Preclinical characterization of EGT710, an oral non-peptidomimetic reversible covalent SARS-CoV-2 main protease inhibitor
Abstract EGT710 is an orally bioavailable non-peptidomimetic reversible covalent coronavirus main protease (Mpro) inhibitor with low nM cellular activity against SARS-CoV-2. Twice daily dosing of 10 mg/kg of EGT710 decreased lung viral load in a mouse model of SARS-CoV-2 infection to below the limit of detection. Resistance selection resulted in the emergence of several Mpro mutations, with recombinant viruses containing L50F + E166A substitutions showing the largest shift in potency. Development of a viral kinetics model using viremia data from clinical trials, along with a human physiologically based pharmacokinetic model, predicted efficacy in humans with once daily oral doses of >360 mg. EGT710 displays favorable pharmacokinetic properties and an acceptable in vitro and in vivo safety profile, with human exposures at the recommended clinical dose of 600 mg predicted to be below the no adverse effect level in preclinical toxicology studies. Together, EGT710 has a promising preclinical profile and has completed a Phase I study.
Authors
- Daniel Fuller (ORCID: https://orcid.org/0000-0002-8896-3746)
- Kamal K. Balavenkatraman
- Birte Kalveram
- Hannah J. Yu (ORCID: https://orcid.org/0000-0003-3827-4915)
- Laura Tandeske
- Xuping Xie (ORCID: https://orcid.org/0000-0003-0918-016X)
- Dustin Dovala (ORCID: https://orcid.org/0000-0002-2278-5027)
- Suresh B. Lakshminarayana (ORCID: https://orcid.org/0000-0002-9133-3147)
- Hilmar Schiller (ORCID: https://orcid.org/0000-0002-1026-3985)
- Johanne Blais (ORCID: https://orcid.org/0000-0001-8139-8855)
- Thierry T. Diagana (ORCID: https://orcid.org/0000-0002-8520-5683)
- Barun Bhhatarai (ORCID: https://orcid.org/0000-0002-0109-7487)
- Ioannis Loisios-Konstantinidis (ORCID: https://orcid.org/0000-0003-2586-3577)
- Chaitanya Kurhade (ORCID: https://orcid.org/0000-0002-6139-2461)
- Julien P. N. Papillon (ORCID: https://orcid.org/0000-0002-8952-5289)
- Julia Zack
- Lidiya Bebrevska
- Renée Bergeron (ORCID: https://orcid.org/0000-0001-7757-2531)
- Pei‐Yong Shi (ORCID: https://orcid.org/0000-0001-5553-1616)
- John Yun-Chung Chen
- Scott A. Busby
- Stephanie Moquin (ORCID: https://orcid.org/0000-0002-8696-4315)
- John A. Tallarico (ORCID: https://orcid.org/0000-0002-8040-8422)
- David T. Barkan
- Elizabeth Ornelas (ORCID: https://orcid.org/0000-0002-2629-3644)
- S. Kirk Wright
- Katarina Vulic
- Allison Claas (ORCID: https://orcid.org/0000-0002-4150-6214)
- Christopher R. Sarko (ORCID: https://orcid.org/0000-0003-0492-908X)
- Suzanne Gaudet (ORCID: https://orcid.org/0000-0002-5701-2825)
- Feng Gu (ORCID: https://orcid.org/0000-0002-0045-4403)
- James E. Bradner (ORCID: https://orcid.org/0000-0003-1422-5318)
- Mark Knapp (ORCID: https://orcid.org/0000-0002-5770-7715)
- Zachary Nguyen
- Jing Zou (ORCID: https://orcid.org/0000-0002-4080-0032)
Institutions
- Novartis (Switzerland) (CH)
- Boston Biomedical (United States) (US)
- Novartis (China) (CN)
- Novartis (United States) (US)
- The University of Texas Medical Branch at Galveston (US)
Publication Details
- Journal
- npj Drug Discovery.
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s44386-025-00030-5
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Bill and Melinda Gates Foundation