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New generation of long acting nucleos(t)ides and immune stimulant for treatment of chronic hepatitis B

Award Number: R01AI163042
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: 03/10/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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New generation of long acting nucleos(t)ides and immune stimulant for treatment of chronic hepatitis B - There is a global aim to reduce the burden of chronic hepatitis B (CHB) infection and prevent the development of HBV-associated end-stage liver disease and cancer. The improvement of existing therapeutics is expected to help achieve this goal. Specifically, the usage of once two-month injectable nucleos(t)ide analogs in combination with immunomodulating antiviral compounds instead of life-long daily pills has the strong potential to help to achieve a functional cure for CHB. To this end, we propose to transform water-soluble antiviral drugs, first-line drugs tenofovir (TFV) and entecavir (ETV), and immunomodulating drug tizoxanide (TIZ) into hydrophobic lipophilic crystalline prodrugs. We will formulate them as nanosuspensions suitable for intramuscular injection. The efficient optimization of physicochemical properties of nanocrystals is expected to improve their pharmacokinetics (PK) and pharmacodynamics (PD) profiles. This optimization will enhance uptake of the prodrug nanocrystals by liver macrophages and hepatocytes to ensure a slow release and sustained therapeutic drug concentrations at the site of hepatitis B viral replication. The treatment with long-acting TFV, ETV, and TIZ is expected to decrease dosing frequency, limit toxicity, and facilitate sustained viral suppression and treatment. A functional cure for HBV is expected to be achieved via multifactorial mechanisms, including inhibition of viral polymerase, prevention of cccDNA formation, and the clearance of HBV micro-chromosomes via stimulation of host innate immunity by TIZ. Thus, the overall objective of this proposal is to develop clinically translatable, long-acting, injectable, antiviral drug nanoformulations to increase adherence and enhance drug delivery to sites of persistent HBV infection, thereby facilitating sustained viral suppression and finite cure. To this end, three specific aims are proposed: Aim 1: Develop long-acting anti-HBV prodrug nanoformulations and evaluate the drug efficacy. Here, we will apply pronucleotide (ProTide) and a modified HepDirect prodrug technology to transform existing drugs into hydrophobic prodrugs suitable for formulation as nanosuspensions to achieve prolonged therapeutic active drug concentrations in hepatocyte. This is expected to improve drug biodistribution to infected hepatocytes without compromising drug potency and safety profile. The prodrug formulations will be screened in vitro in human macrophages as a potential drug depot and in infected hepatocytes as final targets. The anti-HBV activity of prodrug nanocrystals will be examined in vitro and in vivo using HBV-infected humanized mice. Aim 2: To develop long-acting TIZ nanoformulation and evaluate the mechanisms by which TIZ suppresses HBV replication in infected hepatocytes. Aim 3: To evaluate the synergistic efficacy of the selected long-acting TIZ and NUC formulations and evaluate the ability of this combination to eliminate HBV cccDNA from hepatocytes and significantly reduce the concentration of HBsAg.


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: 2025 ( Subtotal = $611,174 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	4	4/7/2025	NON-COMPETING CONTINUATION	$611,174
														Subtotal = $611,174

Issue Date FY: 2024 ( Subtotal = $611,174 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	3	2/23/2024	NON-COMPETING CONTINUATION	$550,057
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$61,117
														Subtotal = $611,174

Issue Date FY: 2023 ( Subtotal = $611,174 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$611,174
														Subtotal = $611,174

Issue Date FY: 2022 ( Subtotal = $610,511 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	1	3/9/2022	NEW	$610,511
														Subtotal = $610,511

Grand Total All Awards = $2,444,033

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New generation of long acting nucleos(t)ides and immune stimulant for treatment of chronic hepatitis B

Award Number: R01AI163042

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: 03/10/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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