2. Academic Validation
  3. Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

  • bioRxiv. 2023 Jun 28:2023.06.27.546784. doi: 10.1101/2023.06.27.546784.
David R Martinez 1 2,  Fernando R Moreira 3,  Mark R Zweigart 3,  Kendra L Gully 3,  Gabriela De la Cruz 4,  Ariane J Brown 3,  Lily E Adams 3,  Nicholas Catanzaro 3,  Boyd Yount 3,  Thomas J Baric 3,  Michael L Mallory 3,  Helen Conrad 3,  Samantha R May 3,  Stephanie Dong 3,  D Trevor Scobey 3,  Stephanie A Montgomery 5,  Jason Perry 6,  Darius Babusis 6,  Kimberly T Barrett 6,  Anh-Hoa Nguyen 6,  Anh-Quan Nguyen 6,  Rao Kalla 6,  Roy Bannister 6,  John P Bilello 6,  Joy Y Feng 6,  Tomas Cihlar 6,  Ralph S Baric 3 7,  Richard L Mackman 6,  Alexandra Schäfer 3 7,  Timothy P Sheahan 3 7
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT, 06510, USA.
  • 2 Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT, 06510, USA.
  • 3 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 5 Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 6 Gilead Sciences, Inc, Foster City, CA, USA.
  • 7 Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
PMID: 37425890 DOI: 10.1101/2023.06.27.546784
Abstract

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the Antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as Antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination Antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

Keywords

Antivirals; GS-5245; Paxlovid™; broad-spectrum drugs; nirmatrelvir; nucleoside; obeldesivir; oral antiviral drugs; pandemic preparedness; remdesivir.

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