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Characterization of Orally Efficacious Influenza Drug With High Resistance Barrier in Ferrets and Human Airway Epithelia

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Characterization of Orally Efficacious Influenza Drug With High Resistance Barrier in Ferrets and Human Airway Epithelia

Mart Toots et al. Sci Transl Med.

Abstract

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 N 4-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.

Conflict of interest statement

Competing interests: G.R.B., M.G.N. and G.R.P. hold patent 20190022116, “N4-Hydroxycytidine and Derivatives and Anti-Viral Uses Related Thereto”, covering composition of matter and method of use of EIDD-2801 for influenza therapy. This study could affect their personal financial status. All other authors declare no competing interests.

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