Discovery of Voxilaprevir (GS-9857): The Pan-Genotypic Hepatitis C Virus NS3/4A Protease Inhibitor Utilized as a Component of Vosevi®

There has been remarkable progress in the treatment of hepatitis C virus (HCV) infection with the approval of multiple direct acting antiviral (DAA) regimens. Although overall high HCV cure rates are now generally obtained, there are patients who fail the currently approved therapeutics and require a retreatment option. While HCV NS3/4A protease inhibitors (PIs) have proven highly effective for treating genotype (GT) 1 infection, decreased potency against GT2 and/or GT3 along with observed ALT elevation for some PIs has limited the broad utility of this treatment class. Described herein are the discovery efforts resulting in the HCV NS3/4A PI voxilaprevir. Distinct interactions with the conserved NS3 protease catalytic triad were identified that improve GT3 potency and activity against some common resistance variants. Furthermore, multiple parameters were analyzed to determine potential drivers of hepatotoxicity for HCV PIs in the clinic and it was determined that protein adduct formation had a high correlation with clinical ALT elevation. Therefore, structural modifications were made that both improved metabolic stability and reduced protein adduct formation, ultimately resulting in voxilaprevir. Consistent with our optimization strategy, the combination of voxilaprevir with sofosbuvir (NS5B inhibitor) and velpatasvir (NS5A inhibitor) has proven highly effective across genotypes in Phase 3 clinical trials and hepatoxicity has not been observed. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) was approved in 2017 as a pan-genotypic treatment option for individuals who have previously failed DAA regimens and, for some DAA-naive patients, represents a treatment regimen of shortened duration (8 weeks).