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The Discovery of Velpatasvir (GS-5816): The Potent Pan-Genotypic Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimens Epclusa and Vosevi®

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HCV: The Journey from Discovery to a Cure

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 32))

Abstract

The initial approval of the single-tablet regimen (STR) Harvoni®, containing the hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitor ledipasvir and the nonstructural 5B protein (NS5B) nucleotide inhibitor sofosbuvir (SOF), provided a major advancement in the treatment of individuals with chronic genotype 1 (GT1) HCV infection. Herein is described the discovery of velpatasvir (VEL, GS-5816), a pan-genotypic NS5A inhibitor with low picomolar activity against GT1–6 HCV and a high resistance barrier. The combinations of SOF/VEL as Epclusa® and SOF/VEL/voxilaprevir (VOX, NS3/4a protease inhibitor) as Vosevi® are the only pan-genotypic STRs for the treatment and cure of HCV infection. Epclusa® is the first approved pan-genotypic STR and affords high cure rates with a single 12-week treatment duration regardless of genotype, cirrhosis status, or the presence of baseline resistance variants. Vosevi® provides high cure rates for GT1–6-infected individuals who have previously failed therapy (96% cure rates for GT1–6 patients who had failed regimens with an NS5A inhibitor or 98% for those who had failed regimens without an NS5A inhibitor). With pan-genotype activity, no need for on-treatment monitoring, and real-world effectiveness comparable to that observed in clinical trials, the safe, simple, and effective STR Epclusa® is an important agent for eradication of HCV infection worldwide.

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Notes

  1. 1.

    Unless otherwise noted, the EC50 values are based on the following replicon constructs for each genotype: 1a = GT1a (strain H77). 1b = GT1b Con-1. 2b = GT2b MD2b-1 NS5A. 3a = GT3a S52 transiently transfected subgenomic HCV replicon. 4a = GT4a ED43. 5a = GT5a SA13 NS5A (9-184) transient chimeric replicons based on GT1b Rluc backbone. 6a = GT6a HK6 stable subgenomic HCV replicon. In these replicons 1a, 1b, 2a, 3a and 4a are stable subgenomic replicon cells; 2aJ6 and 2b are NS5A transient chimeric replicons based on GT2a JFH-1 Rluc. backbone.

  2. 2.

    https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205834s001lbl.pdf. Accessed 10 June 2018.

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Acknowledgment

The author would like to thank the Gilead research and development teams and external clinical investigators who contributed to the discovery and development work described in this chapter and patients and healthy volunteers who have participated in the clinical trials described here.

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  1. Medicinal Chemistry, Gilead Sciences, Foster City, CA, USA

    John O. Link

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  1. John O. Link
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Correspondence to John O. Link .

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

    Michael J. Sofia

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Conflict of Interest: John O. Link 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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Link, J.O. (2019). The Discovery of Velpatasvir (GS-5816): The Potent Pan-Genotypic Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimens Epclusa and Vosevi® . In: Sofia, M. (eds) HCV: The Journey from Discovery to a Cure. Topics in Medicinal Chemistry, vol 32. Springer, Cham. https://doi.org/10.1007/7355_2019_67

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