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

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Book cover HCV: The Journey from Discovery to a Cure

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 31))

Abstract

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).

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Acknowledgements

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.

Ethical Approval

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

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Gilead Sciences, Foster City, CA, USA

    James G. Taylor

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  1. James G. Taylor
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Correspondence to James G. Taylor .

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Editors and Affiliations

  1. Arbutus Biopharma, Inc., Warminster, PA, USA

    Michael J. Sofia

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Taylor, J.G. (2019). Discovery of Voxilaprevir (GS-9857): The Pan-Genotypic Hepatitis C Virus NS3/4A Protease Inhibitor Utilized as a Component of Vosevi® . In: Sofia, M. (eds) HCV: The Journey from Discovery to a Cure. Topics in Medicinal Chemistry, vol 31. Springer, Cham. https://doi.org/10.1007/7355_2018_61

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