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There is an unmet need for safe and efficacious oral therapies for COVID‐19 with low potential for drug–drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS‐CoV‐2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS‐443902), which acts as an inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first‐in‐human, randomized, placebo‐controlled, phase I study following oral administration of obeldesivir and a phase I, open‐label absorption, distribution, metabolism, and excretion study following oral administration of [14C]‐obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT‐concentration analysis. The exposures to GS‐441524 increased dose proportionally in the 100–900‐mg dose range. GS‐441524 accumulated by 35% after twice‐daily and 12% after once‐daily dosing for 5 days. Dose‐proportional increases in the intracellular concentration of GS‐443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS‐441524 was not significantly altered by food intake. Following oral administration of [14C]‐obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]‐dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS‐441524 was the predominant plasma component (90% of 14C‐area under the concentration–time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice‐daily dosing regimen for further evaluation in phase III studies for COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment., Methods: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60., Results: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function., Conclusions: Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment., Clinical Trials Registration: EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351., Competing Interests: Potential conflicts of interest . M. E. S. received research funding from Gilead Sciences, EMD Serono, AbbVie, Angion, Novartis, Merck, Cabaletta Bio, and Otsuka; served as a scientific advisory board member for Travere, Novartis, Vera Therapeutics, Calliditas, and Mallinckrodt; and served as a data and safety monitoring board member for Alpine Immunoscience. J. R. S. received research funding, consulting fees, and lecture sponsorships from and served on advisory boards for Gilead Sciences, GSK, Janssen-Cilag, Bristol Myers Squibb, ViiV Healthcare, and Merck Sharp & Dohme (MSD). J. D. G. consulted for Gilead Sciences, Eli Lilly, GSK, and Karius; received research support or grants from Gilead Sciences, Eli Lilly, Regeneron, and MSD (Biomedical Advanced Research and Development Authority); and received nonfinancial support from Adaptive Biotechnologies, Monogram Biosciences, and Labcorp (outside the current study). J. P. T. is a consultant for Outset Medical and owns stock and/or stock options in Novo Nordisk A/S. Y. K., J. L., S. R., Y. Z., H. H., R. H. H., A. O., and H. W. are stockholders and employees of Gilead Sciences. R. H. is a former employee and stockholder of Gilead Sciences. H. N. H. received consulting fees from Gilead Sciences. R. L. G. served as a consultant for AbbVie, AstraZeneca, Eli Lilly, GSK, Gilead Sciences, Johnson & Johnson, Roivant Sciences, and Roche Pharmaceuticals; served as a national coordinating primary investigator for Johnson & Johnson; served on an academic steering committee for Roivant Sciences; received from Gilead Sciences a gift in kind to Baylor Scott & White Research Institute to facilitate NCT03383419; owns de minimis stock in AbCellera Biologics; and served as a speaker for Pfizer, outside the scope of coronavirus disease 2019 (COVID-19). D. N. F. served on a Gilead Sciences advisory board, outside the scope of COVID-19, and served as a site primary investigator for clinical trials with Gilead Sciences, Regeneron, and MetroBiotech. R. B. served on a scientific advisory board for AstraZeneca, Bayer, Boehringer Ingelheim, MSD, and Mundipharma; and served as a speaker for AstraZeneca, Bayer, MSD, Mundipharma, and Gilead Sciences, outside the scope of COVID-19. C. B. S. has received research support from Gilead Sciences, MSD, GSK, Takeda, Shire, Janssen, AbbVie, and ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)