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.
Article Details
Authors (29)
Sara C. Johnston
Anthony T. Ginnetti
Nancy A. Twenhafel
Sarah L. W. Norris
Shiying Chen
Josh L. Moore
Christopher W. Boyce
Ondraya M. Frick
Dave N. Dyer
Donald J. Marsh
Stephen C. Stevens
Walter F. Knapp
Kerry L. Berrier
Hui Wan
Gregory C. Adam
Timothy J. Hartingh
Heather L. Esham
Jimmy O. Fiallos
Eugene L. Blue
Willie B. Sifford
Jonathan D. Latty
Harold L. Mills
Nazira A. Alli
Ashley E. Piper
Aimee I. Goodson
J. Matthew Meinig
David B. Olsen
Linda A. Lieberman
Rekha G. Panchal