A Randomized Trial on the Combined Effect of Ponesimod and Propranolol on Heart Rate, Cardiac Safety, and Pharmacokinetics in Healthy Adults

The objective of this phase 1 study was to evaluate the pharmacokinetics (PK), pharmacodynamics, and cardiac effect following administration of ponesimod (a selective sphingosine-1-phosphate receptor modulator) and propranolol in healthy adults. In treatment period (TP) 1, participants received ponesimod (2 mg). In TP2, if resting heart rate (HR) was ≥ 55 bpm, the ponesimod up-titration regimen was initiated. Participants were randomized to TP2A (placebo plus ponesimod up-titration) or TP2B (80 mg propranolol plus ponesimod up-titration). Concomitant administration resulted in an increased bradyarrhythmic effect on HR versus ponesimod alone. The mean maximum difference in mean hourly HR from time-matched baseline for TP2B compared with TP2A during the first 12 h post-dose was -12.4 bpm. This was observed after the first dose of ponesimod, persisted for the first 4 doses, then decreased to -7.4 bpm post-up-titration. The lowest mean of the HR_nadir in TP2B was 48.9 bpm (95% CI: 46.4-51.3). There was no significant difference in the occurrence of 1st degree AV block between groups and no occurrences of 2nd or higher degree AV block. No clinically relevant changes were observed in the PK of ponesimod or propranolol. Overall, 88.5% of participants experienced ≥ 1 AE during the study. In TP2, the most reported TEAEs (≥ 5%) considered related to ponesimod were fatigue (12 [25.5%]) and dizziness (10 [21.3%]). No deaths were reported. Co-administration of ponesimod with propranolol resulted in a greater HR-lowering effect compared to ponesimod alone, without significant changes in PK parameters or serious cardiac adverse events in healthy adults.