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

项目总结 酒精性肝炎(AH)是一种严重而急性的酒精性肝病，约34%的重型肝炎患者 酒精饮用者，每年造成约22亿美元的医疗负担。啊，受难者的生命短暂 预计，约70%的人在发病后的前六个月死亡。再次入院治疗发生在 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。作为昂贵和不可持续的肝脏移植的薄弱替代品， 对AH的一线药物干预是基于皮质类固醇的应用，这是一次徒劳的尝试 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存活率和 与几种继发性并发症有关，包括感染，胃肠道出血，急性 胰腺炎和肾功能衰竭。此外，在皮质类固醇治疗后发生感染的患者显示 明显更高的死亡率。对于禁用类固醇的患者，替代方案 治疗方案是己酮可可碱，一种临床上对AH患者无效的磷酸二酯酶抑制剂，AS 在STOPAH-1多中心临床试验中报道。Pleigenix正在开发一种独特的口服(Qd)疗法 基于新型、口服活性的非噻唑二酮PAN-PPAR激动剂(PLG888)的治疗AH的方法， 优化以选择性地调节所有三种PPAR亚型的活性。PLG888型S独特的结构设计 能够完全激活PPAR，同时部分激活PPAR和PPAR克服侧 与完全激活PPAR和PPAR相关的影响(例如，浮肿、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(T2D)患者表明PLG8881)降低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)减少C反应 蛋白质，以及3)增加脂联素(高达200%)，积极改善肝脏脂肪变性、纤维化和 气球在膨胀。该SBIR第一阶段项目的目标是评估PLG888作为一种新型口腔药物的可行性 (Qd)治疗急性胰腺炎。提出了以下目标。在目标1中，Pleigenix将执行剂量发现和 通过长期大量饮酒而产生的急性酒精性肝炎小鼠模型的预防研究； 再加上脂多糖注射，造成第二次打击，增加肝脏损伤。在AIM 2中，最有效的剂量 AIM 1中确定的将被用于评估更大的小鼠队列，以进行临床前研究，以测试 PLG888降低乙醇不良反应的有效性和安全性。尤其是心脏毒性， 将会被评估。与之前执行的毒物学和安全数据相结合 在T2D患者的临床试验中，这项SBIR I期研究的成功结束将验证 建议的PAN-PPAR激动剂，作为一种安全有效的干预措施治疗急性脑出血患者，铺路 临床试验确定中重度急性呼吸窘迫综合征患者剂量范围的方法。

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.