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

项目摘要 酒精相关性肝病（ALD）是肝硬化和肝功能衰竭的主要原因，也是第12大原因。 在美国的成年患者中死亡率。ALD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）。ALD的药物治疗是迫切需要的 因为目前已有FDA批准的药物。在已发表的工作中，我们已经证明 促炎细胞因子白细胞介素-17A（IL-17 A）是酒精相关肝损伤的关键介质， 人类和老鼠IL-17 A主要由CD 4 + Th 17细胞产生。IL-17 A的产生受IL-23调节， 促进Th 17细胞的维持、存活和增殖的细胞因子。我们的临床前研究清楚地表明 证明用基于抗IL-23抗体的治疗阻断IL-17信号传导显著改善了 酒精相关的肝纤维化、肝硬化和癌症。在这里，我们评估IL-23阻断抗体是否 guselkumab可有效降低IL-23和IL-17 A的血清水平以及循环Th 17的数量 细胞48，49在我们的第一阶段临床试验的治疗患者的样品中。这项1期试验将招募成人 有中度至重度酒精使用障碍（AUD）病史的受试者，沿着有记录的临床 酒精所致慢性肝病证据，但无肝硬化或重度肝功能障碍证据，或 酒精性肝炎它将遵循标准的3+3 I期剂量递增试验设计，最多24 科目我们将在满足以下条件的人群中评估药物的安全性、药代动力学和药效学： AUD标准和肝脏终末器官损伤的早期体征，如通过先进的 基于MRI的非侵入性肝脏脂肪和纤维化生物标志物。我们将评估两种guselkumab的生物标志物 靶向参与以及早期治疗反应的生物标志物（ALT、ELF、Pro-C3）。 目的1：评估guselkumab（抗IL-23单克隆抗体）1期剂量的安全性和耐受性 在酒精使用障碍和酒精相关肝病患者中进行的递增研究。 目的2：评估guselkumab在酒精相关肝病患者中的药代动力学。 目的3：评估guselkumab靶点结合的药效学和早期治疗的生物标志物 反应

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.