Anti-Fibrotic Therapy for Pulmonary Fibrosis

描述(申请人提供)：肺纤维化是一种弥漫性间质性肺疾病，以慢性炎症和进行性纤维化为特征，病因不明。肺纤维化影响全球500万人，在美国有20多万肺纤维化患者。其中，每年有超过4万份到期。通常情况下，确诊时患者都是四五十岁。确诊后的中位生存期为5.5年。肺纤维化与明显的发病率和死亡率有关，并且对目前可用的治疗反应很差。虽然类固醇和其他免疫抑制剂是肺纤维化的标准治疗药物，但这些药物已被证明不够充分，并有有害的副作用。最近的研究发现，肝细胞生长因子(HGF)是一种抗纤维化药物，可以对抗转化生长因子(TGFbeta)诱导的肝、肾、肺纤维化模型中上皮细胞的凋亡和细胞外基质的积聚。为了克服蛋白质疗法的缺点和费用，我们通过噬菌体展示和分子建模技术的新颖组合，合理设计了一种模拟HGF活性的小分子。在体外，我们的先导HGF模拟物Ang1170激活HGF受体c-Met，并诱导其生物学功能，包括激活内皮细胞和支气管上皮细胞增殖，而不刺激SMC/成纤维细胞，并抑制类似于HGF的转化生长因子β的表达。在体内，Ang1170抑制胶原合成，减轻肝肾纤维化。我们最近的I期初步研究表明，Ang1170治疗可以降低博莱霉素诱导的体内肺纤维化中的胶原含量。定量组织学评估显示，与赋形剂处理组相比，Ang1170处理的小鼠肺切片减少了间质纤维化、肺泡细胞凋亡和组织损伤。在拟议的研究中，我们将进一步评估Ang1170(通过延迟治疗和口服途径)对三种不同临床前肺纤维化动物模型肺纤维化的保护作用。这项申请的目的是评估我们的先导小分子化合物Ang1170在临床相关肺纤维化模型中的作用，以便提供足够的数据，成功地向FDA提交研究性新药(IND)申请，以执行我们的先导小分子抗肺纤维化疗法的临床试验。 肺纤维化影响着全球500万人和美国20多万患者。确诊后的中位生存期为5.5年。本申请的目的是评估临床相关肺纤维化模型中的领先小分子药物候选药物，以开发足够的数据，成功地向FDA提交研究用新药(IND)申请，以进行临床试验。

DESCRIPTION (provided by applicant): Pulmonary Fibrosis is a diffuse interstitial lung disease characterized by chronic inflammation and progressive fibrosis of unknown etiology. Pulmonary fibrosis affects five million people worldwide and in the United States there are over 200,000 patients with pulmonary fibrosis. Of these more than 40,000 expire annually. Typically, patients are in their forties and fifties when diagnosed. Median survival from time of diagnosis is 5.5 years. Pulmonary fibrosis is associated with pronounced morbidity and mortality and responds poorly to currently available therapy. While steroids and other immunosuppressive agents serve as the standard treatment for pulmonary fibrosis, these agents have proved inadequate and have deleterious side effects. Recent studies have identified hepatocyte growth factor (HGF) as an antifibrogenic agent that protects against transforming growth factor (TGFbeta) mediated apoptotic effects on epithelial cells and extracellular matrix accumulation in liver, kidney and lung fibrosis in animal models. In order to overcome the shortcomings and expense of protein therapy, we have developed a small molecule mimetic of HGF activity that was rationally designed through a novel combination of phage display and molecular modeling technology. In vitro, our lead HGF mimetic, Ang1170, activates the HGF receptor, c-Met, and induces its biological functions including activation of endothelial and bronchial epithelial cell proliferation, without stimulating SMC/fibroblasts and suppresses TGF beta expression similar to HGF. In vivo, Ang1170 inhibits collagen synthesis and decreases the liver and kidney fibrosis. Our recent preliminary PHASE-I studies suggest that Ang1170 treatment decreases collagen content in bleomycin induced pulmonary fibrosis in vivo. Quantitative histological evaluation demonstrated that Ang1170 treated mouse lung sections have reduced interstitial fibrosis, alveolar apoptosis, and damaged tissue compared with the vehicle-treated group. In the proposed studies, we will further evaluate the protective effects of Ang1170 (via delayed treatment and oral route) on lung from lung fibrosis in three different pre- clinical animal models of lung fibrosis. The objective of this application is the evaluation of our lead small molecule compound, Ang1170 in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials of our lead small molecule antifibrotic therapy for pulmonary fibrosis. Pulmonary fibrosis affects five million people worldwide and over 200,000 patients in the United States. Median survival from time of diagnosis is 5.5 years. The objective of this application is to evaluate a lead small-molecule drug candidate in clinically relevant models of lung fibrosis to develop sufficient data to successfully file an investigational new drug (IND) application to the FDA to perform clinical trials.