-55) years and 735 patients (64.9%) were women. The primary end point was the annualized relapse rate. Patients were randomized (1:1) to 20 mg of ponesimod or 14 mg of teriflunomide once daily and the placebo for 108 weeks. Of ponesimod and teriflunomide groups, 83.4% and 83.6% completed the trial, respectively.

The relative rate reduction in the annualized relapse rate for ponesimod compared with teriflunomide was 30.5% (0.202 vs 0.290; P < 0.001). The mean difference in Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS) was −3.57 (−0.01 vs 3.56; P < 0.001). The relative risk reduction in combined unique active lesions per year was 56% (1.405 vs 3.164; P <0.001). The reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates were 17% (10.1% vs 12.4%; P = 0.29) and 16% (8.1% vs 9.9; P =0.37), respectively. Brain volume loss at week 108 was lower by 0.34% (–0.91% vs –1.25%; P < 0.001) in the ponesimod group; the odds ratio for NEDA-3 achievement was 1.70 (25.0% vs 16.4%; P < 0.001).

Incidence of treatment-emergent adverse events (502 of 565 [88.8%] vs 499 of 566 [88.2%]) and serious treatment-emergent adverse events (49 [8.7%] vs 46 [8.1%]) was similar for both groups. Treatment discontinuations because of adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]). Dyspnea (6 [1.1%] vs 0), an increased ALT level (5 [0.9%] vs 6 [1.1%]), an increased aspartate aminotransferase level (3 [0.5%] vs 5 [0.9%]), and macular edema (6 [0.9%] vs 0) were the most commonly reported reasons, of which dyspnea and macular edema were more commin in the ponesimod group.

In a double-blind, placebo-controlled, dose-finding phase IIb study «Olsson T, Boster A, Fernández Ó, ym. Oral ponesimo...»2 a total of 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo (n=121) for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient, recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Here only the results for the dose of 20 mg group (n=114) are shown, as it is the dose currently on the market.

The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 20 mg (1.1; RR 0.17; p<0.0001) group compared with placebo (6.2). The mean ARR was 0,4 for ponesimod 20 mg group and 0,5 for the placebo group, the difference was not statistically significant. The risk of forst confirmed relapse decreased by 21 % in the ponesimod 20 mg group as compared with placebo (HR 0.79, 95% CI 0.43 to 1.45). The proportion of patients with ≥ 1 treatment-emergent adverse events (AEs) was similar across ponesimod and placebo groups. Frequently reported AEs with higher incidence in the ponesimod group compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.

Clinical comment: The number of patients in ponesimod 20 mg and placebo groups was quite small, the follow-up time was short and the primary endpoint was MRI and not a clinical parameter.