VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

Abstract

The NS3-4A serine protease of hepatitis C virus (HCV) is essential for viral replication and therefore has been one of the most attractive targets for developing specific antiviral agents against HCV. VX-950, a highly selective, reversible, and potent peptidomimetic inhibitor of the HCV NS3-4A protease, is currently in clinical development for the treatment of hepatitis C. In this report, we describe the in vitro characterization of anti-HCV activities of VX-950 in subgenomic HCV replicon cells. Incubation with VX-950 resulted in a timeand dose-dependent reduction of HCV RNA and proteins in replicon cells. Moreover, following a 2-week incubation with VX-950, a reduction in HCV RNA levels of 4.7 log 10 was observed, and this reduction resulted in elimination of HCV RNA from replicon cells, since there was no rebound in replicon RNA after withdrawal of the inhibitor. The combination of VX-950 and alpha interferon was additive to moderately synergistic in reducing HCV RNA in replicon cells with no significant increase in cytotoxicity. The benefit of the combination was sustained over time: a 4-log 10 reduction in HCV RNA level was achieved following a 9-day incubation with VX-950 and alpha interferon at lower concentrations than when either VX-950 or alpha interferon was used alone. The combination of VX-950 and alpha interferon also suppressed the emergence of in vitro resistance mutations against VX-950 in replicon cells.

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

“…1 This direct-acting antiviral (DAA) recently demonstrated significantly higher efficacy over placebo in combination with peginterferon/ribavirin in randomized Phase 3 trials conducted in patients infected with HCV genotype 1, [2][3][4] and is now approved in the United States and Europe for the treatment of genotype 1 chronic hepatitis in adult patients with compensated liver disease. 5,6 The efficacy of telaprevir-based treatment in patients for whom prior peginterferon/ribavirin therapy had failed was demonstrated in the Phase 3 REALIZE trial, which enrolled prior relapsers, partial responders, and null responders.…”

A software for parameter optimization with Differential Evolution Entirely Parallel method

“…These (Lin et al, 2004;Lin et al, 2006). (F, G) The predicted kinetics and the suppression rate of the viral RNA in comparison with data not used for parameter estimation.…”

“…The experimental data include kinetic curves of the viral RNA suppression at various inhibitor concentrations of the VX-950 and BILN-2061 inhibitors (Lin et al, 2004;Lin et al, 2006). We seek for the set of parameters that minimizes three criteria.…”

Telaprevir-based triple therapy for re-treatment Chronic HCV patients with Genotype 1, including the Null-Response: A single center experience from Turkey

“…Approximately 60% of the patients, infected with hepatitis C virus (HCV) genotype 1 are not achieved sustained virologic response (SVR) by 48 weeks of peg-interferon alpha(PegIFN) combined with ribavirin(RBV) [4]. Telaprevir (TVR) is an orally bioavailable drug for non-structural 3/4A HCV protease inhibition [5]. When TVR is combined with PegIFN plus RBV, sustained virologic response (SVR) rates are increased significantly in patients with treatment experience [6,7].…”