Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection

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

“…12 This less efficient metabolism has also been reported by independent groups and manifests as weaker antiviral activity across different lung cells in vitro compared to 1. 12,24,26 The reduced 2-NTP formation in vitro was also observed in vivo through analyzing lung tissue samples harvested at 24 h from NHPs and ferrets dosed IV with either 2 or 1. 12,24,27 These results suggest that high plasma exposures of 2 are likely necessary to drive sufficient lung 2-NTP formation in vivo to achieve comparable efficacy to 1.…”

“…12,24,26 The reduced 2-NTP formation in vitro was also observed in vivo through analyzing lung tissue samples harvested at 24 h from NHPs and ferrets dosed IV with either 2 or 1. 12,24,27 These results suggest that high plasma exposures of 2 are likely necessary to drive sufficient lung 2-NTP formation in vivo to achieve comparable efficacy to 1. The second challenge was the poor physicochemical properties of 2 including a low apical to basolateral permeability in Caco-2 cells, a 12-fold efflux ratio, and low pH 7 solubility (Table 1).…”

“…Recently, we have reported on the efficacy of 1 compared to IV administered 2 in a SARS-CoV-2 infection model in AGM and observed strong efficacy for the nucleoside 2 at high systemic exposures. 24 The same AGM model was then utilized to determine if efficacious concentrations of 2-NTP in lung tissue could be achieved from systemic exposure to 2 through orally administered 3. Oral treatment with 3 was initiated at 8 h post-infection with 60 or 120 mg/kg doses and then continued daily for 5 days.…”

“…The doses were selected to provide a daily systemic exposure of 2 that bracketed the exposure from IV administered 2 at 20 mg/kg, which demonstrated strong efficacy relative to 1 in the earlier study. 24 The viral loads (genomic RNA and infectious virus titer) were evaluated on bronchoalveolar lavage fluid (BALF), nasal, and throat swab samples, collected on 1, 2, 4, and 6 days post-infection (dpi) (Figure 3). in the BALF at or above the limit of quantification at day 6 post-infection, meanwhile 6 of the 8 vehicle animals had quantifiable infectious viral loads at this time-point (Figure 3A).…”

“…Collectively, these data demonstrate that oral 3 at 60 mg/kg and 120 mg/kg are both highly efficacious at reducing infectious virus and viral RNA loads throughout the upper and lower respiratory tract of AGMs and similarly efficacious to 1. 24 Having established efficacy from oral dosing in AGMs we considered various methods to estimate the human efficacious dose of 3 for the clinic. One human dose estimation method employed Cmax/Ctrough exposures of 2 relative to the in vitro SARS-CoV-2 antiviral EC50 potency of ~ 1-2 µM in Vero E6 cells and primary lung cultures.…”