The virus entry inhibitor ARN-75039 provides therapeutic protection against Lassa virus infection in guinea pigs

family, causes Lassa fever. There are no vaccines available for prevention of Lassa fever, and the primary therapeutic for treatment (ribavirin) has questionable antiviral activity and no formal approval for use. Here, we evaluated ARN-75039, an orally bioavailable broad-spectrum mammarenavirus entry inhibitor, against LASV infection in outbred Hartley guinea pigs exposed to a guinea pig-adapted LASV. ARN-75039 was administered for 14 days either 3 or 7 days postexposure (dpe) to LASV. In the first two studies, once-daily dosing at 3 dpe provided protection against lethal infection. A third study with twice-daily dosing at 7 dpe also achieved protection. Both drug regimens offered 100% protection at the lowest tested doses of 3.75 mg/kg (once-daily administration) or 7.5 mg/kg (twice-daily administration). ARN-75039-treated animals exhibited minimal disease signs and undetectable viremia. These results suggest that ARN-75039, for which a phase 1 human clinical trial has now been completed, may offer robust protection against LASV infection.