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

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $781,354

## Abstract

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.

## Key facts

- **NIH application ID:** 10266186
- **Project number:** 5U01AA029019-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Tatiana Kisseleva
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $781,354
- **Award type:** 5
- **Project period:** 2020-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266186

## Citation

> US National Institutes of Health, RePORTER application 10266186, Novel IL-23 inhibitor for the treatment of alcohol associated liver disease (5U01AA029019-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10266186. Licensed CC0.

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