Vice President Enanta Pharmaceuticals, Inc. Watertown, Massachusetts, United States
Disclosure(s):
Li-Juan Jiang, Ph. D.: No relevant disclosure to display
Introduction/Rationale: 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.
