Pilot Trial UO1 DUR-928

试点试验 UO1 DUR-928

• 批准号: 10201423
• 负责人: CRAIG J. MCCLAIN
• 金额: $ 6.94万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201423
• 关键词: 25-hydroxycholesterol; ADD-1 protein; Acute; Acute Alcoholic Hepatitis; Acute Renal Failure with Renal Papillary Necrosis; Adrenal Cortex Hormones; Agonist; Alcohol abuse; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Anorexia; Apoptosis; Biology; Cell Nucleus; Cell Survival; Cholesterol; Cholesterol Homeostasis; Chronic; Clinical Data; Cytoplasm; Data; Development; Diet; Disease; Dose; Drug Kinetics; Enzymes; FDA approved; Fatty acid glycerol esters; Fibrosis; Glucocorticoids; Glycols; Hepatic; Hepatocyte; Hepatomegaly; Histology; Hospitals; Human; Hydroxylation; Icterus; In Vitro; Infection; Infiltration; Inflammatory; Inflammatory Response; Injury; Intracellular Accumulation of Lipids; Knowledge; Life; Link; Lipids; Liver; Liver Regeneration; Malaise; Malnutrition; Metabolic Diseases; Mitochondria; Morbidity - disease rate; Multiple Organ Failure; Natural regeneration; Pathway interactions; Patients; Pentoxifylline; Placebos; Prednisone; Prevalence; Safety; Signal Pathway; Signal Transduction; Sterols; Sulfate; Syndrome; Systemic Inflammatory Response Syndrome; Therapeutic Agents; base; cell injury; effective therapy; hepatocellular injury; high risk; improved; in vivo; lipid biosynthesis; lipid metabolism; liver cell proliferation; macrophage; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; open label; organ injury; overexpression; pilot trial; pre-clinical; preclinical study; standard of care; sulfotransferase; treatment guidelines

AH is an acute form of alcoholic liver disease and includes a spectrum that ranges from mild injury to severe, life threatening injury. The prevalence of AH has not been accurately determined; it is believed to occur in 10% to 35% of heavy drinkers. On histology, AH is characterized by infiltration of the liver by inflammatory cells and hepatocellular injury. AH is usually associated with progressive fibrosis in the presence of continued alcohol abuse. No new drugs for AH have been successfully developed since the introduction of corticosteroids as a treatment in the early 1970s. Corticosteroids have been utilized as a standard of care in various treatment guidelines for patients with severe AH. Pentoxifylline has also been used because of its safety, but several well-conducted studies have not supported the efficacy of pentoxifylline for the treatment of severe AH. Importantly, a recent study has questioned the efficacy of both prednisone and pentoxifylline in the treatment of AH. Mortality at 6 months was similar in patients on either prednisone, pentoxifylline, or both as compared with placebo. Therefore, there is a need for novel therapies. DUR-928 is an endogenous intracellular regulatory molecule and sulfated oxysterol: 5-cholesten-3β, 25-diol 3-sulfate (25HC3S). DUR-928 is under development for multiple indications including treatment of chronic metabolic disease, such as NAFLD/NASH and PSC, and treatment of acute organ injuries, such as AKI and AH. DUR-928 is able to lower intracellular lipid accumulation, regulate inflammatory responses, and improve cell survival. Based on the current accumulated knowledge of DUR-928 biology, we believe that DUR-928 represents a novel therapeutic agent for AH with an excellent safety profile (is produced endogenously). In this PILOT UO1, we propose 2 independent, but linked studies. Study #1: An open-label, dose escalation study to assess the safety, pharmacokinetics and efficacy of DUR- 928 in patients with Moderate Alcoholic Hepatitis. Study #2: An open-label, dose escalation study to assess the safety, pharmacokinetics and efficacy of DUR- 928 in patients with Severe Alcoholic Hepatitis.

AH是一种急性酒精性肝病，包括从轻度损伤到重度损伤的范围， 危及生命的伤害。AH的患病率尚未准确确定;据信发生在10% 35%的重度饮酒者。在组织学上，AH的特征是炎性细胞浸润肝脏， 肝细胞损伤在持续饮酒的情况下，AH通常与进行性纤维化相关 虐待自从皮质类固醇作为一种药物引入以来，还没有成功开发出治疗AH的新药 70年代初的治疗。皮质类固醇已被用作各种治疗中的标准护理 严重AH患者的指南。由于其安全性，也使用了Penetraphylline，但几个 进行良好的研究不支持喷替福林治疗重度AH的疗效。 重要的是，最近的一项研究质疑了泼尼松和喷替福林治疗糖尿病的疗效。 啊与对照组相比，泼尼松组、喷替福林组或两者联合组患者6个月时的死亡率相似。 安慰剂因此，需要新的疗法。DUR-928是一种内源性细胞内调节因子， 分子和硫酸化氧甾醇：5-异戊烯-3 β，25-二醇3-硫酸酯（25 HC 3S）。DUR-928正在开发中 用于多种适应症，包括治疗慢性代谢性疾病，如NAFLD/NASH和PSC，以及 治疗急性器官损伤，如阿基和AH。DUR-928能够降低细胞内脂质 在某些情况下，它可以促进细胞的积累，调节炎症反应并改善细胞存活。根据目前累计 根据DUR-928生物学知识，我们认为DUR-928代表了一种新的AH治疗剂， 良好的安全性（内源性产生）。在这个试点UO 1中，我们提出了2个独立的，但链接 问题研究 研究#1：一项开放标签、剂量递增研究，以评估DUR的安全性、药代动力学和疗效- 928例中度酒精性肝炎患者。 研究#2：一项开放标签、剂量递增研究，以评估DUR的安全性、药代动力学和疗效。 928例重度酒精性肝炎患者。