Potency, safety and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

J Hepatol. 2010 Nov 11. [Epub ahead of print]

Manns MP, Bourlière M, Benhamou Y, Pol S, Bonacini M, Trepo C, Wright D, Berg T, Calleja JL, White PW, Stern JO, Steinmann G, Yong CL, Kukolj G, Scherer J, Boecher WO.

Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Center for Internal Medicine, Hannover, Germany.

Abstract

BACKGROUND AND AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.

METHODS: 34 treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.

RESULTS: In treatment naïve patients, median maximal viral load (VL) reductions during 14 day monotherapy were -3.0, -3.6, -3.7 and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (⩾1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15 to 28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL <25 IU/ml at Day 28 in 3/6, 4/7 and 5/6 patients in the 48, 120 and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in 4 patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.

CONCLUSIONS: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145839 [PubMed - as supplied by publisher]

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