Preclinical development of a Nipah Virus inhibitor

Project Summary SARS-CoV-2 has led to an increased urgency to develop treatments for additional emerging viruses and potentially provide broader spectrum antivirals in order to anticipate pandemic viruses. Nipah virus (NiV) is a bat-borne pathogen (family Paramyxoviridae) that results in acute and often fatal (recent outbreaks in India have demonstrated case fatality ~70%) respiratory and neurological disease for which there is currently no FDA approved treatment. There have been very few small molecule antivirals that have demonstrated activity against NiV either in vitro or in vivo. These include favipiravir (EC90 15.87- 123.8 µM) which resulted in survival in the hamster model and remdesivir (EC90 50-100 nM) when dosed daily by the intravenous (IV) route in the African green monkey (AGM) model resulting in their survival. We recently identified the antiviral activity of pyronaridine (EC50 = 65.57 nM and CC50 3.65 µM) for NiV (Malaysia strain, Patent No. 17/092,058). We have also shown that pyronaridine has efficacy against Ebola in vitro and efficacy in vivo in mice and guinea pig. Additionally, pyronaridine has demonstrated promising activity in vitro against Marburg virus and in vivo efficacy against SARS-CoV-2 in mice. We have recently shown that pyronaridine is lysosomotropic and binds to the Ebola glycoprotein as well as decreases the inflammatory cytokine storm in mice induced by SARS-CoV-2. We now propose to assess the oral maximum tolerated dose and pharmacokinetics prior to performing efficacy studies in the hamster model of NiV. If we are successful in demonstrating in vivo efficacy, we will file an orphan drug designation and a preIND with the FDA. If we demonstrate statistically significant efficacy in Phase I we will then perform efficacy testing in Phase II using the African Green Monkey model for NiV, perform IND enabling toxicology studies and manufacture GMP grade pyronaridine tertraphosphate. Our ultimate aim is to bring a treatment to market for NiV which can be stockpiled by the USA and other countries in preparation for future outbreaks.