Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection Michael P. Manns 1,⇑ , Marc Bourlière 2 , Yves Benhamou 3 , Stanislas Pol 4 , Maurizio Bonacini 5 , Christian Trepo 6 , David Wright 7 , Thomas Berg 8 , José L. Calleja 9 , Peter W. White 10 , Jerry O. Stern 11 , Gerhard Steinmann 12 , Chan-Loi Yong 11 , George Kukolj 10 , Joe Scherer 11 , Wulf O. Boecher 12 1 Hannover Medical School, Department of Gastroenterology, Hepatology, and Endocrinology, Center for Internal Medicine, Hannover, Germany; 2 Hopital Saint Joseph, Marseille, France; 3 Hopital Pitie Salpetriere, Paris, France; 4 Hopital Cochin, Paris, France; 5 California Pacific Medical Center Research Institute, San Francisco, CA, USA; 6 Hopital Hotel Dieu, Lyon, France; 7 Central Texas Clinical Research, Austin, TX, USA; 8 Charité Berlin Campus Virchow – Klinikum, Berlin, Germany; 9 Hospital Universitano Puerta de Hierro, Madrid, Spain; 10 Boehringer Ingelheim(Canada) Ltd., Laval, Canada; 11 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 12 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany See Editorial, Pages 1087–1089 Background & 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: Thirty-four 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 À3.0, À3.6, À3.7, and À4.2 log 10 for the 20, 48, 120, and 240 mg groups. VL breakthroughs (P1 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 Peg- IFN/RBV at Days 15–28 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 combina- tion in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four 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. Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction Hepatitis C virus (HCV) infection is a leading cause of chronic hep- atitis, liver cirrhosis, and liver cancer worldwide. Genotype-1 (GT-1) represents the most prevalent and also most difficult-to- treat HCV subtype. Treatment with the current standard-of-care (SOC) i.e. 48 weeks of pegylated interferon alfa (PegIFN) and ribavirin (RBV), leads to a sustained virologic response (SVR) in 40–50% of patients, indicative of the resolution of the infection [1–5]. However, more than 50% of those treated do not respond or relapse. In addition, many patients cannot tolerate interferon and/or RBV-based therapies. Furthermore, SVR rates are much lower for so-called difficult-to-treat populations like patients with decompensated liver cirrhosis, human immunodeficiency virus (HIV)-HCV co-infected patients, post-transplant HCV infection, hemodialysis patients, and others [3]. The HCV protease inhibitor BILN 2061 was the first agent in man to specifically target HCV replication and thus provided the proof-of-concept for directly inhibiting HCV NS3/NS4A prote- ase as a means of suppressing viral replication [6]. This agent showed 3–4 log 10 reductions in HCV RNA within 48 h of treat- Journal of Hepatology 2011 vol. 54 j 1114–1122 Keywords: Hepatitis C virus; Antiviral; Pegylated interferon; Ribavirin; Resistant variants. Received 26 March 2010; received in revised form 18 August 2010; accepted 19 August 2010; available online 11 November 2010 DOI of original articles: 10.1016/j.jhep.2010.12.016,10.1016/j.jhep.2010.11.001. ⇑ Corresponding author. Address: Hannover Medical School, Department of Gastroenterology, Hepatology, and Endocrinology, Center for Internal Medicine, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Tel.: +49 511 532 3305; fax: +49 511 532 4896. E-mail address: Manns.Michael@mh-hannover.de (M.P. Manns). Abbreviations: HCV, hepatitis C virus; GT-1, genotype-1; SOC, standard-of-care; PegIFN, pegylated interferon alfa; RBV, ribavirin; SVR, sustained virologic respo- nse; HIV, human immunodeficiency virus; qd, once-daily; TN, treatment-naïve; TE, treatment-experienced; HBV, hepatitis B virus; LLOQ, lower limit of quanti- fication; LLOD, lower limit of detection; VL, viral load; AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate transaminase; CV%, coefficient of variation. Research Article