Development of PAR2 Inhibitors for the Treatment of Nonalcoholic steatohepatitis

描述（由申请方提供）：非酒精性脂肪性肝炎（NASH）的特征为肝脏脂肪性变化伴炎症和肝细胞损伤，晚期可导致纤维化和肝硬化以及高死亡率。NASH通常与其他常见的代谢异常相关，如胰岛素抵抗和内脏肥胖。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，没有批准的药物治疗。器官移植是一项困难、风险高且昂贵的手术，器官可用性稀缺，移植肝脏从原始肝脏发展为肝硬化的风险增加，突出了对新治疗选择的主要未满足需求。蛋白酶激活受体-2（PAR 2）是一种在肝细胞和炎性细胞中高度丰富的信号传导受体，其控制导致严重NASH和肝硬化的炎性和纤维化过程。PZ-235是利用pepducin技术开发的具有细胞穿透性的脂化PAR 2抑制剂，它提供了一个独特的机会，可以靶向G蛋白偶联受体（GPCR）的细胞内表面，如PAR 2，具有精确的特异性、效力和长半衰期。PZ-235是一种高级抗炎/抗纤维化候选药物，靶向PAR 2并阻断肝星状细胞和炎症细胞中的PAR 2信号传导。PZ-235减少脂肪肝脂肪变性和高脂血症高达50%，并抑制饮食诱导的NASH小鼠模型中的小叶炎症和全身丙氨酸氨基转移酶（ALT）水平，与PAR 2缺陷小鼠品系中的效果相似。PZ-235治疗在小鼠中的NASH活性评分（NAS）中给出了重大改善，这对应于组织学疾病进展的抑制。PZ-235还能显著预防重症胰腺炎，这是几种新批准的II型糖尿病药物的常见后遗症。总之，这些临床前数据将PZ-235确定为用于NASH治疗的强效且潜在有效的候选药物。在目标1中，我们将测试PZ-235的药理学特性，其里程碑是显示显著的肝脏递送和有效性数据，以证明在肝脏/NASH小鼠模型中晚期第二次纤维化发作的阻断，并提供啮齿动物中60天重复剂量每日给药的初步安全性/毒性数据（全身参数、肝酶、体重、注射部位耐受性、血液学）。目的 2将在2个物种中对cGMP生产的PZ-235进行GLP安全性毒理学和PK/PD研究，设计即将在NASH患者中进行的首次人体I期和II期临床试验，我们的胃肠病学和MR成像临床合作者。

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.