Pilot Trial UO1 DUR-928

试点试验 UO1 DUR-928

基本信息

批准号：
9792232
负责人：
CRAIG J. MCCLAIN
金额：
$ 7.28万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
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/9792232
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 Cells Cholesterol Cholesterol Homeostasis Chronic Clinical Data Cytoplasm Data Development Diet Disease Dose Drug Kinetics Enzymes FDA approved Failure 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 Natural regeneration Organ Pathway interactions Patients Pentoxifylline Placebos Prednisone Prevalence Safety Signal Pathway Signal Transduction Sterols Syndrome Systemic Inflammatory Response Syndrome Therapeutic Agents Unspecified or Sulfate Ion Sulfates base effective therapy 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 overexpression pilot trial pre-clinical preclinical study standard of care sulfation sulfotransferase treatment guidelines

项目摘要

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 是酒精性肝病的一种急性形式，包括从轻度损伤到严重损伤的范围， AH 的患病率尚未准确确定，据信其发生率为 10%； 35% 的酗酒者在组织学上，AH 的特点是肝脏被炎症细胞浸润。 AH 通常与持续饮酒时的进行性纤维化有关。自从引入皮质类固醇作为治疗药物以来，尚未成功开发出治疗 AH 的新药。 20 世纪 70 年代初，皮质类固醇已被用作各种治疗的标准治疗方法。由于其安全性，也已使用针对严重 AH 患者的指南。进行良好的研究并未支持己酮可可碱治疗严重 AH 的功效。重要的是，最近的一项研究质疑泼尼松和己酮可可碱治疗以下疾病的疗效： AH 与服用泼尼松、己酮可可碱或两者的患者相比，6 个月时的死亡率相似。因此，需要一种新的内源性细胞内调节疗法。分子和硫酸化氧甾醇：5-cholesten-3β, 25-diol 3-sulfate (25HC3S) 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 AKI 和 AH，DUR-928 能够降低细胞内脂质。积累，调节炎症反应，提高细胞存活率。了解 DUR-928 生物学知识后，我们相信 DUR-928 代表了一种新型 AH 治疗剂，具有以下特点：出色的安全性（是内源性产生的）在此 PILOT UO1 中，我们提出了 2 个独立但相互关联的方案。研究。研究#1：一项开放标签、剂量递增研究，旨在评估 DUR- 的安全性、药代动力学和功效 928 中度酒精性肝炎患者。研究#2：一项开放标签、剂量递增研究，旨在评估 DUR- 的安全性、药代动力学和功效 928 严重酒精性肝炎患者。