539. Efficacy in Multiple SARS-CoV-2 Animal Models Supports Phase 3 Dose Selection for Obeldesivir
Authors: Pitts Jared , Babusis Darius , Humeniuk Rita , Martinez David , Cox Robert M , Schäfer Alexandra , Riola Nicholas C , Feng Joy , Du Pont Venice , Anoshchenko Olena , Vermillion Meghan , Abdelghany Mazin , Hyland Robert H , Girish Sandhya , Sheahan Timothy P , Plemper Richard K , Baric Ralph S , Cihlar Tomas , Llewellyn Joe , Winter Helen , Bannister Roy , Subramanian Raju , Mackman Richard L , Bilello John P 
Published: November 2023

Abstract

Background
Remdesivir (RDV, Veklury) is the first FDA-approved direct-acting antiviral treatment for COVID-19. While RDV requires IV administration, obeldesivir (ODV, GS-5245) is an oral prodrug of GS-441524, the parent nucleoside of RDV, designed for effective oral delivery. ODV is being tested in two Phase 3 clinical studies for outpatient treatment of COVID-19.

Methods
In vitro ODV activity against SARS-CoV-2 was assessed in A549-hACE2 cells. In vivo therapeutic efficacy of oral ODV was evaluated in mouse, ferret, and African Green Monkey (AGM) SARS-CoV-2 models. GS-441524 pharmacokinetics (PK) following ODV oral administration was assessed in animals and in a Phase 1 study in humans.

Results
ODV is a potent inhibitor of SARS-CoV-2 in vitro (EC50 = 1.9 µM) and showed 2- to 7-fold increased GS-441524 oral bioavailability in multiple animal models compared to parent GS-441524. Oral ODV reduced infectious lung viral loads by 2.8 log10 plaque forming units (pfu)/g tissue and ameliorated viral pathophysiological effects in a pathogenic mouse model of SARS-CoV-2 when dosed at 10 mg/kg twice daily beginning 12 hours post infection (hpi). In a SARS-CoV-2 asymptomatic upper airway infection ferret model, oral ODV dosed once daily at 20 mg/kg starting 12 hpi reduced nasal infectious viral titers by &gt;3.3 log10 pfu/mL. Viral transmission among co-housed ferrets was also prevented by ODV. Once daily oral administration of 60 mg/kg ODV in SARS-CoV-2 infected AGMs initiated 8 hpi significantly reduced viral loads in bronchoalveolar lavage and multiple respiratory tissues. Efficacious oral doses of ODV in the mouse, ferret and AGM models were achieved at estimated plasma GS-441524 exposures (AUC0-24h) of 36, 98 and 111 µM·h, respectively. Based on PK data from a Phase 1 dose escalation study in healthy volunteers, an ODV dose of 350 mg twice daily (BID) is expected to achieve plasma GS-441524 exposures (77-103 µM·h) in the efficacious range derived from these animal models.

Conclusion
ODV is a promising investigational oral COVID-19 treatment based on its preclinical in vitro and in vivo SARS-CoV-2 efficacy, its oral bioavailability in preclinical species, and its oral PK and safety profile in a Phase 1 trial. Collectively, these data support the 350 mg BID dose for the ongoing Phase 3 clinical trials.

Disclosures
Jared Pitts, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Darius Babusis, BA, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Rita Humeniuk, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Nicholas C. Riola, BS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Joy Feng, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Venice Du Pont, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Olena Anoshchenko, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Meghan Vermillion, DVM, PhD, Gilead Sciences, Inc.: Employee Mazin Abdelghany, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Sandhya Girish, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Tomas Cihlar, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Helen Winter, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Roy Bannister, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Raju Subramanian, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Richard L. Mackman, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds John P. Bilello, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds