TY - JOUR
T1 - Preclinical profile and clinical efficacy of a novel hepatitis C virus NS5A inhibitor, EDP-239
AU - Owens, Christopher M.
AU - Brasher, Bradley B.
AU - Polemeropoulos, Alex
AU - Rhodin, Michael H.J.
AU - McAllister, Nicole
AU - Peng, Xiaowen
AU - Wang, Ce
AU - Lu, Ying
AU - Cao, Hui
AU - Lawitz, Eric
AU - Poordad, Fred
AU - Rondon, Juan
AU - Box, Terry D.
AU - Zeuzem, Stefan
AU - Buggisch, Peter
AU - Lin, Kai
AU - Qiu, Yao Ling
AU - Jiang, Lijuan
AU - Colvin, Richard
AU - Or, Yat Sun
N1 - Publisher Copyright:
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
PY - 2016/10
Y1 - 2016/10
N2 - 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.).
AB - 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.).
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U2 - 10.1128/AAC.00808-16
DO - 10.1128/AAC.00808-16
M3 - Article
C2 - 27503640
AN - SCOPUS:84992533297
SN - 0066-4804
VL - 60
SP - 6207
EP - 6215
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 10
ER -