Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C.

Abstract

BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these findings.

• Authors: Markus Reiser, Holger Hinrichsen, Yves Benhamou, Henk W Reesink, Heiner Wedemeyer, Cristina Avendano, Neus Riba, Chan-Loi Yong, Gerhard Nehmiz, Gerhard G Steinmann
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 41 Issue 4 Pg. 832-5 (Apr 2005) ISSN: 0270-9139 [Print] United States
• PMID: 15732092 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• BILN 2061
• Carbamates
• Macrocyclic Compounds
• NS3 protein, hepatitis C virus
• Quinolines
• Serine Proteinase Inhibitors
• Thiazoles
• Viral Nonstructural Proteins

Topics

• Administration, Oral
• Adult
• Carbamates (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Double-Blind Method
• Drug Administration Schedule
• Female
• Genotype
• Hepacivirus (genetics, isolation & purification)
• Hepatitis C, Chronic (drug therapy, metabolism, virology)
• Humans
• Kinetics
• Macrocyclic Compounds (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Male
• Middle Aged
• Pilot Projects
• Prospective Studies
• Quinolines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Serine Proteinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Thiazoles (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Viral Load
• Viral Nonstructural Proteins (antagonists & inhibitors)