Preclinical development of a Nipah Virus inhibitor

NIH Pandemic-Era Grants

Pandemic Era Grants

2023

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Principal Investigator: SEAN  EKINS
Organization: COLLABORATIONS PHARMACEUTICALS, INC.
Fiscal Year: 2023
Award: $295,096
Funding agency: National Institute of Allergy and Infectious Diseases

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.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><African Green Monkey><Animals><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-Malarials><Anti-infective Preparation><AntiInfective Drugs><AntiInfectives><Antiinfective Agents><Antimalarial Agents><Antimalarial Drugs><Antimalarials><Antiviral Agents><Antiviral Drugs><Antivirals><Belgian Congo><Binding><Blood><Blood Reticuloendothelial System><Body Tissues><Body Weight><Body Weight decreased><COVID><COVID-19 virus><COVID19 virus><Cavia><Cessation of life><Chlorocebus aethiops><Chlorocebus sabaeus><CoV disease><CoV-2><CoV2><Combined Modality Therapy><Country><Cricetinae><Data><Death><Democratic Republic of the Congo><Disease><Disease Outbreaks><Disorder><Dose><Drug Kinetics><Drugs><EBOV><Ebola><Ebola virus><Ebola-like Viruses><FDA approved><Family><Federation of Malaya><Feedback><Frankfurt-Marburg Syndrome Virus><Future><GS-5734><Glycoproteins><Goals><Government><Green Monkey><Guinea Pigs><Guinea Pigs Mammals><Hamsters><Hamsters Mammals><Human><Hydrogen Oxide><In Vitro><India><Infection><Inflammatory><Injections><Intellectual Property><Intravenous><Investments><Legal patent><Malay Federation><Malaya><Malaysia><Marburg><Marburg virus><Marburg-like Viruses><Marburgvirus><Marketing><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Nervous System Diseases><Neurologic Disorders><Neurological Disorders><Nipah Virus><Oral><Orphan Drugs><Outbreaks><Paramyxoviridae><Paramyxovirus><Patents><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Preparation><Privatization><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 inhibitor><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Science><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome related corona virus 2><Sodium Chloride><Taxes><Testing><Time><Tissues><Toxicology><Veklury><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><Virus Inhibitors><Virus Replication><Water><Weight Loss><Weight Reduction><Work><Wuhan coronavirus><Zaire><anti-malarial agents><anti-malarial drugs><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><bat-borne><batborne><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><body weight loss><clinical development><combination therapy><combined modality treatment><combined treatment><communicable disease control agent><corona virus disease><coronavirus disease><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine release syndrome><cytokine storm><determine efficacy><drug/agent><ebolavirus><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><efficacy testing><evaluate efficacy><examine efficacy><future outbreak><hCoV19><in vitro activity><in vivo><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibitor><intraperitoneal><manufacture><meter><multi-modal therapy><multi-modal treatment><nCoV2><nervous system disorder><neurological disease><next outbreak><non-human primate><nonhuman primate><novel><pandemic virus><pathogen><pharmaceutical><pre-clinical development><pre-clinical study><preclinical development><preclinical study><preparations><pyronaridine><remdesivir><salt><small molecule><viral inhibitor><viral multiplication><viral replication><virus multiplication><wt-loss>