Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis

描述（由申请人提供）：非酒精性脂肪性肝炎（NASH）的特点是肝脏脂肪改变，伴有炎症和肝细胞损伤，晚期可导致纤维化和肝硬化，死亡率高。NASH通常与其他常见的代谢异常相关，如胰岛素抵抗和内脏性肥胖。肝移植是目前治疗严重NASH或其他形式肝纤维化的唯一方法，目前尚无批准的药物治疗。器官移植是一项困难、危险和昂贵的手术，器官稀缺，移植肝脏发生肝硬化的风险增加，突出了对新治疗选择的主要未满足需求。蛋白酶活化受体-2 （PAR2）是一种在肝细胞和炎症细胞中高度丰富的信号受体，它控制导致严重NASH和肝硬化的炎症和纤维化过程。利用pepducin技术开发的细胞穿透性脂化PAR2抑制剂PZ-235提供了一个独特的机会来靶向g蛋白偶联受体（gpcr）的细胞内表面，如PAR2，具有精致的特异性、效力和较长的半衰期。PZ-235是一种先进的抗炎/抗纤维化候选药物，靶向PAR2并阻断肝星状细胞和炎症细胞中的PAR2信号。PZ-235可减少高达50%的脂肪肝脂肪变性和高甘油三酯血症，并在饮食诱导的NASH小鼠模型中抑制小叶炎症和全身性丙氨酸转氨酶（ALT）水平，类似于par2缺陷小鼠品系的作用。PZ-235治疗显著改善了小鼠NASH活性评分（NAS），这与抑制组织学疾病进展相对应。PZ-235还可以显著预防严重胰腺炎，这是几种新批准的ii型糖尿病药物的常见后遗症。总之，这些临床前数据确定PZ-235是一种强有力的、潜在有效的NASH治疗候选药物。在Aim 1中，我们将测试PZ-235的药理学特性，在肝脏/NASH小鼠模型中显示显著的肝脏传递和功效数据，以证明阻断肝脏/NASH小鼠模型的晚期第2期纤维化，并在啮齿动物中提供60天重复每日给药的安全性/毒性数据（系统参数、肝酶、体重、注射部位耐受性、血液学）。目的

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis and cirrhosis and high mortality rates. NASH is frequently associated with other common metabolic abnormalities, such as insulin resistance and visceral obesity. Liver transplantation is currently the only therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments. Organ transplantation is a difficult, risky and costly procedure with scarce organ availability and increased risk of developing cirrhosis in the transplanted liver from the original, highlighting the major unmet need for new therapeutic options. Protease-activated receptor-2 (PAR2) is a signaling receptor that is highly abundant in liver cells and inflammatory cells which controls inflammatory and fibrotic processes that lead towards severe NASH and liver cirrhosis. The cell-penetrating, lipidated PAR2 inhibitor PZ-235 was developed using pepducin technology and offers a unique opportunity to target the intracellular surface of G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives. PZ-235 is an advanced anti-inflammatory/anti-fibrotic drug candidate that targets PAR2 and blocks PAR2 signaling in hepatic stellate and inflammatory cells. PZ-235 reduces fatty liver steatosis and hypertriglyceridemia by up to 50%, and suppresses lobular inflammation and systemic alanine aminotransferase (ALT) levels in mouse models of diet-induced NASH similar to effects in a PAR2-deficient mouse strain. PZ-235 treatment gave a major improvement in NASH activity scores (NAS) in mice, which corresponded to suppression of histologic disease-progression. PZ-235 also significantly protected against severe pancreatitis, a common sequela seen with several of the newly approved type-II diabetes drugs. Together, these preclinical data identify PZ-235 as a potent and potentially effective drug candidate for NASH treatment. In Aim 1, we will test the pharmacologic properties of PZ-235 with the milestones of showing significant delivery into liver and efficacy data to demonstrate blockade of the late 2nd fibrotic hit in liver/NASH mouse models, and provide pilot safety/tox data (systemic parameters, liver enzymes, body weight, injection site tolerability, hematology) in 60 day repeat dose daily administration in rodents. Aim 2 will conduct GLP safety-toxicology and PK/PD studies of cGMP-produced PZ-235 in 2 species, with design of upcoming first-in- human phase I and II clinical trials in NASH patients with our gastroenterology and MR imaging clinical collaborators.