Pilot Trial UO1 DUR-928

试点试验 UO1 DUR-928

基本信息

批准号：
10441277
负责人：
CRAIG J. MCCLAIN
金额：
$ 6.75万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441277
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

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，包括一个频谱，范围从轻度损伤到严重，威胁生命的伤害。 AH的患病率尚未准确确定；据信它发生在10％ 35％的饮酒者中有35％。关于组织学，AH的特征是炎症细胞和肝细胞损伤。 AH通常在持续酒精的情况下与进行性纤维化有关虐待。自从引入皮质类固醇作为一种以来，没有成功开发出AH的新药 1970年代初期的治疗。皮质类固醇已被用作各种治疗的护理标准严重AH患者的指南。由于其安全性，pentoxifyline也被使用了，但有几个经过良好的研究研究不支持五氧化苯丙氨酸对严重AH治疗的效率。重要的是，最近的一项研究质疑泼尼松和五氧化酮在治疗中的效率啊。泼尼松，五氧化苯胺的患者的6个月死亡率相似，或两者兼而有之。安慰剂。因此，需要新颖的疗法。 DUR-928是内源性细胞内调节分子和硫酸化氧甲醇：5-胆固醇3β，25-二醇3-硫酸盐（25HC3S）。 DUR-928正在开发对于包括治疗慢性代谢疾病的多种迹象，例如NAFLD/NASH和PSC，以及治疗急性器官损伤，例如AKI和AH。 DUR-928能够降低细胞内脂质积累，调节炎症反应并改善细胞存活。基于累积的电流对DUR-928生物学知识，我们认为Dur-928代表AH的新型热剂出色的安全性（内生产生）。在这个飞行员UO1中，我们提出了2个独立的建议，但链接研究。研究＃1：一项开放标签的剂量升级研究，以评估持续时间的安全性，药代动力学和效率中度酒精性肝炎的患者为928。研究＃2：一项开放标签的剂量升级研究，以评估持续时间的安全性，药代动力学和效率严重酒精性肝炎患者的928。