A novel therapy for acute alcoholic hepatitis

美国每年约有500万人患上急性酒精性肝炎 (Ah)，进行性炎症性肝损伤综合征。在大多数急性肝炎患者中， 疾病是轻微的。然而，在重症急性肝炎患者中，早期死亡的风险很高，而且 需要以最低限度的药理药剂进行密集管理。封印 Rock Treateutics正在开发SRT-015，一种有效的、选择性的 激活了ASK1激酶，以满足这一未得到满足的需求。ASK1存在于所有细胞中，并且 对包括活性氧(ROS)在内的应激因素的反应被激活， 细胞因子和内毒素。SRT-015显示出直接抗炎、抗纤维化和 刺激的人免疫细胞、成纤维细胞和细胞的体外抗凋亡活性 肝细胞。SRT-015治疗在体内也被证明是有效的 急性和慢性肝病小鼠模型和GLP毒理学证明是安全的 学习。在一期临床试验中，SRT-015耐受性良好，没有剂量限制 毒物。SRT-015有可能治疗包括急性肝炎在内的多种肝病。 在这项SBIR R43中，我们将进行SRT-015治疗的IND使能疗效研究 严重的急性呼吸窘迫。这些研究旨在确定最低有效率 暴露，定义临床相关的生物标记物，并表征 SRT-015对AH动物模型的微生物区系和肠道通透性的影响 目的1：评价SRT-015的最低有效暴露剂量和疗效生物标志物。 一种慢性酒精加暴饮性治疗性急性脑出血动物模型。我们将使用鼠标 慢性Lieber-DeCarli酒精流质饮食(8周)+狂饮酒精模型最好 反映了人类的急性胰腺炎。最小有效剂量将使用三个 慢性阻塞性肺疾病最后四周内SRT-015治疗的剂量水平 酒精喂养和纤维化、炎症和肝毒性生物标志物的评估。 目的2：评估肠道通透性、细菌移位和肠道 治疗性急性脑出血动物模型中SRT-015治疗后的生物失调。来补充 并扩展疗效数据，全面表征SRT-015对肠道的作用 将进行炎症和肠道屏障功能的测试。 SRT-015在慢性暴饮性治疗急性肝炎中的临床前疗效 模型将是在急性胰腺炎患者进行临床试验的关键。一旦获得批准，SRT-015将 预计将极大地改善重症急性肝炎患者的生活。

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.