Abstract
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.
Highlights
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery
Having determined the plasma pharmacokinetic (PK) profile following oral administration of GS-621763 in ferrets, we examined the effect of oral GS-621763 administered therapeutically against the original SARS-CoV-2 USA-WA1/2020 (WA1/2020) strain and the recently emerged, highly prevalent variants of concern (VOC) P.1 (γ) lineage[18,19]
The efficacy of GS-441524 and GS-621763 was in parallel assessed on well-differentiated primary human airway epithelium cultures grown at the air-liquid interface and apically infected with VOC γ (Fig. 1f–g)
Summary
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS441524. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection. Having determined the plasma pharmacokinetic (PK) profile following oral administration of GS-621763 in ferrets, we examined the effect of oral GS-621763 administered therapeutically against the original SARS-CoV-2 USA-WA1/2020 (WA1/2020) strain and the recently emerged, highly prevalent VOC P.1 (γ) lineage[18,19]
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