Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor

Abstract

EDP-239, a potent and selective hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor developed for the treatment of HCV infection, has been investigated in vitro and in vivo This study sought to characterize genotypic changes in the HCV NS5A sequence of genotype 1 (GT1) replicons and to compare those changes to GT1 viral RNA mutations isolated from clinical trial patients. Resistance selection experiments in vitro using a subgenomic replicon identified resistance-associated mutations (RAMs) at GT1a NS5A amino acid positions 24, 28, 30, 31, and 93 that confer various degrees of resistance to EDP-239. Key RAMs were similarly identified in GT1b NS5A at amino acid positions 31 and 93. Mutations F36L in GT1a and A92V in GT1b do not confer resistance to EDP-239 individually but were found to enhance the resistance of GT1a K24R and GT1b Y93H. RAMs were identified in GT1 patients at baseline or after dosing with EDP-239 that were similar to those detected in vitro Baseline RAMs identified at NS5A position 93 in GT1, or positions 28 or 30 in GT1a only, correlated with a reduced treatment response. RAMs at additional positions were also detected and may have contributed to reduced EDP-239 efficacy. The most common GT1a and GT1b RAMs found to persist up to weeks 12, 24, or 48 were those at NS5A positions 28, 30, 31, 58 (GT1a only), and 93. Those RAMs persisting at the highest frequencies up to weeks 24 or 48 were L31M and Q30H/R for GT1a and L31M and Y93H for GT1b. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.).

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

HCV RNA IU/ml log10 change from baseline plotted over time (hours) for patients with baseline Q30, Y93, or M28 RAMs. Results for individual patients with baseline RAMs are represented by solid lines, and those for patients without Y93 or Q30 (GT1a only) RAMs are averaged by dose and represented by dotted lines. All dose cohort averages represent an n of 2, except the 10-mg dose in panel D, which represents a single patient. Error bars represent the standard deviation for each time point and dose. Results for GT1a patients are illustrated in panels A, B, and C, and results for GT1b patients are illustrated in panel D. The mutation and its percent frequency at baseline is indicated for each patient. (A) Impact of baseline M28V RAMs on EDP-239 potency. The viral population of the patient with the M28V mutation (43%) also expressed an E62V mutation (25%). (B) The patient with Q30H/R/L RAM (71%) also expressed K24N/R/S (7%), M28T (90%), and F36L (99%) mutations; the patient receiving a 10-mg dose also expressed a K24R mutation (4%); both patients in the 200-mg dose cohort without Q30 or Y93 RAMs expressed the M28V mutation (>29%). (C) The patient receiving a 10-mg dose and with a Y93F RAM also expressed an M28V mutation (23%), as did both patients receiving a 10-mg dose without baseline Q30 or Y93 RAMs. (D) Effect of baseline Y93 mutations on GT1b viral RNA reduction.