title: Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment.
abstract: BACKGROUND
  BILB 1941 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro.
  
  
  METHODS
  In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0-2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10-450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan assays.
  
  
  RESULTS
  VL decreased by > or =1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued.
  
  
  CONCLUSIONS
  BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.
authors.affiliation: Klinik für Gastroenterologie, Hepatologie and Infektiologie, Universitätsklinik Düsseldorf, Düsseldorf, Germany. erhardt@uni-duesseldorf.de
authors.forename: Andreas
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authors.lastname: Erhardt
authors.forename: Katja
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authors.lastname: Deterding
authors.forename: Yves
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authors.lastname: Benhamou
authors.forename: Markus
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authors.lastname: Reiser
authors.forename: Xavier
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authors.lastname: Forns
authors.forename: Stanislas
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authors.lastname: Pol
authors.forename: José Luis
authors.initials: JL
authors.lastname: Calleja
authors.forename: Susanne
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authors.lastname: Ross
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Spangenberg
authors.forename: Javier
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authors.lastname: Garcia-Samaniego
authors.forename: Michael
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authors.lastname: Fuchs
authors.forename: Jaime
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authors.lastname: Enríquez
authors.forename: Johannes
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authors.lastname: Wiegand
authors.forename: Jerry
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authors.lastname: Stern
authors.forename: Kate
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authors.lastname: Wu
authors.forename: George
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authors.lastname: Kukolj
authors.forename: Martin
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authors.lastname: Marquis
authors.forename: Pierre
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authors.lastname: Beaulieu
authors.forename: Gerhard
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authors.lastname: Nehmiz
authors.forename: Jürgen
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authors.lastname: Steffgen