PAR2 Pepducins as a Novel Treatment of Idiopathic Pulmonary Fibrosis

特发性肺纤维化（IPF）是最常见的间质性肺病，发生在约128，000 在美国，每年诊断出48，000例新病例。典型的临床过程是渐进的 一种纤维化疾病，其特征是肺的瘢痕形成和“蜂窝样变”， 组织运输氧气的能力。共病肺动脉高压常见于IPF患者 并导致临床预后恶化。IPF最终剥夺了患者的呼吸能力， 确诊后五年的死亡率为66%。这种高死亡率对应于 每年有大量未被重视的死亡人数（n= 40，000），与由于以下原因导致的死亡率大致相同 乳腺癌目前的治疗主要集中在阻断肺成纤维细胞的增殖。一种新型 靶点-蛋白酶激活受体2（PAR 2）-最近已被鉴定为免疫调节中的重要介质。 IPF的发病机制。PAR 2是一种细胞表面受体，在反应性肺上皮细胞、成纤维细胞 以及肺中PAR 2高表达的IPF患者 生存率和临床指标较差。促凝血蛋白酶（因子VIIa/Xa/TF）活性增加， 肺和局部炎性蛋白酶如肥大细胞类胰蛋白酶触发异常PAR 2信号传导， 激活纤维化反应。这个绿洲快速通道STTR提案的目标是基于我们的发现， PAR 2抑制剂OA-235 c作为异常肺纤维化过程的有效抑制剂。细胞穿透， 脂化抑制剂OA-235 c使用我们专有的Pepducin™技术开发。Pepducin™ 技术提供了一个独特的机会，靶向细胞内表面的降钙素G蛋白偶联， 受体（GPCR），例如PAR 2，具有极高的特异性、效力和长半衰期，可延长药物作用 暴露于靶组织，即肺。在临床前研究中，我们发现OA-235 c显著地 抑制IPF和其他纤维化器官模型中的纤维化和炎症。在初步的毒理学研究中， OA-235 c在犬、大鼠和小鼠中是安全和耐受的，没有胰腺、肝脏、心脏、肾脏、 肺、骨髓或其他器官毒性或任何实验室异常，高倍数的治疗剂量 次给药结束Oasis Pharmaceuticals成功地预先配制并生产了纯度为98%的OA-235 c， 化学和蛋白水解稳定性。第1阶段（目标1）将确定并验证50-100 mg/mL的制剂 对OA-235 c溶解性，并显示出显著的肺纤维化抑制，并确定任何药物-药物 与两种标准治疗IPF药物的相互作用。第2阶段（Aim 2）的目标是完成IND 在GLP条件下使用GMP OA-235 c进行数据包，最终向FDA提交IND 里程碑快速完成拟议的临床前和IND使能研究将产生一种新药 具有抗纤维化作用模式的候选药物，用于潜在治疗患者的IPF。

Idiopathic pulmonary fibrosis (IPF), the most common of the interstitial lung diseases, occurs in about 128,000 people, with 48,000 new cases diagnosed annually in the US. The typical clinical course is a progressive fibrotic disease characterized by scarring and `honeycombing' of the lungs causing an irreversible loss of the tissue's ability to transport oxygen. Co-morbid pulmonary hypertension is commonly seen in patients with IPF and contributes to a worsening clinical prognosis. IPF ultimately robs a patient of the ability to breathe leading to a mortality rate of 66% at five years following diagnosis. This high death rate corresponds to an unappreciated large number of fatalities per year (n=40,000), about the same yearly rate as deaths due to breast cancer. Current treatments have mainly focused on blocking proliferation of lung fibroblasts. A novel target—Protease-Activated Receptor-2 (PAR2)—has recently been identified as an important mediator in the pathogenesis of IPF. PAR2 is a cell surface receptor that is upregulated in reactive lung epithelium, fibroblasts, and inflammatory cells during progression of IPF, and IPF patients with high expression of PAR2 in the lung have worse survival and clinical indices. Increased pro-coagulant protease (factors VIIa/Xa/TF) activity in the lung, and local inflammatory proteases such as mast cell tryptase trigger aberrant PAR2 signaling and activation of the fibrotic response. The goal of this Oasis fast-track STTR proposal is based on our discovery of a PAR2 inhibitor, OA-235c, as a potent suppressor of aberrant lung fibrotic processes. The cell-penetrating, lipidated inhibitor OA-235c, was developed using our proprietary Pepducin™ technology. Pepducin™ 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 lung. In pre-clinical studies, we show that OA-235c significantly suppresses fibrosis and inflammation in IPF and other fibrotic-organ models. In preliminary toxicology studies, OA-235c was safe and tolerated in dogs, rats, and mice with no evidence of pancreas, liver, heart, kidney, lung, bone marrow, or other organ toxicity or any laboratory abnormalities at high multiples of the therapeutic dose. Oasis Pharmaceuticals successfully preformulated and produced OA-235c at 98% purity and high chemical and proteolytic stability. Phase 1 (Aim 1) will identify and validate a formulation at 50-100 mg/mL solubility for OA-235c and demonstrate significant suppression of lung fibrosis and determine any drug-drug interactions with the two standard-of-care IPF agents. The goal of Phase 2 (Aim 2) will be to complete the IND Data Package under GLP conditions with GMP OA-235c with submission of the IND to the FDA as the final milestone. Rapid completion of the proposed preclinical and IND-enabling studies would generate a novel drug candidate with an anti-fibrotic mode of action for the potential treatment of IPF in patients.