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Evaluation of the Anti-HCV Activity and Pharmacokinetics of ATI-0810,
a Novel Inhibitor of HCV Replication
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Reported by Jules Levin
CROI 2010 Feb 16 SF
Todd Parsley*1, L Yang1, and R Buckheit1,2
1ImQuest BioSci, Frederick, MD, US and 2Arisyn Therapeutics, Pittsburgh, PA, US
Background: ATI-0810 is a small molecule inhibitor being developed as a once a day oral therapeutic for the treatment of hepatitis C virus (HCV) infection. Research suggests a novel mechanism of antiviral action involving suppression of viral RNA synthesis.
Methods: ATI-0810 resistant replicon cells have been generated in vitro. Sequence evaluation and sensitivity testing of the resistant replicon cells defined resistance-engendering mutations which were then engineered into parental replicon sequences. The in vitro and in vivo toxicology of ATI-0810 has been performed in tissue culture cells and Fisher rats. The pharmacokinetics of ATI-0810 has been examined in both non-fasted and fasted Fisher rats and fasted beagle dogs. Pharmacokinetic analysis of a nanoparticle formulation of ATI-0810 was examined in mice and rats.
Results: Selection of ATI-0810 resistant replicons resulted in replicons with resistance engendering mutations in NS3 and NS5A. Cell lines harboring a HCV replicon with a single mutation at NS5A C446R were 21-fold less sensitive to ATI-0810. A secondary site mutation at NS3 D168N was also detected. Analysis of HCV RNA accumulation in ATI-0810 treated cells indicated that the 50% reduction in viral RNA occurs between 8 and 24 hours. Differential gene expression revealed no significant alterations in cellular RNA accumulation in the presence of ATI-0810. Toxicology studies in rats yielded a maximal feasible dose of 5000 mg/kg/day and a maximal tolerated dose over a two week period of 620 mg/kg/day. Pharmacokinetic studies showed dose-dependent oral absorption in both rats and dogs and an increase in the half-life and plasma levels of ATI-0810 in non-fasted rats over fasted rats. Nanoparticle formulation resulted in further improvements in oral bioavailability and a prolonged plasma level maintenance of ATI-0810 in both mice and rats.
Conclusion: We hypothesize that ATI-0810 inhibits HCV replication through a novel mechanism of action that involves the disruption of viral replication complexes and processing of the NS5A/5B polyprotein. Disruption of the replication complex is independent of a direct effect on cellular gene expression. ATI-0810 is well tolerated in rats at daily doses up to 620 mg/kg/day over a two week period. Pharmacokinetics of ATI-0810 are greatly improved with a nanoparticle formulation and when dosed orally under non-fasted conditions.
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