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Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: A randomized phase II study

Authors


  • Potential conflict of interest: Dr. Manns is on the speakers' bureau of, and serves as a consultant to Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, and Merck; serves as consultant to Boehringer-Ingelheim, Novartis, Tibotec, and Vertex; he has received grant/research support from Roche, Gilead, Novartis, Boehringer-Ingelheim, Bristol-Myers Squibb, and Merck. Dr. Gane has served as an advisor to Novartis, Janssen Cilag, and Gilead. Dr. Rodriguez-Torres consults for Hoffmann- La Roche, Abbott Laboratories, Pharmasset, Akros, Genentech, Bristol-Myers Squibb, Novartis, Merck, Inhibitex, Santaris, and GlaxoSmithKline and has received grant/research support from Vertex, Anadys, Hoffman La Roche, Genentech, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, Vertex Pharmaceuticals, Idera, Pharmasset, Sanofi-Aventis, Merck, Abbott Laboratories, Pfizer, Human Genome Sciences, Gilead, Johnson & Johnson, Zymogenetics, Akros, Scynexis, Santaris, Mochida, Boehringer-Ingelheim, Inhibitex, Idenix, and Siemens. Dr. Stoehr is on the speakers' bureau of Merck and Roche. Dr. Yeh has nothing to disclose. Dr. Marcellin has received grants from and served as investigator, speaker, and expert for Roche, Gilead, Janssen-Tibotec, and Merck; he has served as investigator, speaker, and expert for Bristol-Myers Squibb, Novartis, and Pharmasset; has served as investigator and expert for Vertex and Abbott; an has served as investigator for Boehringer-Ingelheim and Pfizer; and received grants and served as an investigator for Echosens. Drs. Wiedmann, Hwang, Caro, and Lee are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ. Dr. Barnard is an employee of and owns stock in Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ.

Abstract

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3log10 IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. Conclusion: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration. (HEPATOLOGY 2012;56:884–893)

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