946 PK-PD MODELING OF VIRAL KINETICS DURING TREATMENT WITH DEBIO-025 PLUS PEGYLATED INTERFERON ALPHA-2A IN TREATMENT-NAIVE HCV PATIENTS

Poster Session -Saturday, April 25 we demonstrate that our compounds selectively and covalently modify the target residue in genotype 1b as well as in NS3 protease from multiple genotypes.Notably, our compounds also covalently bond to and inhibit clinically relevant drug-resistant NS3 mutant proteins (e.g.R155K).In cell-based assays, covalent silencing leads to potent inhibition of NS3, and, importantly, to prolonged duration of action (>24 h) after brief exposure to our compounds.In contrast, treatment with the reversible inhibitor Telaprevir, resulted in rapid return (~1 h) of protease activity after drug removal.In cell-based assays, this novel class of inhibitors was active against clinically relevant drug-resistant mutants and affords the same significant prolonged inhibition of mutant NS3.Conclusion: Covalent silencing of NS3 protease leads to potent and sustained inhibition of wild type NS3 and clinically relevant NS3 breakthrough mutants.This novel mechanism of action against HCV-P has the potential to impact dosing schedules, emergence of resistance mutations, and treatment options for multiple HCV genotypes.