Elsevier

Antiviral Research

Volume 99, Issue 3, September 2013, Pages 214-220
Antiviral Research

Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics

https://doi.org/10.1016/j.antiviral.2013.05.015Get rights and content

Highlights

  • A placebo-controlled dose-ranging phase 1b study of vaniprevir monotherapy.

  • Forty adult patients with genotype 1 chronic hepatitis C virus infection.

  • Mean drop in HCV RNA of 1.8–4.6 log10 IU/ml after 1 week of treatment.

  • Most commonly reported drug-related AEs were diarrhea (n = 5) and nausea (n = 5).

  • Further development of vaniprevir is ongoing.

Abstract

Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >106 IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25 mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log10 IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n = 5) and nausea (n = 5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.

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.

Section snippets

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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