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Treating flu, escaping resistance: Influenza viruses can cause severe illness and death. Although vaccines are continuously developed, their efficacy is moderate, particularly in the elderly. Current therapies based on neuraminidase inhibitors are only partially effective and subjected to resistance. Now, Toots et al. developed a drug called EIDD-2801 with anti-influenza virus activity. The authors demonstrated that EIDD-2801 had therapeutic effects in infected ferrets, reducing symptoms and virus load. The treatment was effective against multiple influenza strains in human airway epithelial cultures, and the viruses did not develop pharmacoresistance. The results suggest that EIDD-2801 is a promising candidate for treating seasonal and pandemic influenza. Influenza viruses constitute a major health threat and economic burden globally, frequently exacerbated by preexisting or rapidly emerging resistance to antiviral therapeutics. To address the unmet need of improved influenza therapy, we have created EIDD-2801, an isopropylester prodrug of the ribonucleoside analog N4-hydroxycytidine (NHC, EIDD-1931) that has shown broad anti-influenza virus activity in cultured cells and mice. Pharmacokinetic profiling demonstrated that EIDD-2801 was orally bioavailable in ferrets and nonhuman primates. Therapeutic oral dosing of influenza virus–infected ferrets reduced group pandemic 1 and group 2 seasonal influenza A shed virus load by multiple orders of magnitude and alleviated fever, airway epithelium histopathology, and inflammation, whereas postexposure prophylactic dosing was sterilizing. Deep sequencing highlighted lethal viral mutagenesis as the underlying mechanism of activity and revealed a prohibitive barrier to the development of viral resistance. Inhibitory concentrations were low nanomolar against influenza A and B viruses in disease-relevant well-differentiated human air-liquid interface airway epithelia. Correlating antiviral efficacy and cytotoxicity thresholds with pharmacokinetic profiles in human airway epithelium models revealed a therapeutic window >1713 and established dosing parameters required for efficacious human therapy. These data recommend EIDD-2801 as a clinical candidate with high potential for monotherapy of seasonal and pandemic influenza virus infections. Our results inform EIDD-2801 clinical trial design and drug exposure targets. [ABSTRACT FROM AUTHOR]