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Orally available Hepatitis C Virus (HCV) Protease Inhibitor (BILN 2061, Boehringer Ingelheim Pharma) Demonstrates Potent Anti-viral Activity in Persons Infected with HCV Genotype 1
Written by Mark Sulkowski, MD, Johns Hopkin University School of Medicine
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The results of two studies presented at the 53rd Annual Meeting of the American Association of the Study of Liver Disease (AASLD) provided a stunning glimpse into the future of HCV therapy and shook the foundation of the new 2002 NIH Consensus Statement on the Management of Hepatitis C.
Researcher presented four papers describing the discovery, safety and early antiviral activity of BILN 2061, a serine protease inhibitor (Hepatology Volume 36 October 2002).
Abstract 464. Lamaree and colleagues from BI reported the discovery of a small, selective and potent inhibitor of the NS3 serine protease. The drug, BILN 2061, demonstrated potent in vitro activity and good pharmacokinetics and safety in animal species. Furthermore, BILN 2061 demonstrated low nanomolar inhibition of replication in the replicon cell model system. Based on these data, the drug was selected for further evaluation in man.
Abstract 800. Narjes and coworkers reported on the tolerability and pharmacokinetics of BILN 2061 after oral single doses (5 to 2400 mg) in healthy male subjects. The study evaluated increasing doses of the drug in groups of 8 mean (6 active drug and 2 placebo) and found no serious adverse events. The maximum tolerated dose was 2000 mg since the higher dose was limited by minor intestinal adverse events. The medication was administered in a PEG 400:ethanol solution and demonstrated pharmacokinetics evidence to support twice daily dosing of up to 200 mg with or without food.
Abstract 866. Hinrichsen and colleagues presented the results of the initial phase 1 study of BILN 2061 in 31 patients with HCV genotype 1 infection and minimal liver fibrosis. Subjects were treated with placebo, 25 mg, 200 mg or 500 mg of BILN 2061 given twice daily by mouth for two days with 10 -14 days of follow-up after treatment. The mean age of subjects was 47 years and 48% were HCV treatment naive. The serum HCV RNA level decreased by greater than one (1.0) log10 in 7 of 9 subjects at the 25 mg dose and 8 of 8 subjects at the 200 and 500 mg dose. No differences were noted in the responsiveness of interferon naive patients and those who had previously failed interferon based therapy. HCV RNA levels returned to baseline within 1 - 7 days after stopping the drug. Tolerability was good and no safety issues were identified among the 25 active drug recipients including clinical, laboratory and ECG assessments.
Abstract 563. Benamou and coworkers reported on the safety, tolerability and antiviral effect of BILN 2061 after oral treatment over two day in subjects with HCV genotype 1 and significant liver fibrosis (Ishak stage 3 and 4 but not cirrhosis). In a randomized, double-blind group comparison, 10 patients were treated with BILN 2061 200 mg orally twice daily or placebo for 2 days (8 active drug and 2 placebo). The mean age of the patient was 46 years and 50% were HCV treatment naive. All 8 patients treated with BILN 2061 demonstrated at least a two (2.0) log10 decrease in serum HCV RNA level at the end of the two day dosing period (Cobas Amplicor Monitor v2.0) and 2 patients had a decrease of greater than three (3.0) log10. After stopping therapy, the HCV RNA level returned to baseline in all subjects. No safety issues were identified by analysis of adverse events, vital signs, routine laboratory tests, and ECG.
Phase 2 studies of BILN 2061 for patients with chronic HCV are currently planned in the United States and Europe in early 2003.
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