To assess safety and tolerability of oral ponesimod and teriflunomide in patients with relapsing multiple sclerosis (RMS) in phase 3 OPTIMUM study.

Patients (18-55 years) with RMS were randomized (1:1) to ponesimod 20 mg or teriflunomide 14 mg for 108 weeks. For ponesimod, a 14-day gradual up-titration, starting with 2-mg, was implemented to mitigate potential first-dose cardiac effects associated with S1P-receptor modulators. Safety was assessed based on incidence of treatment-emergent adverse events (TEAEs), AEs of special interest (AESIs), cardiac monitoring and laboratory results.

Of 1131 patients treated (ponesimod: n=565, teriflunomide: n=566), 83.1% and 83.6% patients completed treatment, respectively. Incidence of TEAEs (88.8% vs 88.2%) and serious AEs (8.7% vs 8.1%) were similar. Most common TEAEs in ponesimod vs. teriflunomide groups were increased alanine aminotransferase (ALT) levels (19.5% vs 9.4%), nasopharyngitis (19.3% vs 16.8%), headache (11.5% vs 12.7%), and upper respiratory tract infection (10.6% vs 10.4%). Two deaths were reported in the teriflunomide group. TEAEs leading to treatment discontinuation were 8.7% and 6.0% in ponesimod and teriflunomide groups. Most common AESIs up to end-of-treatment (EOT)+15 days, unless otherwise specified, were hepatobiliary disorders/liver enzyme abnormalities (EOT+1 day) (22.7% vs 12.2%), hypertension (10.1% vs 9.0%), and pulmonary events (8.0% vs 2.7%). ALT increase ≥3×upper limit of normal (ULN) was higher with ponesimod (17.3% vs 8.3%), while ALT increase ≥8×ULN was more frequent with teriflunomide (0.7% vs 2.1%) treatment. Events related to heart rate and rhythm (including hypotension) on Day 1 occurred in 2.1% of ponesimod patients and were neither serious nor led to permanent discontinuation.

Ponesimod’s safety profile was consistent with previous safety observations of ponesimod and the known profile of other S1P receptor modulators.