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.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Conflict of interest statement
Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model.Transl Res. 2020 Apr;218:16-28. doi: 10.1016/j.trsl.2019.12.002. Epub 2019 Dec 25. Transl Res. 2020. PMID: 31945316
Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses.Antimicrob Agents Chemother. 2018 Jul 27;62(8):e00766-18. doi: 10.1128/AAC.00766-18. Print 2018 Aug. Antimicrob Agents Chemother. 2018. PMID: 29891600 Free PMC article.
The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection.Antiviral Res. 2019 Nov;171:104597. doi: 10.1016/j.antiviral.2019.104597. Epub 2019 Sep 5. Antiviral Res. 2019. PMID: 31494195
Influenza Virus: Small Molecule Therapeutics and Mechanisms of Antiviral Resistance.Curr Med Chem. 2018;25(38):5115-5127. doi: 10.2174/0929867324666170920165926. Curr Med Chem. 2018. PMID: 28933281 Review.
Peramivir (BCX-1812, RWJ-270201): potential new therapy for influenza.Expert Opin Investig Drugs. 2002 Jun;11(6):859-69. doi: 10.1517/13543722.214.171.1249. Expert Opin Investig Drugs. 2002. PMID: 12036429 Review.
Cited by 2 articles
Next-generation direct-acting influenza therapeutics.Transl Res. 2020 Feb 4. doi: 10.1016/j.trsl.2020.01.005. Online ahead of print. Transl Res. 2020. PMID: 32088166 Free PMC article. Review.
Analysis of the Potential for N 4-Hydroxycytidine To Inhibit Mitochondrial Replication and Function.Antimicrob Agents Chemother. 2020 Jan 27;64(2):e01719-19. doi: 10.1128/AAC.01719-19. Print 2020 Jan 27. Antimicrob Agents Chemother. 2020. PMID: 31767721 Free PMC article.