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

Abstract

EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10 IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10 IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.).

FIG 1

Chemical structure of EDP-239.

FIG 2

Bliss additivity excess for combinations of EDP-239 with simeprevir (protease inhibitor), sofosbuvir (nucleoside inhibitor), alisporivir (cyclophilin inhibitor), or interferon alpha (IFN) in GT1a replicon cells at 95% confidence intervals. Combinations were analyzed using a mathematical model, MacSynergy II. The dose matrix responses represent the difference between experimental and predicted combination effects at each combination concentration. Positive values above the zero plane signify synergy, negative values signify antagonism, and values close to zero signify additivity. The results are an average for four biological replicates of a representative experiment.

FIG 3

Suppression of resistant colony formation by combinations of EDP-239 with sofosbuvir in GT1a replicon cells (A) or alisporivir in GT1b replicon cells (B). Huh1a7 (GT1a) or Huh11-7 (GT1b) cells were seeded on 6-well plates at subconfluence. Compounds were diluted in DMSO and applied as single agents or in combination every 3 days to growth medium containing G418 for approximately 2 weeks. Cells were incubated and continuously cultured with compound until macroscopic colonies were visible and G418-sensitive cells had died. Colonies were subsequently fixed and stained with 1% crystal violet in 70% ethanol.

FIG 4

Mean log₁₀ HCV RNA change from baseline over time by dose cohort for patients infected with GT1a HCV (A) and GT1b HCV (B). A single dose of EDP-239 was given at time zero. The results for one patient in the 200-mg dose cohort were excluded from the mean calculation due to viral RNA levels at <10⁵ IU/ml at baseline.

FIG 5

Maximum reduction in HCV RNA log₁₀ IU/ml by dose cohort for patients infected with GT1a HCV (A) and GT1b HCV (B). The maximum change from baseline in HCV RNA plasma concentrations is plotted for each patient receiving EDP-239 (cohort mean indicated by horizontal bar). In panel A, the results for one GT1a HCV patient receiving 200 mg EDP-239 were excluded from the dot plot and the mean calculation due to viral RNA levels at <10⁵ IU/ml at baseline.