Efficacy evaluation of the S-adenosylhomocysteine hydrolase inhibitor MSD-914 in rhesus macaques (Macaca Mulatta) challenged with Ebola virus by the intramuscular route.

Abstract

Ebola virus (EBOV) causes a severe and often fatal hemorrhagic fever in humans for which effective postexposure countermeasures are lacking. Herein, we describe the evaluation of an S-adenosylhomocysteine hydrolase inhibitor, MSD-914, using mouse and nonhuman primate (NHP) models of lethal EBOV. Mice were completely protected from severe disease and death at doses as low as 0.31 mg/kg/day administered orally. From the pharmacological data and a toxicokinetic study, a predicted protective dose was selected for rhesus macaques (RMs). Surprisingly, orally administered MSD-914 was unable to protect RMs at doses as high as 0.8 mg/kg/day despite providing similar exposure of the drug to the efficacious dose observed in the mouse model.