Influenza viruses are a major health threat that causes a great economic burden worldwide. Preexisting or rapidly emerging resistance to antiviral therapeutics further worsens the situation. For the long-standing demand for an improved influenza therapy, EIDD-2801, an isopropyl ester prodrug of the ribonucleoside analog N4-hydroxycytidine (NHC, EIDD-1931) was created, which demonstrated a broad anti-influenza virus activity in cultured cells and mice. 

Pharmacokinetic profiling proved EIDD-2801 to be orally bioavailable in ferrets and nonhuman primates. When given as oral therapy to the influenza virus-infected ferrets, it showed a reduction in group pandemic 1 and group 2 seasonal influenza A shed virus load along with ameliorating fever, airway epithelium histopathology, and inflammation, while postexposure prophylactic dosing resulted in sterilization. 

Lethal viral mutagenesis was proven to be the underlying mechanism of activity by deep sequencing and also indicated a protective barrier for the development of viral resistance. low nanomolar Inhibitory concentrations were found against influenza A and B viruses in disease-relevant well-differentiated human air-liquid interface airway epithelia. When the antiviral efficacy and cytotoxicity thresholds were investigated with the pharmacokinetic profiles in human airway epithelium models, a therapeutic window >1713 was found along with dosing parameters needed for efficacious human therapy. These data support the clinical use of EIDD-2801 as monotherapy for seasonal and pandemic influenza virus infections. 

Source- Science Translational Medicine, 2019; 11(515). DOI: 10.1126/scitranslmed.aax5866