Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics
Introduction
An estimated 3% of the world’s population is infected with the hepatitis C virus (HCV), equivalent to 170–200 million patients (Report of a World Health Organization Consultation, 1999). Given the asymptomatic nature of early infection and the slow progression to severe liver disease, it is expected that the prevalence of HCV will peak over the coming decades (Davis et al., 2003, El-Serag, 2004). The former standard-of-care treatment consisted of peginterferon (PEG-IFN) and ribavirin (RBV) which yielded sustained virologic response (SVR) rates of approximately 40% in patients with genotype (GT) 1 HCV infection (McHutchison et al., 2009). More recently, inhibitors of the HCV non-structural (NS) 3/4A serine protease have been shown to improve rates of SVR to 66–79% in treatment-naive patients with GT1 HCV infection (Bacon et al., 2011, Poordad et al., 2011).
The NS3/4A protein contains both serine protease activity and RNA helicase activity essential for viral replication. NS3/4A protease activity is also implicated in viral inhibition of innate immunity, by interfering with the interferon regulatory factor 3 (IRF-3) signaling pathway, which plays an important role in activating intracellular antiviral defense. Therefore, inhibition of NS3/4A effectively reduces viral polyprotein processing and may rapidly restore cellular innate immune responses (De Francesco et al., 2003, Goudreau and Llinàs-Brunet, 2005).
Vaniprevir is a competitive inhibitor of the HCV NS3/4A protease that has shown antiviral efficacy when administered orally to HCV-infected chimpanzees (Olsen et al., 2011). The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and antiviral efficacy of multiple doses of vaniprevir in patients with GT1 HCV infection.
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Study design
This was a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00704184), conducted in accordance with the principles of Good Clinical Practice and approved by the appropriate institutional review boards and regulatory agencies. Patient safety was overseen by an external Data Monitoring Committee, and informed consent was documented prior to enrollment. This study was funded by Merck & Co., Inc.
Participants were admitted to the Clinical Research Unit for the
Baseline characteristics and duration of therapy
This study was conducted at 12 centers in Germany and the United States between July 2007 and August 2008. A total of 165 patients were screened, of whom 40 were randomized, and 39 patients completed 8 days of therapy and 14 days of follow-up (Fig. 1). The most common reasons for screen failure were: regular user of illicit drugs or a history of drug use within 1 year of the study, HCV RNA levels below the minimum required at baseline, and liver biopsy within 3 years of study start unavailable. The
Discussion
Despite the small sample size, vaniprevir demonstrated robust antiviral activity given the substantial reduction in plasma HCV RNA from baseline. In all vaniprevir groups there was an average decrease of ⩾2 log10 IU/ml in HCV RNA relative to baseline at ⩾1 time point during the treatment period. However, doses greater than 25 mg were associated with a more rapid initial decline in HCV RNA and a greater nadir decline from baseline compared with the 25-mg group. The most rapid decrease in HCV RNA
Role of the funding source
This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The study sponsor and the authors were responsible for the study design, protocol, statistical analysis plan, and data analysis. The sponsor performed the statistical analysis. The authors had unrestricted access to the data, were integral to the development of the
Acknowledgement
The authors would like to thank Melanie Anderson for the bioanalytical analysis of PK samples.
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