Pre-IND Development of an Arenavirus Antiviral

Summary
Arenaviruses comprise a diverse family. Several species are associated with severe
arenaviral hemorrhagic fever (AVHF) in humans that exhibit case-fatality rates as high as
30%. Human infection with arenaviruses typically occurs through contact with materials
contaminated with the excretions of an infected rodent although direct human- to-human
transmission may occur in clinical settings. AVHF resulting from infection with the Old
World arenavirus Lassa is estimated to cause over 300,000 annual infections in Africa, of
which 15-20% of hospitalized patients die while survivors often suffer permanent
sequelae. Similar outcomes are observed with Argentine hemorrhagic fever (AHF), caused
by infection with Junin virus. A prophylactic vaccine has been developed against JUNV,
however, no vaccines are available against Lassa or the other human hemorrhagic fever
arenaviruses and broad-spectrum vaccines effective against both current and emerging
arenaviruses are unlikely to be developed. Ribavirin, the only available antiviral, can be
effective in treating arenavirus infection (particularly with IV administration in the first 6
days), however, there are serious side effects including thrombocytopenia and anemia. Given
the limited treatment and prophylactic options, the high mortality rate, the potential for
both zoonotic and human-to-human transmission, and the potential for geographical
transplantation and bio- weaponization six arenaviruses have been recognized as
Category A pathogens. W e have identified a novel chemical series of entry inhibitors including
drug-like candidate compounds with sub-nanomolar, broad spectrum arenavirus activity,
which exhibit remarkable in vivo efficacy. Here we propose Phase IIb studies to provide
IND-enabling studies of the lead candidate, including CMC, API process chemistry and scale up
as well as in vitro and in vivo toxicity and safety studies.