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

项目总结 酒精相关性肝病(ALD)是导致肝硬变和肝功能衰竭的主要原因，也是第12位主要原因 美国成年患者的死亡人数。ALD从脂肪肝发展到酒精性脂肪性肝炎， 肝纤维化/肝硬变和肝细胞癌。ALD的药物治疗亟待解决 因为FDA批准的药物目前是可用的。在已发表的作品中，我们已经证明了 促炎细胞因子白介素17A(IL-17A)是酒精性肝损伤的关键介质 人类和老鼠。IL-17A主要由CD4Th17细胞产生。IL-17A的产生受IL-23，一种 促进Th17细胞维持、存活和增殖的细胞因子。我们的临床前研究很清楚 证明用基于IL-23抗体的抗IL-17治疗阻断IL-17信号显著改善 与酒精有关的肝纤维化、肝硬变和癌症。在这里，我们评估IL-23封闭抗体是否 Guselkumab有效降低血清IL-23、IL-17A水平及循环Th17 在我们I期临床试验的治疗患者的样本中有48，49个细胞。这一阶段的试验将招收成人 有中到重度酒精使用障碍(AUD)病史并有记录的临床记录的参与者 有因酒精引起的慢性肝病的证据，但没有证据表明有肝硬变或严重肝功能障碍或 酒精性肝炎。它将遵循标准的3 3期I期剂量递增试验设计，最多24 研究对象。我们将在符合以下条件的人群中评估该药物的安全性、药代动力学和药效学 AUD的标准和肝脏终末器官损害的早期迹象，由Advanced 基于非侵入性磁共振成像的肝脏脂肪和纤维化生物标志物。我们将评估Guselkumab的生物标记物 靶参与以及早期治疗反应的生物标志物(ALT、ELF、Pro-C3)。 目的1：评价Guselkumab(抗IL-23单抗)第1期剂量的安全性和耐受性 酒精使用障碍和酒精相关性肝病患者的升级研究。 目的2：评价古赛库单抗在酒精性肝病患者体内的药代动力学。 目的3：评估Guselkumab的药效学和早期治疗的生物标志物 回应。

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.