Remdesivir (RDV) is the first direct-acting antiviral drug that has been FDA-approved for treating COVID-19. Though it has displayed some efficacy in patients with COVID-19, RDV its obligatory intravenous (IV) administration and dose limiting toxicities to the liver and kidney challenges widespread use and prevents dose escalation to potentially improve its efficacy. Structurally, RDV is a nucleotide prodrug of the McGuigan class that is designed for the intracellular delivery of a nucleotide monophosphate analogue, which is then phosphorylated twice to yield the active anti-SARS-CoV-2 nucleoside triphosphate. After carefully analyzing the pharmacokinetic (PK) properties of RDV in pre-clinical species and in humans, we conclude that the McGuigan phosphate prodrug moiety is responsible for the major shortcomings of RDV and that its parent nucleoside, GS-441524, would be the better candidate for COVID-19 treatment. Systematic review of the PK properties of RDV in preclinical species and humans consistently demonstrates the exceedingly short half-life (&lt; 1 h) of RDV in plasma due to premature hydrolysis of the McGuigan phosphate prodrug. As a result, GS-441524 is the dominant metabolite following IV administration of RDV, with a half-life of over 12 hours across all species. Head-to-head comparison between RDV and GS-441524 in SARS-CoV-2 infected cells in vitro demonstrates similar potency by both compounds and superior safety with GS-441524. PK experiments with GS-441524 in model species support its ability to be administered orally. We present novel data on the safety, tolerability, and oral bioavailability of GS-441524 in pre-clinical species, including various primates. GS-441524 exhibits similar potency as RDV in cell-based models of COVID-19 while demonstrating superior PK properties in vivo. Coupled with its structural integrity, these qualities present GS-441524 as a promising treatment for COVID-19 that could be administered orally and could be dosed higher than RDV while still exhibiting an excellent safety profile.

GS-441524: An oral version of remdesivir for outpatient COVID-19 treatment

ACS Spring Meeting 2021

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