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-naïve patients, represents a treatment regimen of shortened duration (8 weeks).
KeywordsGS-9857 HCV Hepatis C virus Hepatotoxicity NS3/4A protease Protein adducts Single tablet regimen SOF/VEL/VOX STR Vosevi Voxilaprevir
The author would like to thank the many individuals who contributed to the discovery and development of voxilaprevir. The author would also like to thank the patients and their families as well as study site staff who participated in the clinical trials of Vosevi.
Compliance with Ethical Standards
Conflicts of Interest James G. Taylor is an employee of Gilead Sciences, Inc.
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.WHO (2017) Global hepatitis report, 2017Google Scholar
- 3.Hedskog C et al (2017) Identification of novel HCV genotype and subtypes in patients treated with Sofosbuvir-based regimens. J Hepatol 66Google Scholar
- 8.Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) [EMA Summary of Product Characteristics] (2017) Gilead Sciences Ireland UC, CarrigtohillGoogle Scholar
- 9.Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) [package insert] (2017) Gilead Sciences, Inc, Foster CityGoogle Scholar
- 15.Caro L, Du L, Huang S, Wenning L, Su J, Hwang P, Valesky R, Gilbert C, Gress J, Klaassen F, Gendrano IN, Brunhofer J, Cooreman M, Huisman J, Mobashery N (2013) Relationship between transaminase levels and plasma pharmacokinetics following administration of MK-5172 with pegylated interferon alfa-2b and ribavirin to GT1 treatment-naive HCV patients. In: Proceedings of the 8th international workshop on clinical pharmacology of hepatitis therapyGoogle Scholar
- 17.Sunvepra (asunaprevir) (2017) Bristol-Myers Squibb Australia Pty Ltd, MulgraveGoogle Scholar
- 18.Zepatier (elbasvir and grazoprevir) [package insert] (2016) Merck & Co., Inc, Whitehouse StationGoogle Scholar
- 19.Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [package insert] (2014) AbbVie, Inc, ChicagoGoogle Scholar
- 28.Goelzer P et al (2012) Coadministration of ritonavir with the HCV protease inhibitor danoprevir substantially reduces reactive metabolite formation both in vitro and in vivo (abstract 796). J Hepatol 56(2):580AGoogle Scholar
- 30.Lin C (2006) HCV NS3-4A serine protease. In: Tan SL (ed) Hepatitis C viruses: genomes and molecular biology. Horizon Scientific Press, NorfolkGoogle Scholar