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Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

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Cox, Robert | Wolf, Josef | Lieber, Carolin | Sourimant, Julien | Lin, Michelle | Babusis, Darius | Dupont, Venice | Chan, Julie | Barrett, Kim | Lye, Diane | Kalla, Rao | Chun, Kwon | Mackman, Richard | Ye, Chengjin | Cihlar, Tomas | Martinez-Sobrido, Luis | Greninger, Alexander | Bilello, John | Plemper, Richard

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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