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

• 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
• 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

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）是一种严重的急性酒精介导的肝病，影响约34%的重型肝炎患者。 饮酒者，每年的医疗保健负担约为22亿美元。所有的患者都是短命的 约70%的患者在发病后的前六个月内死亡。再次住院发生在 近40%的患者在首次出院后90天内出院，进一步推高了成本 与这种致命疾病有关。作为昂贵且不可持续的肝脏移植的一种弱替代方案， AH的一线药物干预以皮质类固醇给药为基础， 减少炎症和肝纤维化。不幸的是，皮质类固醇不能改善患者的生存率， 与几种继发性并发症有关，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生感染的患者显示， 死亡率明显更高。对于禁用类固醇的患者， 治疗选择是喷替福林，一种磷酸二酯酶抑制剂，在AH患者中临床无效， 在STOPAH-1多中心临床试验中报告。Pleiogenix正在开发一种独特的口服（qd）治疗 基于新型口服活性非噻唑烷二酮泛-PPAR激动剂（PLG 888）的AH治疗方法， 优化以选择性地调节所有三种PPAR同种型的活性。PLG 888独特的结构设计 能够沿着对PPAR β的完全激动和对PPAR β克服侧的部分激动 与完全PPAR γ和PPAR γ激活相关的效应（例如水肿、体重增加、骨折）。初步 在非酒精性脂肪性肝炎小鼠、肥胖恒河猴和多项临床试验中获得的数据 2型糖尿病（T2 D）患者表明PLG 888 1）降低了肝脏关键标志物的活性， 损伤，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（高达200%），积极改善肝脏脂肪变性，纤维化，和 气球。该SBIR第一阶段项目的目标是评估使用PLG 888作为新型口服药物的可行性 (qd)治疗AH。提出了以下目标。在AIM 1中，Pleiogenix将执行剂量探索， 在经验证的AH小鼠模型中进行的预防研究，该模型通过长期和酗酒乙醇喂养产生; 再加上脂多糖注射造成第二次感染，增加肝损伤在AIM 2中， 将使用AIM 1中鉴定的新基因来评估更大的小鼠队列，以进行临床前研究， PLG 888在减少乙醇有害影响方面的有效性和安全性。尤其是心脏毒性， 将被评估。结合先前执行的毒理学和安全性数据， 在T2 D受试者中进行的临床试验，这项SBIR I期研究的成功结论将验证 提出的泛-PPAR激动剂，作为治疗AH受试者的安全有效的干预措施， 通过临床试验确定中度和重度AH患者的剂量范围。

项目成果

Rifaximin-α in alcohol-associated liver disease.

利福昔明-α 治疗酒精相关性肝病。

• DOI: 10.1016/s2468-1253(23)00033-x
• 发表时间: 2023
• 期刊: The lancet. Gastroenterology & hepatology
• 作者: Xie,Chencheng;Singal,AshwaniK
• 通讯作者: Singal,AshwaniK