Potent STAT6 Inhibitor EPS-3903 Has Excellent Preclinical Pharmacokinetics Enabling Sustained STAT6 Inhibition with Once-Daily Oral Dosing in Humans 2257175

Abstract

Abstract Introduction STAT6 plays a pivotal role in driving type 2 inflammation. Here we present the preclinical pharmacokinetics of EPS-3903, a potent, selective, and potentially best-in-class STAT6 inhibitor for the treatment of type 2 inflammatory diseases. Methods Metabolic stability was evaluated in liver microsomes and hepatocytes across preclinical species and humans. The in vivo pharmacokinetic studies were conducted in mice, rats and dogs with an intravenous administration of 2.5 or 5 mg/kg or an oral dose of 25 mg/kg. Human PK prediction was based on allometric scaling and in vitro/in vivo DMPK data. Results After oral administration of EPS-3903 at 25 mg/kg, plasma exposures were 141.7 α¼g-hr/mL in mice, 43.0 α¼g-hr/mL in rats, and 174.0 α¼g-hr/mL in dogs, with an oral bioavailability of 96 - 100% using a simple oral formulation of 0.5% methylcellulose. EPS-3903 exhibits drug-like characteristics with very low clearance and excellent in vitro - in vivo correlation, and was stable in human hepatocytes. These favorable in vitro metabolic properties, combined with an excellent in vivo pharmacokinetic profile, support the efficacious, once-daily oral dose projection of 50 — 300 mg with a long half-life of > 16 hours in humans. Conclusion EPS-3903 demonstrates a highly favorable pharmacokinetic profile across preclinical species, supporting sustained STAT6 inhibition and feasibility of once-daily oral dosing in humans. These attributes underscore its potential for the treatment of type 2 inflammatory diseases including asthma and atopic dermatitis. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)