Characterization of HCV resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3/4A protease inhibitor.

Background: Voxilaprevir (VOX; GS-9857) is a pangenotypic HCV NS3/4A protease inhibitor (PI) with potent antiviral activity against HCV genotypes (GTs) 1-6 and improved coverage of GT1 NS3 resistance-associated substitutions (RAS) associated with other HCV Pls. In a 3-day Phase Ib monotherapy study in patients infected with HCV GT1a, 1b, 2, 3 and 4, VOX was well-tolerated and resulted in maximal mean viral load reduction >3 log(10) IU/ml at the 100 mg dose across all genotypes evaluated. This report characterizes the HCV NS3 RAS in the study. Methods: The NS3 gene was amplified and successfully deep sequenced using MiSeq for 66 patients at baseline and 61 patients post-baseline using 15% and 1% assay cutoffs. Results: With a 15% assay cutoff, pretreatment HCV NS3 RAS were present in the HCV of 38 0 /0 (9/24) of patients with GT1a and 5% (1/19) with GT3a; there were no pretreatment NS3 RAS present in patients with GT1b (n=6), GT2 (n=7) or GT4 (n=4). In patients with and without pretreatment NS3 RAS, >= 3.4 log(10) mean maximal viral load reductions over 3 days of VOX administration were observed. The majority of patients did not have detectable treatment-emergent NS3 RAS and only 12% (7/53) and 26% (14/53) had emergent NS3 RAS using 15% and 1% cutoffs, respectively. No NS3 RAS were detected in patients with GT2 or GT4. A156T or A156V were the most prevalent emergent NS3 RAS in patients with GT1 a or GT1b infection, but were not observed in patients with GT3 infection. Conclusions: The lack of selection of NS3 RAS in the majority of patients demonstrates a high resistance barrier for VOX.