Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

Abstract

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3−7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350−400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment.

Oral administration of obeldesivir protects nonhuman primates against Sudan ebolavirus

“…ns, not significant. evaluation, a pharmacokinetics study performed at the same 100 mg/kg dose level in uninfected macaques yielded anticipated, dose-normalized exposures consistent with those recently published (25). Of note, the daily GS-441524 plasma area under the curve from time zero to 24 hours [AUC (0-24 h) ] exposure values with the once-daily 100 mg/kg ODV dose evaluated in this NHP study are expected to be similar to those after the 350-mg twice-daily human dose.…”

“…The higher EC 50 values of ODV (1.89 to 4.16 μM) relative to those of RDV (0.01 to 0.05 μM) against filoviruses (Table 1) suggest that metabolism of ODV to GS-443902 may be less efficient than the metabolism of RDV in Huh7 cells. This phenomenon has also been observed in A549-hACE2 lung carcinoma and primary normal human bronchial epithelial (NHBE) cell cultures infected with SARS-CoV-2 ( 25 ).…”

“…Clearly, there is a need for oral antivirals to better control and manage filovirus outbreaks. Recently, the discovery of obeldesivir (ODV), an oral alternative to parenterally administered RDV, was described ( 25 ). ODV is an isobutyl ester prodrug of the same parent nucleoside (GS-441524) as that contained in RDV, with enhanced oral bioavailability relative to GS-441524 itself.…”

“…ODV is hydrolyzed presystemically to GS-441524, which is then converted within cells to its active triphosphate metabolite (GS-443902) ( 26 , 27 ). GS-443902 is an adenosine triphosphate (ATP) analog that inhibits RNA-dependent RNA polymerases across a broad spectrum of RNA viruses ( 25 , 28 ).…”

“…Previous studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed that oral treatment of mice with ODV reduced viral load and prevented lung pathology ( 29 ). Oral ODV was also efficacious against SARS-CoV-2 in African green monkeys ( 25 ) and is presently in phase 3 trials for COVID-19 ( 30 ). In this work, we report on the in vitro antiviral activity of ODV against filoviruses and demonstrate the postexposure protective efficacy of ODV in the cynomolgus monkey model of SUDV infection.…”