pf-00868554 and Hepatitis-C--Chronic

Filibuvir (PF-868554), being developed by Pfizer, is an orally administered, non-nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase for the potential treatment of chronic HCV infection. An estimated 180 million people worldwide are infected with HCV and at risk of developing chronic liver diseases that can lead to cirrhosis or hepatocellular carcinomas. HCV infection is the main cause of liver transplantation in industrialized nations. Filibuvir is a potent and specific inhibitor of the virally-encoded NS5B polymerase, and inhibited genotype 1 subgenomic HCV replication in the cell-based replicon system. Filibuvir demonstrated a good pharmacokinetic profile and oral bioavailability in preclinical animal studies, which is consistent with twice-daily dosing in humans. In phase I and a IIa clinical trial in treatment-naïve patients infected with genotype 1 HCV, filibuvir monotherapy or in combination with pegylated IFNα2a/ribavirin (the standard of care [SoC] for HCV infection) for up to 4 weeks significantly reduced HCV RNA levels compared with placebo or SoC alone. The incidence and severity of adverse events were similar to SoC and placebo. At the time of publication, phase I pharmacokinetic clinical trials were ongoing in healthy volunteers and a phase IIb clinical trial was assessing filibuvir in combination with SoC for up to 24 weeks in treatment-naïve patients infected with genotype 1 HCV. Results of this trial will help to characterize the potential of this drug class for the treatment of HCV infections.

Topics: Administration, Oral; Animals; Antiviral Agents; Hepacivirus; Hepatitis C, Chronic; Humans; Nucleic Acid Synthesis Inhibitors; Pyrones; RNA-Dependent RNA Polymerase; Triazoles; Viral Nonstructural Proteins

Filibuvir (PF-00868554) is an investigational nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural 5B (NS5B) RNA-dependent RNA polymerase currently in development for treating chronic HCV infection. The aim of this study was to characterize the selection of filibuvir-resistant variants in HCV-infected individuals receiving filibuvir as short (3- to 10-day) monotherapy. We identified amino acid M423 as the primary site of mutation arising upon filibuvir dosing. Through bulk cloning of clinical NS5B sequences into a transient-replicon system, and supported by site-directed mutagenesis of the Con1 replicon, we confirmed that mutations M423I/T/V mediate phenotypic resistance. Selection in patients of an NS5B mutation at M423 was associated with a reduced replicative capacity in vitro relative to the pretherapy sequence; consistent with this, reversion to wild-type M423 was observed in the majority of patients following therapy cessation. Mutations at NS5B residues R422 and M426 were detected in a small number of patients at baseline or the end of therapy and also mediate reductions in filibuvir susceptibility, suggesting these are rare but clinically relevant alternative resistance pathways. Amino acid variants at position M423 in HCV NS5B polymerase are the preferred pathway for selection of viral resistance to filibuvir in vivo.

Topics: Antiviral Agents; Base Sequence; Cell Line, Tumor; Cloning, Molecular; Drug Resistance, Viral; Hepacivirus; Hepatitis C, Chronic; Humans; Inhibitory Concentration 50; Methionine; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Pyrones; Replicon; RNA-Dependent RNA Polymerase; Transfection; Triazoles; Viral Nonstructural Proteins; Virus Replication