Molnupiravir, first small molecule therapeutic to demonstrate therapeutic efficacy against Venezuelan equine encephalitis virus in the cynomolgus macaque model.

Venezuelan equine encephalitis virus (VEEV) is an emergent arbovirus of major epidemic concern. Associated with periodic outbreaks in Central and South America, VEEV has a high morbidity rate in humans due to a 1:1 clinical-to-subclinical ratio and can cause neurological disease in up to 14% of cases. Concerningly, no FDA-approved vaccines or therapeutics for VEEV exist. Molnupiravir, an isopropyl ester prodrug of β-D-N4-hydroxycytidine, has previously showcased notable antiviral activity against VEEV in vitro and in rodents. While molnupiravir emergency use authorization has been granted for SARS-CoV-2, drug efficacy against VEEV in a translational model of human disease has yet to be investigated. We therefore performed the first study examining molnupiravir efficacy against VEEV in cynomolgus macaques, a non-lethal animal model known to reiterate clinical hallmarks of VEEV human disease. Animals treated twice-daily with 150 mg/kg molnupiravir approximately 8 hours post-VEEV exposure demonstrated improved human-relevant clinical parameters, including reduced viremia, febrile illness, and lymphopenia, as well as diminished histopathological evidence of encephalitis and cerebral RNA persistence. We additionally showcased that the calculated human equivalent dose of molnupiravir (97 mg/kg BID) was insufficient in decreasing viremia or improving clinical parameters. Our study is the first to characterize a small molecule therapeutic as an effective treatment against VEEV in a macaque model accurately recapitulating human VEEV disease [Words: 215].