An innovative non-thiazolidinedione pan-PPAR agonist therapeutic for Alcoholic Hepatitis

一种创新的非噻唑烷二酮类泛 PPAR 激动剂，用于治疗酒精性肝炎

基本信息

批准号：
10482468
负责人：
Prasad Manchem
金额：
$ 29.59万
依托单位：
PLEIOGENIX INC.
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：
2022-05-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482468
关键词：
Acute Adrenal Cortex Hormones Affect Affinity Agonist Alanine Transaminase Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcohols Animal Model Anti-Inflammatory Agents Apoptosis Aspartate Transaminase Automobile Driving Biochemical C-reactive protein COVID-19 Caliber Cardiac Myocytes Cardiotoxicity Cells Chronic Clinical Clinical Drug Development Clinical Trials Coupling Data Death Rate Disease Dose Edema Elements Ensure Ethanol Fatty Liver Fibrosis Fracture Gastroenterology Gastrointestinal Hemorrhage Goals Health Health Care Costs Healthcare Hepatocyte Hepatology Hospitalization Hospitals Hypertrophy Immunomodulators Immunosuppression Infection Inflammation Interleukin-13 Interleukin-14 Interleukin-4 Interleukin-6 Interleukins Intervention Kidney Failure Life Life Expectancy Link Lipids Liver Liver Fibrosis Liver diseases Lobular Macaca mulatta Mediating Metabolic Diseases Molecular Weight Multi-Institutional Clinical Trial Mus Myocardial No-Observed-Adverse-Effect Level Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Pathology Patients Pentoxifylline Peroxisome Proliferator-Activated Receptors Persons Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Phosphodiesterase Inhibitors Preclinical Testing Prevention Production Protein Isoforms Pulmonary Fibrosis Reporting Safety San Francisco Side Small Business Innovation Research Grant South Dakota Steroids TNF gene Testing Therapeutic Toxicology Validation Weight Gain acute pancreatitis adiponectin alcohol effect alternative treatment base cohort cost cytokine release syndrome design effective intervention effective therapy efficacy evaluation efficacy study efficacy testing experience feeding hospital readmission improved in vivo innovation insight liver inflammation liver injury liver transplantation macrophage mortality mouse model neutrophil nonalcoholic steatohepatitis novel novel therapeutic intervention phase 1 study pre-clinical assessment preclinical study prednisolone prevent safety assessment safety study screening side effect small molecule libraries standard care stellate cell success

项目摘要

PROJECT SUMMARY Alcoholic Hepatitis (AH) is a severe and acute form of alcohol-mediated liver disease, affecting ~34% of heavy alcohol drinkers, and presents a healthcare burden of ~$2.2 billion/yearly. AH sufferers have a short life expectancy, with about ~70% dying in the first six months after presentation. Re-hospitalization occurs in nearly 40% of the patients within 90 days of their first hospital discharge, further driving upward the costs associated with this deadly disease. As a weak alternative to expensive and unsustainable liver transplants, the first-line pharmaceutical intervention for AH is based on corticosteroids’ administration, in a vain attempt to reduce inflammation and liver fibrosis. Unfortunately, corticosteroids do not improve patients' survival and are linked to several secondary complications including infections, gastrointestinal bleeding, acute pancreatitis, and renal failure. Moreover, patients that develop an infection after corticosteroid treatment show a significantly higher mortality rate. For patients for whom steroids are contraindicated, the alternative treatment option is pentoxifylline, a phosphodiesterase inhibitor that is clinically ineffective in AH patients, as reported in the STOPAH-1 multi-center clinical trial. Pleiogenix is developing a unique oral (qd) therapeutic approach for AH based on the novel, orally-active, non-thiazolidinedione pan-PPAR agonist (PLG888), optimized to selectively modulate the activities of all three PPAR isoforms. PLG888’s unique structural design enables full agonism of PPAR along with partial agonism towards PPAR and PPAR overcoming side effects (e.g. edema, weight gain, fractures) associated with full PPAR and PPAR activation. Preliminary data obtained in non-alcoholic steatohepatitis mice, obese Rhesus monkeys, and multiple clinical trials in patients with type 2 diabetes (T2D) indicate that PLG888 1) reduces the activities of the key markers of liver damage, including alanine transaminase (ALT) and aspartate transaminase (AST), 2) reduces C-reactive protein, and 3) increases adiponectin (up to 200%), positively improving liver steatosis, fibrosis, and ballooning. The goal of this SBIR Phase I project is to assess the feasibility of using PLG888 as a novel oral (qd) treatment for AH. The following aims are proposed. In AIM 1, Pleiogenix will execute a dose-finding and prevention study in a validated mouse model of AH, generated through chronic and binge ethanol feeding; plus LPS administration to create a second hit, to increase liver damage. In AIM 2, the most efficacious dose identified in AIM 1 will be used to evaluate a larger cohort of mice to conduct a preclinical study to test the efficacy and safety of PLG888 in reducing the detrimental effects of ethanol. Cardiac toxicity, in particular, will be evaluated. In combination with previously executed toxicology and safety data derived from completed clinical trials in subjects with T2D, the successful conclusion of this SBIR Phase I study will validate the proposed pan-PPAR agonist, as a safe and effective intervention for the treatment of subjects with AH, paving the way to clinical trials to define dose-ranging in moderate and severe AH patients.

项目摘要酒精性肝炎（AH）是酒精介导的肝病的一种严重而急性的形式，影响了约34％的重量饮酒者，并提供约22亿美元/年度的医疗保健伯恩。啊，患者寿命很短预期，在介绍后的前六个月中，约有约70％死亡。重新住院发生在第一次出院后的90天内，将近40％的患者进一步向上推动了费用与这种致命疾病有关。作为昂贵且不可持续的肝移植的弱选择， AH的一线药物干预措施是基于皮质类固醇的给药，徒劳的尝试减少感染和肝纤维化。不幸的是，皮质类固醇不能改善患者的生存和与几种次要并发症有关，包括感染，胃肠道出血，急性胰腺炎和肾衰竭。此外，皮质类固醇治疗后发育感染的患者表明死亡率明显更高。对于禁忌类固醇的患者，替代品治疗方案是戊昔丁林，这是一种磷酸二酯酶抑制剂，在AH患者中无效，AS临床无效在Stopah-1多中心临床试验中报告。 Pleiogenix正在开发独特的口服（QD）疗法基于新颖的，口中活性的非噻唑烷二酮泛帕普激动剂（PLG888）的AH方法，优化以选择性调节所有三个PPAR同工型的活性。 PLG888的独特结构设计使PPAR的全部激动和部分激动剂朝PPAR和PPAR克服一侧效果（例如水肿，体重增加，裂缝）与全pPar和PPAR激活相关。初步的在非酒精性脂肪性肝炎小鼠，肥胖恒河猴和多个临床试验中获得的数据 2型糖尿病患者（T2D）表明PLG888 1）降低了肝的关键标记活性损害，包括丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST），2）降低C反应性蛋白质和3）增加脂联素（最高200％），从而积极改善肝脏脂肪变性，纤维化和气球。该SBIR I期项目的目的是评估使用PLG888作为新颖的口头的可行性（QD）AH的治疗。提出了以下目标。在AIM 1中，pleiogenix将执行剂量找到和通过经过验证的AH小鼠模型进行预防研究，该模型是通过慢性和暴饮暴食摄食产生的；加上LPS管理，以创建第二次命中，以增加肝脏损害。在AIM 2中，最有效的剂量在AIM 1中确定的将用于评估较大的小鼠队列以进行临床前研究以测试 PLG888在减少乙醇的有害作用方面的有效性和安全性。尤其是心脏毒性将进行评估。结合先前执行的毒理学和从完成的毒理学和安全数据 T2D受试者的临床试验，这项SBIR I期研究的成功结论将验证拟议的泛帕皮动力学家，作为治疗AH受试者的安全有效干预措施在中度和重度AH患者中定义临床试验的方法。