Development of PAR2 Pepducins as a Novel NASH Treatment

非酒精性脂肪性肝炎(NASH)的特征是肝脏中的脂肪变化伴随炎症和 晚期肝细胞损伤会导致纤维化、肝硬变和高死亡率。纳什是 经常与其他常见的代谢异常有关，如胰岛素抵抗和内脏 肥胖。肝移植是目前治疗严重NASH或其他疾病的唯一有效方法 迄今未获批准药物治疗的各种形式的肝纤维化。蛋白水解酶激活受体-2(PAR2)是一种 在肝星状细胞、肝细胞和炎性细胞中高度丰富的信号受体 控制导致严重NASH和肝硬变的纤维化、炎症和代谢过程。这个 细胞穿透性、脂化的PAR2抑制剂OA-235I是使用我们的专利PepducinTM技术开发的。 PepducinTM技术为靶向顽固性G蛋白的细胞内表面提供了一个独特的机会 偶联受体(GPCRs)，如PAR2，具有极高的特异性、效力和较长的半衰期，具有 药物长期暴露于靶组织，即肝脏。OA-235i是一种先进的抗纤维化/抗 炎性药物候选阻断PAR2信号在肝星状，炎症细胞和 肝细胞。在过去的3年里，在NIDDK的快速通道支持下，绿洲制药成功地 研制生产了纯度97-98%、稳定性高的cGMP OA-235I。在体内疗效研究中，OA- 235I显著降低脂肪肝脂肪变性/小叶炎症/气球损伤(NAS评分)和ALT水平 50%，并在饮食诱导的NASH小鼠模型中完全抑制AST PAR2缺乏所提供的保护。OA-235I对体重增加、肝脏的抑制作用非常显著 在6个月的DEN-NASH模型中，喂食HFD的小鼠的体重、TGS、脂肪变性和肝肿瘤灶的发展。 延迟性OA-235I治疗对8周诱导的严重肝纤维化有显著的44-49%的抑制作用 接触到CCl4。在7-28天的重复给药安全性/毒理学研究中，OA-235I在狗身上是安全和耐受的 在没有肝、心、肾、肺、骨髓或其他器官毒性或 治疗剂量高倍数的实验室异常。这一阶段的翻译研究 2B应用提供了快速的临床验证，并加速了OA-235i的商业化 与杜克医疗中心和塔夫茨医疗中心合作治疗NASH患者。目标1将 在资助的第一年完成OA-235i的IND数据包，并将IND作为 第一个里程碑。在2-3年，AIM 2将在17名正常人中进行I期-单次递增剂量(SAD)研究 健康志愿者(NHV)和NASH患者进行多次递增7天重复剂量研究(MAD)15例 NHV/NASH主题作为第二个重大里程碑。这项首次人体研究将确定安全剂量 用体外PAR2试验和生物标志物检测OA-235I的范围、耐受性和PK/PD疗效，并将通知 将在纳什人口中进行的第二阶段研究的设计和终点。 1

Non-alcoholic steatohepatitis (NASH) is characterized by fatty changes in the liver with inflammation and hepatocellular injury that in advanced stages leads to fibrosis, 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 effective therapeutic approach for severe NASH or other forms of liver fibrosis with no approved drug treatments to date. Protease-activated receptor-2 (PAR2) is a signaling receptor that is highly abundant in liver stellate cells, hepatocytes and inflammatory cells which controls fibrotic, inflammatory and metabolic processes that lead towards severe NASH and liver cirrhosis. The cell-penetrating, lipidated PAR2 inhibitor OA-235i, was developed using our proprietary PepducinTM technology. PepducinTM technology offers a unique opportunity to target the intracellular surface of recalcitrant G-protein coupled receptors (GPCRs) such as PAR2 with exquisite specificity, potency and long half-lives, with prolonged drug exposure to the target tissue, namely liver. OA-235i is an advanced anti-fibrotic/anti- inflammatory drug candidate that blocks PAR2 signaling in hepatic stellate, inflammatory cells and hepatocytes. In the past 3 years, with Fast-Track support from the NIDDK, Oasis Pharmaceuticals successfully formulated and produced cGMP OA-235i at 97-98% purity and high stability. In in vivo efficacy studies, OA- 235i significantly reduced fatty liver steatosis/lobular inflammation/ballooning injury (NAS score) and ALT levels by 50% and gave complete suppression of AST in mouse models of diet-induced NASH to the same level of protection afforded by PAR2-deficiency. OA-235i afforded highly significant suppression of weight gain, liver weight, TGs, steatosis and development of liver tumor foci in a 6-month DEN-NASH model in mice fed a HFD. Delayed OA-235i treatment gave a significant 44-49% suppression of severe liver fibrosis induced by 8-weeks of CCl4 exposure. In 7-28 day repeat-dose safety/toxicology studies, OA-235i was safe and tolerated in dogs and in rat GLP studies with no evidence of liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. The translational studies in this Phase 2b application provide a rapid clinical validation and accelerate the commercialization of OA-235i for the treatment of NASH patients in collaboration with Duke Medical Center and Tufts Medical Center. Aim 1 will complete the IND Data Package for OA-235i in year 1 of funding with submission of the IND to the FDA as the first milestone. In years 2-3, Aim 2 will conduct a Phase I-single ascending dose (SAD) study in 17 normal healthy volunteers (NHV) and NASH patients followed by multi ascending 7-day repeat dose study (MAD) in 15 NHV/NASH subjects as the second major milestone. This First-in-Human study will establish the safe dose range, tolerability and PK/PD efficacy of OA-235i using ex vivo PAR2 assays and biomarkers and will inform the design and endpoints of Phase 2 studies to be conducted in the NASH population. 1