The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C

Authors


  • Potential conflict of interest: The authors disclose the following financial relationships. S.Z. has been a clinical investigator and/or consultant for Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, iTherX, Merck & Co., Novartis Pharmaceuticals, Pharmasset, Roche/Genentech, Santaris Pharma A/S, Tibotec Pharmaceuticals, Transgene, and Vertex Pharmaceuticals. P.B. has been a consultant and invited speaker for Janssen Pharmaceuticals, Roche, Schering-Plough Corporation, Merck & Co., Gilead Sciences, and Novartis Pharmaceuticals. K.A. has received grant support from Gilead Sciences, Roche, and Astellas Pharma and has been a consultant and speaker for Gilead Sciences, Merck Sharp & Dohme, Janssen Pharmaceuticals, Abbott Pharmaceuticals, GlaxoSmithKline, Roche, Astellas Pharma, Novartis Pharmaceuticals, and Bristol-Myers Squibb. P.M. has received grant support, served as a speaker, and/or participated as an investigator for Roche, Schering Plough, Gilead, Bristol-Myers Squibb, Vertex Pharmaceuticals, Novartis Pharmaceuticals, Pharmasset, Tibotec Pharmaceuticals, MSD, Boehringer Ingelheim, Abbott Laboratories, Pfizer, and Echosens. D.S. has been a clinical investigator for Gilead Sciences. H.K. has been a consultant for and/or received honoraria for speaking engagements from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Roche, and Tibotec Pharmaceuticals. C.M. has been a consultant for Janssen Pharmaceuticals, adviser for Janssen Pharmaceuticals and Merck Sharp & Dohme, speaker for Bristol-Myers Squibb, Janssen Pharmaceuticals, and Merck Sharp & Dohme, and received research grants from Roche and Merck Sharp & Dohme. J.-P.Z. has been a consultant and speaker for Merck & Co., Roche, Janssen Pharmaceuticals, Bristol-Myers Squibb, and Gilead Sciences. Y.H. has served as a consultant for Gilead Sciences, Roche, Merck & Co., Ipsen, Helsinn, and Johnson & Johnson Pharmaceuticals, a clinical investigator for Gilead Sciences, Novartis, Merck & Co., Tibotec Pharmaceuticals, Boehringer Ingelheim, Roche, and GlaxoSmithKline, and received grants from GlaxoSmithKline, Roche, Merck & Co., and AstraZeneca. M.P.M, has received grant support, consulting fees or honoraria, and support for travel from Merck & Co., consultant fees from Roche, Bristol-Myers Squibb, Gilead Sciences, Boehringer-Ingelheim, Novartis Pharmaceuticals, Tibotec Pharmaceuticals, Vertex Pharmaceuticals, GlaxoSmithKline, and Merck & Co., grants from Roche, Gilead Sciences, Novartis Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb, and Merck & Co., and payment for development of educational presentations from Merck & Co., Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Gilead Sciences. G.F. has received personal and institutional funding from Gilead Sciences, Roche, Bristol-Myers Squibb, Merck & Co., Chugai Pharma, and GlaxoSmithKline. H.M., S.A., S.K., D.O., and J.G.M. are current or former employees of Gilead Sciences.

  • This trial was supported by Gilead Sciences.

Abstract

Tegobuvir (GS-9190), a non-nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS-9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS-9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg-IFN) alpha-2a and RBV, was assessed in a phase II, randomized, open-label trial. Treatment-naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice-daily (BID) and GS-9256 75 mg BID (n = 16), tegobuvir and GS-9256 plus RBV 1,000-1,200 mg daily (n = 15), or tegobuvir and GS-9256 plus Peg-IFN alpha-2a (180 μg once-weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg-IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5-log10 increase in HCV RNA from nadir or <2-log decrease at day 5, initiated Peg-IFN/RBV immediately. Median maximal reductions in HCV RNA were −4.1 log10 IU/mL for tegobuvir/GS-9256, −5.1 log10 IU/mL for tegobuvir/GS-9256/RBV, and −5.7 log10 IU/mL for tegobuvir/9256/Peg-IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS-9256, 38% (5 of 13) receiving tegobuvir/GS-9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG-IFN/RBV. The addition of Peg-IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups. Conclusion: In genotype 1 HCV, adding RBV or RBV with Peg-IFN provides additive antiviral activity to combination therapy with tegobuvir and GS-9256. (HEPATOLOGY 2012)

Ancillary