Anti
-hepatitis C virus (HCV) drug development has been challenged by a lack of experience with inhibitors inclusive of in vitro, animal model, and clinical study. This manuscript outlines activity and correlation across such a spectrum of models and into clinical trials with a novel selective nonstructural protein 5B (NS5B) polymerase inhibitor, HCV796. Enzyme assays yielded median inhibitory concentration (IC 50 ) values of 0.01 to 0.14 M for genotype 1, with half maximal effective concentration (EC 50 s) of 5 nM and 9 nM against genotype 1a and 1b replicons. In the chimeric mouse model, a 2.02 Ψ 0.55 log reduction in HCV titer was seen with monotherapy, whereas a suboptimal dose of 30 mg/kg three times per day in combination with interferon demonstrated a 2.44 log reduction (P β«Ψβ¬ 0.001 versus interferon alone) Clinical outcomes in combination with pegylated interferon and ribavirin have revealed additive efficacy in treatment naΔ± Β¨ve patients. Abnormal liver function test results were observed in 8% of HCV-796 patients treated for over 8 weeks, resulting in suspension of further trial activity. Conclusion: The RNA-dependent RNA polymerase inhibitor HCV796 demonstrated potent anti-HCV activity consistently through enzyme inhibition assays, subgenomic replicon, and chimeric mouse studies. Strong correlations of outcomes in the mouse model were seen with subsequent clinical trials, including a plateau in dose-related antiviral activity and additive impact from combination therapy with interferon. These outcomes demonstrate the utility of the range of in vitro and in vivo models now available for anti-HCV drug development and support the potential utility of polymerase inhibitors in future combination therapies for HCV treatment. (HEPATOLOGY 2009;49: 745-752.)
H epatitis C virus (HCV) infects an estimated 170 million people across the world, 1 with substantial risk of severe chronic liver disease, cirrhosis, and hepatocellular cancer. 2,3 Standard therapy with pegylated interferon and ribavirin clears virus in only half of those treated, is associated with significant treatment-related morbidity, and is cost-prohibitive in much of the world. 4,5 HCV is the leading indication for liver transplantation across the developed world. Despite intensive effort, no new drugs have been approved for therapy in the last decade. More effective and less toxic anti-HCV therapeutics as well as preventive vaccines are greatly needed. A major challenge with development of anti-HCV drugs has been the lack of in vitro, animal model, and clinical experience with inhibitors. Although correlation exists for interferon, there are limited data for molecules with novel mechanisms. The goal of the current work was to delineate the activity of a selective nonstructural protein 5B (NS5B) polymerase inhibitor in vitro by enzyme assay and in the replicon, in vivo in the chimeric mouse model, and in patients infected with HCV.