Cardiovascular Evaluation of Etrasimod, a Selective Sphingosine 1‐phosphate Receptor Modulator, in Healthy Adults: Results of a Randomized, Thorough QT/QTc Study

Abstract

AbstractEtrasimod is an investigational, once‐daily, oral, selective sphingosine 1‐phosphate receptor 1,4,5 modulator used as an oral treatment option for immune‐mediated inflammatory disorders. This randomized, double‐blind, placebo‐ and positive‐controlled, parallel‐group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod‐matched placebo on day 1. Group A received once‐daily, multiple ascending doses of etrasimod (2‐4 mg) on days 1‐14 and moxifloxacin‐matched placebo on days 1 and 15. Group B received etrasimod‐matched placebo on days 1‐14 and either moxifloxacin 400 mg or moxifloxacin‐matched placebo on days 1 and 15. The primary analysis was a concentration‐QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration‐QTc analysis predicted placebo‐corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest‐by‐time point mean placebo‐corrected changes in heart rate from time‐matched day −1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were −15.1, −8.5, and −6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo‐corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.