title: 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.).
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA cmowens@gmail.com.
authors: Christopher M
authors: CM
authors: Owens
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Bradley B
authors: BB
authors: Brasher
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Alex
authors: A
authors: Polemeropoulos
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Michael H J
authors: MH
authors: Rhodin
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Nicole
authors: N
authors: McAllister
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Xiaowen
authors: X
authors: Peng
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Ce
authors: C
authors: Wang
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Lu
authors: L
authors: Ying
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Hui
authors: H
authors: Cao
authors: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors: Eric
authors: E
authors: Lawitz
authors: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors: Fred
authors: F
authors: Poordad
authors: Elite Research Institute, Miami, Florida, USA.
authors: Juan
authors: J
authors: Rondon
authors: University of Utah, Salt Lake City, Utah, USA.
authors: Terry D
authors: TD
authors: Box
authors: Goethe University Hospital, Frankfurt, Germany.
authors: Stefan
authors: S
authors: Zeuzem
authors: Institute for Interdisciplinary Medicine, Hamburg, Germany.
authors: Peter
authors: P
authors: Buggisch
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Kai
authors: K
authors: Lin
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Yao-Ling
authors: YL
authors: Qiu
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Lijuan
authors: L
authors: Jiang
authors: Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts, USA.
authors: Richard
authors: R
authors: Colvin
authors: ENANTA Pharmaceuticals Inc., Watertown, Massachusetts, USA.
authors: Yat Sun
authors: YS
authors: Or
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002219:Carbamates; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; D014633:Valine; D017361:Viral Nonstructural Proteins; C000621307:EDP-239; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir