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Background

Etrasimod is an oral, potent, next-generation S1P modulator in clinical development for the chronic treatment of ulcerative colitis. Etrasimod was designed to selectively target S1P receptor subtypes 1, 4, and 5 to provide systemic and local immune cell modulation. We present the unique preclinical pharmacology and safety profile of etrasimod.

Methods

The potency of etrasimod at mouse, rat, dog, monkey and human S1P receptors was assessed in intracellular β-arrestin recruitment and cAMP accumulation assays using S1P receptor-expressing cells. Following a conventional panel of safety pharmacology studies, etrasimod was administered by oral gavage to Sprague Dawley rats or Beagle dogs and compared with vehicle control. In acute, single dose studies, the effects of etrasimod (25, 150 or 350 mg/kg) on the central nervous system and respiratory system were evaluated in rats. The acute cardiovascular effects of etrasimod (10, 20 or 40 mg/kg) were assessed in conscious telemeterized dogs. The chronic safety profile of etrasimod was evaluated by administering etrasimod once daily to rats (≤250 mg·kg−1·d−1) for 26 weeks, and to dogs (≤15 mg·kg−1·d−1) for 39 weeks, followed by a 4-weeks, post-dose observation period. Comprehensive toxicokinetic assessments and evidence of reversibility were evaluated in each of the Good Laboratory Practice safety studies.

Results

Etrasimod is a potent, full agonist at the mouse, rat, dog, monkey and human S1P1 receptors with mean half maximal effective concentration (EC50) values from 0.2 to 8.7 nM. Etrasimod was selective for S1P1, with no activity at human S1P2 and S1P3 (>1000-fold selectivity) and 24-fold and 4-fold selectivity versus human S1P4 and S1P5, respectively. Acute administration of etrasimod at ≤350 mg/kg had no effects on the gross behavioural or neurological state of the rats. Similar, acute doses of etrasimod had no effects on respiratory frequency, tidal volume or minute volume in rats. Following administration of etrasimod at 40 mg/kg in conscious telemeterized dogs, transient increases in systolic (11.7%), diastolic (14.2%), and mean arterial pressure (12.4%) were reported, as compared to time-matched control values. No test article-related differences were observed in heart rate, pulse pressure, body temperature, or any ECG parameter at any dose level. The no-observed-adverse-effect level was 40 mg/kg in the dog telemetry model. Chronic administration of etrasimod to rats for 26 weeks was generally well tolerated at ≤150 mg·kg−1·d−1, but at 250 mg·kg−1·d−1, etrasimod had significant adverse effects, including mortality and prolongation of coagulation times. Chronic administration of etrasimod to dogs at ≤15 mg·kg−1·d−1 for 39 weeks was generally well tolerated, with no evidence of morbidity or mortality. Human safety margin estimates relating steady-state systemic exposures from the chronic toxicology studies to a clinically relevant dose of 2 mg etrasimod were 1068-fold and 402-fold for rats and dogs, respectively.

Conclusions

Etrasimod is a potent, full agonist at the S1P1 receptor across a range of species, with selectivity at S1P1 versus the other S1P receptors. Results from preclinical studies indicate an exceptional safety profile with potential therapeutic benefit in the management of ulcerative colitis.

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Copyright © 2017 Crohn's & Colitis Foundation of America, Inc.
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