Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19

Zhou et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkae122 (date from preprint), NCT04877769

Jan 2024

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Phase 1 study showing effective lung delivery and safety of the oral COVID-19 antiviral candidate bemnifosbuvir (AT-527) at 550mg twice daily. Authors found AT-527 550mg BID achieved sustained antiviral drug levels in lung fluids that exceeded the EC90 target concentration of 0.5μM required to inhibit SARS-CoV-2 replication in human airway cells. Although AT-527 underwent rapid systemic clearance, it demonstrated good lung distribution, and its active metabolite was detected in alveolar macrophages. The 550 mg BID regimen was well tolerated over 2.5 days with mostly mild adverse effects.

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Zhou et al., 8 Jan 2024, United Kingdom, peer-reviewed, 9 authors, study period May 2021 - June 2021, trial NCT04877769 (history). Contact: zhou.xj@ateapharma.com.

This Paper Bemnifosbuvir All

Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19

Xiao-Jian Zhou, Arantxa Horga, Adeep Puri, Lee Winchester, Maureen Montrond, Keith Pietropaolo, Bruce Belanger, Courtney V Fletcher, Janet Hammond

doi:10.1093/jac/dkae122/7665247

Background: Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. Objectives: This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir. Methods: A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days. Results: AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC 90 ) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. Conclusions: The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.

Supplementary data Supplementary Methods are available as Supplementary data at JAC Online.

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Zhou, None

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Direct assessment of drug ' 'disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug ' 'levels at the primary site of SARS-CoV-2 infection are achieved.\n' ' \n' ' \n' ' Objectives\n' ' This Phase 1 study in healthy subjects aimed to assess the ' 'bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of ' 'bemnifosbuvir.\n' ' \n' ' \n' ' Methods\n' ' A total of 24 subjects were assigned to receive bemnifosbuvir twice ' 'daily at doses of 275, 550 or 825\u2005mg for up to 3.5\u2005days.\n' ' \n' ' \n' ' Results\n' ' AT-511, the free base of bemnifosbuvir, was largely eliminated from ' 'the plasma within 6\u2005h post dose in all dosing groups. Antiviral drug levels of ' 'bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550\u2005mg twice ' 'daily. 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