Oral STAT6 Inhibitor EPS-3903 Demonstrates Good Preclinical In Vivo Tolerability without Reactive Metabolites or Metabolic/Safety Liabilities 2257506

Introduction Reactive metabolites can lead to idiosyncratic toxicity in humans, and thus their assessments are critical for drug development. EPS-3903 is a potent, selective, potentially best-in-class STAT6 inhibitor for the treatment of type 2 inflammatory diseases including asthma and atopic dermatitis. Here we present the in vitro and in vivo reactive metabolite evaluations and in vivo tolerability in preclinical species. Methods Reactive metabolite assessments were conducted in liver S9, hepatocytes, HepatoPac, and animal plasma across multiple species. Preclinical in vivo tolerability was determined in mice. Results No reactive metabolites or glutathione (GSH) adducts were detected in vitro (including mice, rats, dogs, monkeys, and humans) or in vivo across preclinical species. EPS-3903 exhibits drug-like properties with excellent in vitro-in vivo correlation for the evaluation of reactive metabolites. EPS-3903 was well tolerated in mice at doses up to 250 mg/kg for 8 days with steady-state plasma exposure reaching 918 µg-hr/mL. The steady-state plasma exposure provides a safety margin up to 160-fold over the projected exposure at human efficacious doses. Conclusion EPS-3903 generated no reactive metabolites in vitro or in vivo, minimizing metabolic/safety liabilities in humans. The highly favorable preclinical in vivo tolerability of EPS-3903 supports its development as a potential oral therapeutic for the treatment of allergic diseases including asthma and atopic dermatitis.