icon-folder.gif   Conference Reports for NATAP  
  AASLD (American Association for the Study of Liver Diseases)
Nov 2-5, 2002, Boston, MA
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1st HCV protease Inhibitor: effective over 2-day study
Reported by Jules Levin
  Today at AASLD Boerhinger Ingleheim researchers, the maker of nevirapine (a non-nucleoside reverse transcriptase inhibitor for HIV), presented for the first time publicly data on study results where HCV+ patients received the HCV protease inhibitor. Patients have chronic HCV, genotype 1, and advanced liver fibrosis. This study found short-term administration of this protease inhibitor had antiviral effect and was well tolerated.
BILN 2061 is a potent and specific inhibitor of HCV serine protease. Itıs a product of rational drug development by Boerhinger Ingleheim. In pre-clinical studies BILN 2061 was orally bioavailable in several animal species. Pre-clinical toxicology data sipport administration of repeated doses in humans, there was no evidence of genotoxicity. The investigators said there is no validated animal model to assess the potential pharmacologic response to BILN 2061.
The aim of this study is to assess the antiviral activity, tolerability, and pharmacokinetics of BILN 2061 given for two days twice a day in patients with chronic genotype 1 HCV-infection, who had advanced liver fibrosis but no cirrhosis (Ishak score 3 or 4).
This is a placebo controlled study (4:1). The BILN 2061 dose is 200 mg twice a day. BILN 2061 is administered in polyethylene-glycol (PEG) 400: ethanol solution. They have not yet formulated the drug in a capsule, so a liquid was used for this study. Direct observed therapy was used. Patients were required to have >50,000 copies/ml (Amplicor); moderate to severe fibrosis: Ishak score 3 or 4 or METAVIR F2 or F3 (if Ishak is not 5). Tomorrow study results will be presented from patients with genotype 1 and chronic HCV, not with advanced fibrosis. No breast feeding and risk of pregnancy was permitted.
Drug or placebo was administered for 2 days with a 10-day follow-up period. Viral load was measured with Cobas Amplicor Monitor v 2.0 (Roche), sensitivity 1500 copies/ml; bDNA v 3.0 (Bayer), sensitivity 600 IU/ml; and TMA (Bayer): sensitivity 50 copies/ml.
Treatment success was defined as a decline in viral load of 1 or more log copies/ml. 10 patients were in study (7 male, 1 female); 2 received placebo and 8 200 mg bid BILN 2061. Average age was 45-50. Most patients were white.
5 of 10 patients had received HCV therapy before. 4 of 8 receiving BILN 2061 had prior treatment: 2 had no response, 1 had breakthrough, 1 relapsed. 1 of 2 patients receiving placebo had treatment.
All 10 patients completed the study. Adherence was 100%. There were no relevant drug-induced changes in vital signs, routine lab findings, or ECG observed.
All patients regardless of genotype had at least a 2 log drop in viral load, 4 patients had at least a 3 log drop. All patients were genotype 1. Following completion of the 2 day study viral load increased in all patients back towards baseline within 1-7 days. At all time points the sensitive TMA assay was positive in all patients.
The investigators decribed BILN 2061 as having good tolerability in 7/8 patients and satisfactory tolerability in 1/8. There was no indication of BILN 2061 induced liver injury, increases in AST or ALT levels not observed.
3/8 patients reported adverse events: diarrhea (1), fatigue (1), headache (1), vasovagal attack (1). 2/8 patients had increased uric acid. All resolved within followup period. There were no deaths or serious adverse events. Further studies are planned.