Antiviral Effect, Safety, and Pharmacokinetics of Five-Day Oral Administration of Deleobuvir (BI 207127), an Investigational Hepatitis C Virus RNA Polymerase Inhibitor, in Patients with Chronic Hepatitis C

Antimicrob. Agents Chemother. October 2013 vol. 57 no. 10 4727-4735

Dominique Larrey^a, Ansgar W. Lohse^b, Christian Trepo^c, Jean-Pierre Bronowicki^d, Keikawus Arastéh^e, Marc Bourlière^f, Jose Luis Calleja^g, Jerry O. Stern^h, Gerhard Nehmizⁱ, Nasri Abdallah^j, Kristi L. Berger^k, Martin Marquis^k, Jürgen Steffgenⁱ and  George Kukolj^k for the BI 207127 Study Group

+ Author Affiliations

ABSTRACT

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log₁₀ (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log₁₀. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

FOOTNOTES

Received 15 March 2013. Returned for modification 2 May 2013. Accepted 9 July 2013.

Address correspondence to Dominique Larrey, dom-larrey@chu-montpellier.fr.

Published ahead of print 15 July 2013

Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00565-13

Source.