Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia
- 23 October 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 11 (515)
- https://doi.org/10.1126/scitranslmed.aax5866
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 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.Keywords
Funding Information
- National Institute of Allergy and Infectious Diseases (AI071002)
- National Institute of Allergy and Infectious Diseases (AI119196)
- National Institute of Child Health and Human Development (HD079327)
- Defense Threat Reduction Agency (HDTRA1-15-C-0075)
- Defense Threat Reduction Agency (HHSN272201500008C)
This publication has 42 references indexed in Scilit:
- T-705 (Favipiravir) Induces Lethal Mutagenesis in Influenza A H1N1 Viruses In VitroJournal of Virology, 2013
- VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencingGenome Research, 2012
- Assessment of the efficacy of the neuraminidase inhibitor oseltamivir against 2009 pandemic H1N1 influenza virus in ferretsAntiviral Research, 2011
- The Human Airway Epithelial Basal Cell TranscriptomePLOS ONE, 2011
- The first influenza pandemic of the new millenniumInfluenza and Other Respiratory Viruses, 2011
- Higher Level of Replication Efficiency of 2009 (H1N1) Pandemic Influenza Virus than Those of Seasonal and Avian Strains: Kinetics from Epithelial Cell Culture and Computational ModelingJournal of Virology, 2011
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Can Animal Models of Disease Reliably Inform Human Studies?PLoS Medicine, 2010
- Emergence and pandemic potential of swine-origin H1N1 influenza virusNature, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009