title: A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4.
abstract: OBJECTIVE
  Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4.
  
  
  METHODS
  Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10.
  
  
  RESULTS
  Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms.
  
  
  CONCLUSIONS
  Samatasvir 25-100mg monotherapy for 3days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.
authors.affiliation: Vince and Associates Clinical Research, Overland Park, KS, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Vince
authors.affiliation: Avail Clinical Research, DeLand, FL, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hill
authors.affiliation: Alamo Medical Research, San Antonio, TX, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: eStudySite, San Diego, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: O'Riordan
authors.affiliation: CRI Lifetree Clinical Research, Salt Lake City, UT, USA.
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Webster
authors.affiliation: CRI Worldwide, Philadelphia, PA, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gruener
authors.affiliation: St. Louis Clinical Trials, St. Louis, MO, USA.
authors.forename: Ricky S
authors.initials: RS
authors.lastname: Mofsen
authors.affiliation: AMPM Research Clinic, Miami, FL, USA.
authors.forename: Abel
authors.initials: A
authors.lastname: Murillo
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Donovan
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: McCarville
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: John Z
authors.initials: JZ
authors.lastname: Sullivan-Bólyai
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Mayers
authors.affiliation: Idenix Pharmaceuticals, Inc., Cambridge, MA, USA. Electronic address: zhou.xj@idenix.com.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002219:Carbamates; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C000597389:samatasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Chronic hepatitis C; Direct-acting antiviral agents; IDX719; NS5A; Pan-genotypic antiviral activity; Pharmacokinetics; Samatasvir