Research ArticlePotency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection
Introduction
Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, 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], [2], [3], [4], [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 protease as a means of suppressing viral replication [6]. This agent showed 3–4 log10 reductions in HCV RNA within 48 h of treatment in HCV GT-1 patients [7], as well as a smaller but significant activity against GT-2/3 infection [8]. However, the development of BILN 2061 was halted due to ultrastructural cardiotoxic changes observed in animals treated with supratherapeutic doses. The encouraging viral response to this first protease inhibitor, however, has led to the development of several follow-up agents, many of which are now in different stages of drug development. Two developmental protease inhibitors, telaprevir and boceprevir, are now being tested in phase III trials, after successful completion of phase II studies [9], [10], [11]. In these trials, telaprevir is given for 8 or 12 weeks on a background of 24 or 48 weeks of PegIFN/RBV, while boceprevir is given for 24 or 44 weeks in combination with 28 to 48 weeks of PegIFN/RBV. However, both drugs are being given every 8 h or three times per day and have significant side effects including skin rash, anemia, and gastrointestinal symptoms. Therefore, HCV protease inhibitors with improved pharmacokinetics, safety, and tolerability are needed.
Protease inhibitors given as monotherapy also show rapid selection of drug-resistant variants. These variants result from the poor replication fidelity of the virus and are selected due to the pressure placed on the virus. Consequently, combination of a HCV protease inhibitor with PegIFN/RBV is currently required in order to minimize the risk of virologic breakthrough due to resistance [9], [10], [11].
BI201335 is a peptidomimetic HCV-specific protease inhibitor with high in vitro activity against GT-1a and -1b subtypes, with EC50 values of 6.5 and 3.1 nM, respectively. Preclinical and preliminary human pharmacokinetic studies suggested that BI201335 maintains sufficient plasma concentrations at steady-state to allow once-daily (qd) dosing (Boehringer Ingelheim, unpublished data). A multiple rising dose study in volunteers indicated that BI201335 was safe and well tolerated at doses of 20–240 mg qd for 21–28 days (Boehringer Ingelheim, unpublished data). These observations allowed progression to the phase Ib trial (1220.2) reported here.
Section snippets
Study design
This was a randomized, multi-center, multiple rising-dose trial, performed between December 2007 and June 2008 at 16 sites in France, Germany, Spain, and USA. The trial was double-blind and placebo-controlled for groups with treatment-naïve (TN) patients. The trial was conducted in full compliance with the Guidelines of Good Clinical Practice and the Declaration of Helsinki and approved by all competent institutional review boards, ethical committees, and national authorities. All patients gave
Patient disposition and baseline characteristics
In 2007 and 2008, a total of 171 patients were screened: 53 patients were randomized to treatment in this study; 75 patients did not meet the inclusion criteria, 43 patients were entered into later cohorts that will be reported in a separate manuscript. The rate of study completion was high; 52 out of 53 patients randomized to treatment completed the study. The reason for the discontinuation of one subject was the diagnosis of an unexpected pregnancy of his partner representing an exclusion
Discussion
This trial investigated the antiviral activity, safety and pharmacokinetics of BI201335 in 53 patients with HCV GT-1 infection treated with BI201335 ± PegIFN and RBV for 28 days.
When given qd as monotherapy in TN patients for 14 days, 48–240 mg BI201335 qd induced a rapid, dose-dependent decrease in plasma HCV RNA by ⩾2 log10 from baseline in all patients. Maximal VL declines from baseline occurred within 2–3 days of first administration. At the 240 mg qd dose, the median maximal decline from baseline
Financial disclosures
Michael Manns has received grant support, contributed to clinical trials, and is a member of a speaker bureau and/or consulted for Schering Plough, Roche, Merck, Bristol-Myers Squibb, Vertex, Tibotec, Astra/Arrows, Novartis, Human Genome Sciences, Boehringer Ingelheim, and Valeant. Peter W. White, Jerry Stern, Gerhard Steinmann, Chan-Loi Yong, George Kukolj, Joe Scherer and Wulf O. Boecher are employees of Boehringer Ingelheim.
ClinicalTrials.gov identifier: NCT00793793.
Acknowledgments
Editorial assistance was provided by StemScientific, supported by Boehringer Ingelheim.
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