Vaccine development has far outpaced antiviral discovery for COVID-19. Hydroxychloroquine was a disaster, and the repurposed remdesivir, which must be administered intravenously, has modest effect when given to hospitalized patients. The situation is unfortunate because antiviral drugs may be used to either prevent infection (prophylactic) or treat infection (therapeutic). A promising antiviral drug candidate is EIDD-2801/MK-4482 which has been shown to block SARS-CoV-2 transmission among ferrets, and more recently, to treat or prevent infection in mice. In both cases the drug is active after oral administration.
EIDD-2801 is a pro-drug of the nucleoside analog N4-hydroxycytidine (NHC) (pictured above). An earlier version of the drug, EIDD-1931, was not effective because of phosphorylation of the 5’-OH in intestinal epithelial cells. Addition of an ester group prevents phosphorylation. After oral uptake, EIDD-2801 enters the blood where the blocking ester is removed. NHC enters cells and is incorporated into RNA chains by the viral RNA-dependent-RNA polymerase. As a consequence, mutations are introduced in the viral genome leading to error catastrophe and loss of viral infectivity. Some years ago NHC was found to be a broadly-acting inhibitor of multiple RNA viruses, including coronaviruses and influenza viruses.
Activity of EIDD-2801 against SARS-CoV-2 has been recently examined in human lung-only mice (LoM). These mice are made by implanting human lung tissue into the back of immune deficient mice. The implants multiply and develop into a lung-like tissue that includes multiple respiratory cell types, alveolar sac structures, and blood vessels. When SARS-CoV-2 is inoculated directly into these lung implants, the virus reproduces primarily in ciliated epithelial cells and alveolar type II pneumocytes. Infection leads to cell death and infectious virus particles are produced.
To determine if EIDD-2801 can prevent infection with SARS-CoV-2, LoM mice were orally administered the drug 24 and 48 hours after infection and every 12 hours thereafter. Virus titers were reduced by 25,000 fold and 96%, respectively. When administered 12 hours before virus infection, and every 12 hours thereafter, virus titers were reduced over 100,000 fold. These observations support therapeutic and prophylactic efficacy of EIDD-2801 when given orally.
Phase 2/3 human trials of EIDD-2801 for treatment of COVID-19 are currently in progress. If shown to be effective, the drug will fill a substantial void in our antiviral armamentarium. It has been known since 2015 that EIDD-2801 inhibits the reproduction of other coronaviruses. One wonders how the trajectory of the COVID-19 pandemic might have been altered had EIDD-2801 been ready for efficacy trials against SARS-CoV-2 in early 2020.