title: Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin.
abstract: OBJECTIVE
  BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro.
  
  
  METHODS
  In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n=27 treatment-naïve [TN]; n=30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay.
  
  
  RESULTS
  HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log(10), TE 4.2 log(10)) and 800 mg (TN 5.4 log(10), TE 4.5 log(10)). Rapid virological response (RVR; HCV RNA <15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound >1 log(10) from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg.
  
  
  CONCLUSIONS
  BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg.
authors.affiliation: Servise d'Hépato-Gastro-Entérologie et Transplantation, Hôpital Saint Eloi, 80 Avenue Augustin Fliche, 34295 Montepellier, France. dom-larrey@chu-montpellier.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Victor
authors.initials: V
authors.lastname: de Ledinghen
authors.forename: Christian
authors.initials: C
authors.lastname: Trepo
authors.forename: Tilman
authors.initials: T
authors.lastname: Gerlach
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Zarski
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arastéh
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.forename: Nektarios
authors.initials: N
authors.lastname: Dikopoulos
authors.forename: Marcus
authors.initials: M
authors.lastname: Schuchmann
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
authors.forename: Katherine
authors.initials: K
authors.lastname: Wu
authors.forename: Nasri
authors.initials: N
authors.lastname: Abdallah
authors.forename: Birgit
authors.initials: B
authors.lastname: Girlich
authors.forename: Joseph
authors.initials: J
authors.lastname: Scherer
authors.forename: Frank
authors.initials: F
authors.lastname: Berger
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Wulf
authors.initials: W
authors.lastname: Böcher
authors.forename: Jürgen
authors.initials: J
authors.lastname: Steffgen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a