September 25, 2013

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

Dominique Larreya, Ansgar W. Lohseb, Christian Trepoc, Jean-Pierre Bronowickid, Keikawus Arastéhe, Marc Bourlièref, Jose Luis Callejag, Jerry O. Sternh, Gerhard Nehmizi, Nasri Abdallahj, Kristi L. Bergerk, Martin Marquisk, Jürgen Steffgeni and  George Kukoljk 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

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