92 SAFETY, TOLERABILITY AND ANTIVIRAL ACTIVITY OF VCH-916, A NOVEL NON-NUCLEOSIDE HCV POLYMERASE INHIBITOR IN PATIENTS WITH CHRONIC HCV GENOTYPE-1 INFECTION

Background: ANA598 is a novel HCV non-nucleoside polymerase inhibitor currently in clinical development for the treatment of hepatitis C. Due to the high potential for developing resistance to any single direct antiviral used as monotherapy in hepatitis C, future therapies for HCV are expected to involve combinations of direct antivirals to increase antiviral potency and suppress viral resistance.The results from in vitro combination studies provide support for future clinical exploration of combination regimens that include ANA598.Methods: Combination studies were conducted using wt Huh7-Luc or M414T-containing 1b dicistronic replicons.Cells were cultured in the presence of compounds for 72 hours using both fixed ratios and checkerboard concentration matrices of test agents.Cultured media from PBMCs treated with the active metabolite of ANA773 were used to evaluate the combination effects of this agent with ANA598.The observed inhibitory activity of two agents in combination was compared to the combined action predicted from the dose responses for individual agents assuming Loewe additivity or Bliss independence.Results using CalcuSyn and internally developed analytical procedures were compared.Results: ANA598 was combined pairwise in vitro with IFN-a, the HCV NS3/4 protease inhibitor Telaprevir, the NS5B nucleoside polymerase inhibitor PSI-6130, or the TLR7 agonist ANA773 (currently in clinical development by Anadys).We have previously demonstrated that there is no overlap in viral mutations conferring resistance to these agents in vitro.Combinations were evaluated in both wt and mutant replicons containing the M414T mutation that confers resistance to palm site non-nucleoside NS5B inhibitors.No cytotoxicity was detected for any of the combinations tested.For each combination evaluated, the antiviral interaction between the compounds was determined to be additive to synergistic. Conclusions:The in vitro combination studies demonstrate that additive to synergistic antiviral effects are observed when ANA598 is combined with other anti-HCV agents having distinct mechanisms of action and nonoverlapping resistance profiles.Such combinations may produce a greater viral load reduction and potentially delay the emergence of drug resistance in vivo.Consequently, appropriately constructed combination regimens may provide clinical benefit by improving response rates and allowing non-responders to current therapies to be treated more effectively.