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.

项目概要酒精性肝炎 (AH) 是一种严重且急性的酒精介导性肝病，影响约 34% 的重型肝炎患者。饮酒者的健康负担约为 22 亿美元/年。 AH 患者的寿命很短。预计，约 70% 会在就诊后的前六个月内死亡。近 40% 的患者在首次出院后 90 天内就诊，进一步推高了费用作为昂贵且不可持续的肝脏移植的一种较弱的替代方案， AH的一线药物干预以皮质类固醇给药为主，但未成功不幸的是，皮质类固醇并不能改善患者的生存率和生存率。与一些继发并发症有关，包括感染、胃肠道出血、急性此外，皮质类固醇治疗后出现感染的患者也会出现胰腺炎和肾功能衰竭。对于禁忌使用类固醇的患者，替代方案的死亡率明显更高。治疗选择是己酮可可碱，一种磷酸二酯酶抑制剂，在临床上对 AH 患者无效，因为 STOPAH-1 多中心临床试验中报道，Pleiogenix 正在开发一种独特的口服（QD）疗法。基于新型口服活性非噻唑烷二酮泛 PPAR 激动剂 (PLG888) 的 AH 方法， PLG888 独特的结构设计可选择性地调节所有三种 PPAR 同工型的活性。能够完全激动 PPAR 以及部分激动 PPAR 和 PPAR 克服方与 PPAR 和 PPAR 初步激活相关的影响（例如水肿、体重增加、骨折）。在非酒精性脂肪性肝炎小鼠、肥胖恒河猴以及多项临床试验中获得的数据 2 型糖尿病 (T2D) 患者表明 PLG888 1) 降低肝脏关键标志物的活性损伤，包括降低丙氨酸转氨酶 (ALT) 和天冬氨酸转氨酶 (AST)，2) C 反应性蛋白质，3) 增加脂联素（高达 200%），积极改善肝脏脂肪变性、纤维化和该 SBIR 第一阶段项目的目标是评估使用 PLG888 作为新型口服药物的可行性。 (qd) AH 治疗在 AIM 1 中，Pleiogenix 将执行剂量探索和治疗。在经过验证的 AH 小鼠模型中进行预防研究，该模型是通过长期和狂饮乙醇喂养产生的；加上 LPS 给药以产生第二次打击，以增加 AIM 2 中最有效的剂量。 AIM 1 中鉴定的结果将用于评估更大的小鼠群体，以进行临床前研究来测试 PLG888 在降低乙醇的心脏毒性方面的功效和安全性，特别是将结合之前完成的毒理学和安全性数据进行评估。 T2D 受试者的临床试验，这项 SBIR I 期研究的成功结束将验证提出泛 PPAR 激动剂作为治疗 AH 受试者的安全有效的干预措施，为治疗 AH 受试者铺平了道路临床试验的方式来确定中度和重度 AH 患者的剂量范围。