SBIR-STTR Award

Arenaviruses comprise a diverse group of Old (Africa) and New World (Americas) species. Several species are associated with hemorrhagic fever (HF) with case-fatality rates as high as 30%. Arenaviruses infection typically occurs via the mucosal route through contact with excretions of an infected rodents although direct human-to-human transmission may occur in clinical settings. Lassa arenavirus endemic to Western Africa has significantly higher rate of annual infections (over 300,000) between both Old and New World species. With the exception of a New World Junin virus vaccine, no approved broad-spectrum vaccines or therapeutics are available. We identified a novel broad-spectrum small molecule arenavirus entry inhibitor that exhibits remarkable post-exposure in vivo efficacy including, a guinea pig Lassa model. However, efficacy was evaluated when the virus was inoculated via parenteral routes. Interestingly, current vaccines and monoclonal antibodies when tested in Ebola animal models demonstrate less efficacy when virus is inoculated via aerosol route versus parenteral routes. Because of the potential for aerosol weaponization as well as natural infection via mucosal route, it is important to demonstrate efficacy against arenaviruses through the typical route of infection. Therefore, we propose to evaluate efficacy of our lead candidate in a guinea pig aerosol Lassa model.

Arenaviruses comprise a diverse group of Old (Africa) and New World (Americas) species. Several species are associated with hemorrhagic fever (HF) with case-fatality rates as high as 30%. Arenavirus infections typically occur via the mucosal route through contact with excretions of an infected rodents or the inhalation of aerosolized particles from soiled rodent urine or saliva although direct human-to-human transmission may occur in clinical settings. Lassa virus, an arenavirus endemic to Western Africa, infects an estimated 300,000 people each year while infections of other hemorrhagic arenavirus species are significantly more sporadic and limited. With the exception of a vaccine for the New World Junin virus, no approved broad-spectrum arenavirus vaccines or therapeutics are currently available. We identified a novel small molecule broad-spectrum arenavirus entry inhibitor that exhibits remarkable in vivo post-exposure efficacy in a mouse Tacaribe (New World) virus model as well as in both the guinea pig Lassa (Old World) and Junin (New World) models. In each of these models, virus was inoculated via parenteral routes. Recently, it has been reported that several vaccines and monoclonal antibodies in development for Ebola virus demonstrated less in vivo efficacy when virus was inoculated via aerosol versus a parenteral route. Given the potential for aerosol weaponization as well as natural infection via mucosal routes, it is important to determine efficacy against arenaviruses utilizing routes of infection that most closely imitate their natural condition. In the Phase I SBIR it was found that 3 days of q.d. oral administration of 30 mg/kg ARN-75039 achieved steady-state trough levels in lung, 24 hours after the last dose >>1000x the in vitro Lassa virus EC90. Thus, ARN-75039 is a strong candidate for efficacy testing in an aerosol Lassa virus guinea pig model. In addition, 20g of ARN-75039 was produced at a defined single polymorph form with >99% purity to support in vivo efficacy studies. Because Lassa is our primary development indication, for this Phase II SBIR we propose to 1) better define minimal efficacious dose and therapeutic windows for post-infection dosing and length of a course of treatment with parenteral Lassa virus infection in guinea pigs and 2) using set parameters from part 1, to execute comparative efficacy testing of ARN-75039 in aerosolized vs parenteral Lassa infection routes in guinea pigs. The information gained from these studies will help to determine potential differences in therapeutic treatments dependent upon route of infection and subsequently used to prepare an IND package and guide clinical studies in human patients.