A novel therapy for acute alcoholic hepatitis

急性酒精性肝炎的新疗法

基本信息

  • 批准号:
    10604068
  • 负责人:
  • 金额:
    $ 35.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-20 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Each year approximately 5 million people in the US develop acute alcoholic hepatitis (AH), a syndrome of progressive inflammatory liver injury. In most patients with AH, the illness is mild. However, in patients with severe acute AH, risk of early death is high and intensive management is required with minimal pharmacological agents available. Seal Rock Therapeutics is developing SRT-015, a potent and selective inhibitor of the activated ASK1 kinase to address this unmet need. ASK1 is present in all cells and activated in response to stress factors including reactive oxygen species (ROS), cytokines and LPS. SRT-015 demonstrates direct anti-inflammatory, anti-fibrotic and anti-apoptotic activity in vitro on stimulated human immune cells, fibroblasts and hepatocytes, respectively. SRT-015 treatment was also proven efficacious in vivo using acute and chronic liver disease mouse models and demonstrated safe in GLP toxicology studies. In a Phase 1 clinical trial SRT-015 was well tolerated with no dose-limiting toxicities. SRT-015 is a possible therapeutic for multiple liver diseases including AH. In this SBIR R43, we will conduct IND-enabling efficacy studies of SRT-015 for treatment of severe AH. These studies are designed to determine the minimal efficacious exposure, define clinically relevant biomarkers, and characterize changes in the microbiota and intestinal permeability after SRT-015 treatment in an AH animal model Aim 1: Estimate of minimal efficacious exposure of SRT-015 and efficacy biomarkers in a chronic ethanol plus binge therapeutic AH animal model. We will be using the mouse chronic Lieber-DeCarli ethanol liquid diet (8 weeks) plus binge ethanol model that best reflects human AH disease. The minimum efficacious dose will be identified using three dose levels of SRT-015 treatment administered during the final four weeks of chronic ethanol feeding and biomarkers for fibrosis, inflammation and hepatoxicity evaluated. Aim 2: Evaluation of intestinal permeability, bacterial translocation and intestinal dysbiosis after SRT-015 treatment in a therapeutic AH animal model. To complement and extend the efficacy data, a full characterization of SRT-015 effects on intestinal inflammation and gut barrier function will be conducted. Demonstrating preclinical efficacy of SRT-015 in a chronic plus binge therapeutic AH model will be critical to conduct clinical trials in AH patients. Once approved, SRT-015 is anticipated to greatly improve the lives of patients with severe AH.
在美国,每年约有500万人患急性酒精性肝炎。 (AH)是一种进行性炎症性肝损伤综合征。大多数AH患者, 病情轻微。然而,在严重急性AH患者中,早期死亡的风险很高, 需要用最少的药物进行强化管理。密封 Rock Therapeutics正在开发SRT-015,这是一种有效的选择性抑制剂。 激活ASK 1激酶来解决这一未满足的需求。ASK1存在于所有细胞中, 响应于包括活性氧(ROS)的应激因素而被激活, 细胞因子和LPS。SRT-015显示出直接的抗炎、抗纤维化和 体外对刺激的人免疫细胞、成纤维细胞和 肝细胞。SRT-015治疗也被证明是有效的体内使用 急性和慢性肝病小鼠模型,并在GLP毒理学中证明安全 问题研究在1期临床试验中,SRT-015耐受性良好,无剂量限制性 毒性SRT-015是一种可能的治疗多种肝脏疾病,包括AH。 在本SBIR R43中,我们将开展SRT-015治疗的IND有效性研究 严重的啊。这些研究旨在确定最小有效 暴露,定义临床相关的生物标志物,并表征 AH动物模型中SRT-015治疗后的微生物群和肠通透性 目的1:估计SRT-015的最小有效暴露量和治疗中的疗效生物标志物 慢性乙醇加暴食治疗AH动物模型。我们将使用鼠标 慢性Lieber-DeCarli乙醇液体饮食(8周)加狂饮乙醇模型最好 反映了人类AH疾病。最小有效剂量将使用三个 在慢性给药的最后四周期间施用的SRT-015治疗的剂量水平 乙醇喂养并评价纤维化、炎症和肝毒性的生物标志物。 目的2:评价肠道通透性、细菌移位和肠道 在治疗性AH动物模型中,SRT-015治疗后的微生态失调。以补充 并扩展了疗效数据,SRT-015对肠道效应的全面表征 炎症和肠道屏障功能。 证明SRT-015在慢性加暴饮暴食治疗性AH中的临床前疗效 模型将是在AH患者中进行临床试验的关键。一旦获得批准,SRT-015将 预计将大大改善重度AH患者的生活。

项目成果

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