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Novel IL-23 inhibitor for the treatment of alcohol associated liver disease

Award Number: U01AA029019
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Novel IL-23 inhibitor for the treatment of alcohol associated liver disease - PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a major cause of cirrhosis and liver failure, and the 12th leading cause of death in adult patients in the United States. ALD progresses from fatty liver, to alcoholic steatohepatitis, fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Pharmacological therapies for ALD are urgently needed as FDA-approved medications are currently available. In published work, we have demonstrated that the proinflammatory cytokine interleukin-17A (IL-17A) is a critical mediator of alcohol-related liver damage in both humans and mice. IL-17A is mainly produced by CD4+ Th17 cells. IL-17A production is regulated by IL-23, a cytokine that promotes the maintenance, survival, and proliferation of Th17 cells. Our preclinical studies clearly demonstrate that blocking IL-17 signaling with an anti-IL-23 antibody-based treatment significantly improves alcohol-related liver fibrosis, cirrhosis, and cancer. Here, we evaluate whether the IL-23 blocking antibody guselkumab effectively reduces serum levels of IL-23 and IL-17A as well as the number of circulating Th17 cells48,49 in samples from treated patients from our Phase I clinical trial. This Phase 1 trial will enroll adult participants who have a history of moderate to severe alcohol use disorder (AUD) along with documented clinical evidence of chronic liver disease due to alcohol but no evidence of cirrhosis or severe hepatic dysfunction or alcoholic hepatitis. It will follow a standard 3+3 Phase I dose escalation trial design with a maximum of 24 subjects. We will assess the drug’s safety, pharmacokinetics, and pharmacodynamics in a population that meets criteria for AUD and early signs of end-organ-damage to the liver, as made evident and quantified by advanced non-invasive MRI based biomarkers of liver fat and fibrosis. We will assess biomarkers for both guselkumab target engagement as well as biomarkers for early treatment response (ALT, ELF, Pro-C3). Aim 1: Assess safety and tolerability of guselkumab (anti-IL-23 monoclonal antibody) in a Phase 1 dose escalation study in patients with alcohol use disorder and alcohol-associated liver disease. Aim 2: Assess the pharmacokinetics of guselkumab in patients with alcohol-associated liver disease. Aim 3: Assess pharmacodynamics of guselkumab target engagement and biomarkers of early treatment response.


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: 2024 ( Subtotal = $711,945 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	5	8/16/2024	NON-COMPETING CONTINUATION	$711,945
														Subtotal = $711,945

Issue Date FY: 2023 ( Subtotal = $742,984 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	4	9/18/2023	NON-COMPETING CONTINUATION	$742,984
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	4/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $742,984

Issue Date FY: 2022 ( Subtotal = $699,515 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	8/24/2022	NON-COMPETING CONTINUATION	$699,515
														Subtotal = $699,515

Issue Date FY: 2021 ( Subtotal = $781,354 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	9/6/2021	NON-COMPETING CONTINUATION	$781,354
														Subtotal = $781,354

Issue Date FY: 2020 ( Subtotal = $782,852 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	9/18/2020	NEW	$782,852
														Subtotal = $782,852

Grand Total All Awards = $3,718,650

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Novel IL-23 inhibitor for the treatment of alcohol associated liver disease

Award Number: U01AA029019

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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