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：
10482350
负责人：
Tatiana Kisseleva
金额：
$ 69.95万
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/10482350
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 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.

项目概要酒精相关性肝病 (ALD) 是肝硬化和肝衰竭的主要原因，也是第 12 位主要病因美国成年患者的死亡人数从脂肪肝发展为酒精性脂肪性肝炎，纤维化/肝硬化和肝细胞癌 (HCC) 迫切需要药物治疗。由于 FDA 批准的药物目前可用，在已发表的工作中，我们已经证明了促炎细胞因子白细胞介素 17A (IL-17A) 是酒精相关肝损伤的关键介质 IL-17A 主要由 CD4+ Th17 细胞产生，IL-17A 的产生受 IL-23 的调节。我们的临床前研究清楚地表明了促进 Th17 细胞维持、存活和增殖的细胞因子。证明用基于抗 IL-23 抗体的治疗阻断 IL-17 信号传导可显着改善在此，我们评估IL-23阻断抗体是否与酒精相关的肝纤维化、肝硬化和癌症有关。 guselkumab 有效降低血清 IL-23 和 IL-17A 水平以及循环 Th17 数量来自我们一期临床试验的治疗患者样本中的细胞48,49 该一期试验将招募成人。有中度至重度酒精使用障碍 (AUD) 病史以及临床记录的参与者酒精引起的慢性肝病的证据无肝硬化或严重肝功能障碍的证据或它将遵循标准的 3+3 I 期剂量递增试验设计，最多 24 次。我们将在符合条件的人群中评估药物的安全性、药代动力学和药效学。 AUD 的标准和肝脏终末器官损伤的早期迹象，如先进的证据所示和量化基于非侵入性 MRI 的肝脏脂肪和纤维化生物标志物我们将评估 guselkumab 的生物标志物。目标参与以及早期治疗反应的生物标志物（ALT、ELF、Pro-C3）。目标 1：评估 1 期剂量中 guselkumab（抗 IL-23 单克隆抗体）的安全性和耐受性酒精使用障碍和酒精相关性肝病患者的升级研究。目标 2：评估古塞奇尤单抗在酒精相关性肝病患者中的药代动力学。目标 3：评估古塞奇尤单抗靶点参与的药效学和早期治疗的生物标志物回复。