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

用于治疗酒精相关性肝病的新型 IL-23 抑制剂

基本信息

批准号：
10266186
负责人：
Tatiana Kisseleva
金额：
$ 78.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10266186
关键词：
Adult Adverse effects Affect Alcoholic Hepatitis Alcoholic steatohepatitis Alcohols Anti-Inflammatory Agents Antibodies Antibody Therapy Autoimmune Biological Biological Markers Blocking Antibodies Cause of Death Cells Cirrhosis Clinic Clinical Clinical Research Clinical Trials Collagen Type I Dose Drug Kinetics Enrollment FDA approved Family Fatty Liver Fatty acid glycerol esters Fibrosis Functional disorder Funding Future Hepatic Hepatocyte Human Inflammation Inflammatory Interleukin-1 Interleukin-17 Interleukin-6 Interleukins Liver Liver Failure Liver Fibrosis Liver diseases Magnetic Resonance Elastography Magnetic Resonance Imaging Maintenance Malignant Neoplasms Mediating Mediator of activation protein Meta-Analysis Monoclonal Antibodies Mus Myelogenous Myeloid Cells Myofibroblast Organ Participant Patient Recruitments Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phase I Clinical Trials Population Primary carcinoma of the liver cells Principal Investigator Production Protons Psoriasis Publishing Recording of previous events Regimen Research Infrastructure Role Safety Sampling Schedule Serum Serum Markers Severity of illness Signal Transduction Steatohepatitis TNF gene Testing Therapeutic Translating United States Work alcohol abuse therapy alcohol use disorder base chronic liver disease clinical development clinical trial analysis commercialization complement C3 precursor cytokine density early detection biomarkers first-in-human improved inhibitor/antagonist interleukin-23 lipid biosynthesis liver inflammation liver injury mRNA Expression medication safety member novel pharmacokinetics and pharmacodynamics phase I trial phase II trial phase III trial pre-clinical preclinical study prevent receptor response safety testing success treatment response trial design

项目摘要

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.

项目总结