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Advanced development of a viral entry inhibitor as a therapeutic for arenavirus hemorrhagic fever

Award Number: R01AI141102
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Advanced development of a viral entry inhibitor as a therapeutic for arenavirus hemorrhagic fever - PROJECT SUMMARY This project is focused on developing a broad-spectrum antiviral drug for treating viral hemorrhagic fever diseases caused by Old World and New World arenaviruses. There are no FDA-approved therapeutics for treating infections caused by these viruses, and hemorrhagic fever arenaviruses are listed as NIAID Category A priority pathogens. Our small-molecule drug, LHF-535, is an investigational new drug (IND)-ready oral antiviral therapeutic against Lassa virus, an Old World arenavirus that causes Lassa fever. The drug targets the Lassa virus envelope glycoprotein and functions as a viral entry inhibitor. In this project, our goals are to assemble a data package to expand the labeled indication for LHF-535 to include infection with the New World hemorrhagic fever arenaviruses Junín virus and Machupo virus, address pre-IND recommendations by the FDA to more fully characterize the genotypic and phenotypic characteristics of arenaviruses that develop resistance to LHF-535, and formulate LHF-535 for intravenous (i.v.) administration. To achieve these goals, the following Specific Aims are proposed: 1) Define the antiviral activity of LHF-535 against New World hemorrhagic fever arenaviruses. Junín virus and Machupo virus are endemic in distinct regions of South America, where they cause sporadic outbreaks of severe disease with high morbidity and mortality. We will use well-established guinea pig infection models to define antiviral efficacy and to determine pharmacokinetic- pharmacodynamic relationships. 2) Determine the nature, emergence, and virulence of LHF-535-resistant viruses. We will evaluate the ability of LHF-535 to inhibit the infectivity of lentiviral pseudotypes expressing envelope glycoproteins of Junín virus that contain specifically engineered amino acid substitutions. Junín virus variants that are resistant to LHF-535 will also be identified by serial passage in LHF-535-treated cells and by isolating viruses from animals that fail LHF-535 treatment. To assist in monitoring the development of antiviral resistance during initial clinical efficacy studies, we will also generate and test an expanded library of genetic variants within the Lassa virus envelope glycoprotein. 3) Develop an i.v. formulation for LHF-535. Intravenous administration provides an option for drug delivery in situations where oral administration is not feasible. We will also explore the possibility that the rapid drug exposure provided by i.v. administration might enhance therapeutic efficacy, particularly in late stages of disease. Formulation development will include evaluation of antiviral efficacy (including fixed-dose and loading-dose strategies), toxicology, and safety pharmacology. Together, our studies will enhance the clinical value and efficacy of LHF-535 across multiple indications and support and inform Phase II clinical trials. LHF-535 is intended to both improve global health and serve as a medical countermeasure to the bioterrorism threat posed by hemorrhagic fever arenaviruses.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $1,063,683 )
2023	2023	KINETA INC	219 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	5	12/6/2022	NON-COMPETING CONTINUATION	$1,063,683
														Subtotal = $1,063,683

Issue Date FY: 2022 ( Subtotal = $1,118,000 )
2022	2022	KINETA, INC.	219 TERRY AVE N STE 300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	12/10/2021	NON-COMPETING CONTINUATION	$1,118,000
														Subtotal = $1,118,000

Issue Date FY: 2021 ( Subtotal = $1,134,275 )
2021	2021	KINETA, INC.	219 TERRY AVE N STE 300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	12/15/2020	NON-COMPETING CONTINUATION	$1,134,275
														Subtotal = $1,134,275

Issue Date FY: 2020 ( Subtotal = $1,163,830 )
2020	2020	KINETA, INC.	219 TERRY AVE N STE 300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	12/4/2019	NON-COMPETING CONTINUATION	$1,163,830
														Subtotal = $1,163,830

Issue Date FY: 2019 ( Subtotal = $1,370,459 )
2019	2019	KINETA, INC.	219 TERRY AVE N STE 300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	8/12/2019	NEW	$0
2019	2019	KINETA, INC.	219 TERRY AVE N STE 300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	12/28/2018	NEW	$1,370,459
														Subtotal = $1,370,459

Grand Total All Awards = $5,850,247

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Advanced development of a viral entry inhibitor as a therapeutic for arenavirus hemorrhagic fever

Award Number: R01AI141102

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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