Background: Etrasimod is an oral, potent, next-generation S1P modulator in clinical development for ulcerative colitis.
Methods:In vitro, etrasimod potency and selectivity was assessed at mouse, rat, dog and human S1P receptors in intracellular β-arrestin recruitment and cAMP accumulation assays using S1P receptor-expressing cells. In vivo, etrasimod (1 and 3 mg/kg, until Day 32) was evaluated in a CD4+CD45RBhigh T cell adoptive transfer model in SCID mice. Chronic toxicology studies of etrasimod once daily (QD) were conducted in rats (≤250mg/kg/day for 26 weeks) and dogs (≤15mg/kg/day for 39 weeks). In healthy adults, two randomised, double-blind studies evaluated safety, tolerability and pharmacology of single or repeat etrasimod QD dosing.
Results: Etrasimod is a potent, full agonist at human S1P1 receptors with a mean EC50 value of 6.10nM. It was selective for S1P1, with 24 fold and 4 fold selectivity versus human S1P4 and S1P5, respectively, and no activity at S1P2 and S1P3 (>1000 fold selectivity). Similar results were found in all species tested. In the T-cell adoptive transfer model, etrasimod (3 mg/kg/day) significantly inhibited weight loss and colon inflammation versus vehicle-treated controls. Chronic administration to rats was well tolerated at ≤150mg/kg/day, but 250mg/kg/day showed significant adverse effects, including mortality. Chronic administration to dogs at ≤15mg/kg/day was well tolerated. The no-observed-adverse-effect level (NOAEL) was therefore 150mg/kg/day for rats and 15mg/kg/day for dogs. Based on these study data, human safety margin for a clinically relevant dose of 2mg etrasimod were 1,068-fold and 402-fold for rats and dogs, respectively. In healthy adults, single doses of etrasimod 0.1–3mg were well tolerated; 4 events (3 subjects) of first/second degree atrioventricular block, with/without bradycardia, were reported in the 5 mg cohort. No other clinically significant safety issues were reported. Etrasimod exposure was dose proportional from 0.1–5mg, with a consistent mean terminal t1/2 (30.7–37.4 hours), and no quantifiable levels in urine analysis. With multiple QD dosing for 21 days, no safety concerns were reported and etrasimod was well tolerated at all doses (0.7–3.0mg). Etrasimod plasma exposure accumulation after 21 days was >2-fold versus single dose administration across all doses: Cmax: 2.12–2.72; AUC0–24: 2.33–3.03. Etrasimod produced a dose-dependent, sustained decrease in total lymphocyte count, with the maximal effect at the 2mg dose.
Conclusions: The combined preclinical/clinical safety and pharmacology profile of etrasimod provides rationale for further evaluation of this selective S1P modulator in clinical studies.