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 - Funding Information:
We thank the patients for their participation in this study. We acknowledge the ENANTA Pharmaceuticals and Novartis chemistry departments for their compound synthesis contributions. This study was supported by ENANTA Pharmaceuticals, Inc., and Novartis. All authors from Enanta and Novartis were employees of Enanta and Novartis at the time the research was completed. We disclose the following commercial relationships with the indicated entities: Stefan Zeuzem discloses Abbvie, BMS, Gilead, Janssen, and Merck/MSD; Fred Poordad discloses Abbvie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics, Kadmon, Onyx/Bayer, Salix, and Tibotec/Janssen; Peter Buggisch discloses Abbott, AbbVie, BMS, Falk, Gilead, Janssen, Merck, Merz, MSD, Novartis, and Roche; Eric Lawitz discloses AbbVie, Achillion, Regulus, Theravance, Enanta, Idenix, Janssen, Merck and Co., Novartis, Gilead, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Intercept, Nitto Denko, and Salix; and Terry D. Box discloses Gilead, AbbVie, Salix, Bristol-Myers Squibb, Janssen, Merck and Co., Intercept, Idenix, Boehringer Ingelheim, Sundise, and Ikaria. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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 -