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.
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: Jianmin Duan; Gordon Bolger; Michel Garneau; Ma'an Amad; Joëlle Batonga; Hélène Montpetit; François Otis; Martin Jutras; Nicole Lapeyre; Manon Rhéaume; George Kukolj; Peter W White; Richard C Bethell; Michael G Cordingley Journal: Antimicrob Agents Chemother Date: 2012-08-06 Impact factor: 5.191
Authors: Karen L Rigat; Hao Lu; Ying-Kai Wang; Argyrides Argyrou; Caroline Fanslau; Brett Beno; Yi Wang; Jovita Marcinkeviciene; Min Ding; Robert G Gentles; Min Gao; Lynn M Abell; Susan B Roberts Journal: J Biol Chem Date: 2014-10-09 Impact factor: 5.157