667. Preclinical Pharmacokinetic and Pharmacodynamic Characterization of EDP-938, a Novel and Potent NonFusion Replication Inhibitor of Respiratory Syncytial Virus

Abstract

Background

Respiratory syncytial virus (RSV) infection presents a significant health challenge in young children, elderly and immunocompromised patients. To date, there are no effective treatments available. EDP-938 was designed to meet this unmet medical need and is currently in Phase 2 clinical trials. Herein we report its preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties.

Methods

The pharmacokinetics of EDP-938 following single intravenous and oral doses were determined in mice, rats, dogs, and monkeys. In vitro cellular permeability and metabolic stability were assayed using Caco-2 cells and human liver microsomes, respectively. In vivo pharmacodynamic efficacy of EDP-938 was conducted in the African green monkey model, in which animals experimentally challenged with RSV were orally dosed twice daily with 100 mg/kg EDP-938 for 6 days starting 24 hours prior to infection.

Results

EDP-938 was well absorbed in the preclinical species with oral bioavailability values ranging from 27.1% in dogs, 35.4% in mice, 35.7% in rats, and 39.5% in monkeys, after a single oral dose when formulated in 0.5% methylcellulose. EDP-938 showed a moderate in vitro permeability of 3.6 x 10^–6 cm/sec in Caco-2 cells. Based on the outcome of these absorption studies, EDP-938 was projected to have good oral absorption in humans. EDP-938 had low intrinsic clearance of 5 mL/minute/mg in human liver microsomes. Moreover, EDP-938 demonstrated potent antiviral efficacy in an African green monkey model of RSV infection. In untreated monkeys the RSV RNA viral load in the bronchoalveolar lavage fluid peaked at 10⁶ copies/mL on day 5 post-infection, by comparison in animals treated with EDP-938 the viral load was below the limit of detection by day 3 post-infection. The PK/PD modeling suggested that plasma trough concentrations ≥10 × EC₉₀ led to >4-log viral load reduction in EDP-938 treated monkeys.

Conclusion

The favorable preclinical PK and PD properties of EDP-938 support its further clinical development as a novel treatment for RSV infection.

Disclosures

All authors: No reported disclosures.

Session: 68. Novel Antimicrobials and Approaches Against Resistant Bugs

Thursday, October 3, 2019: 12:15 PM