Anti-Fibrotic Therapy for Pulmonary Fibrosis

描述（由申请人提供）：肺纤维化是一种弥漫性间质性肺病，其特征为慢性炎症和病因不明的进行性纤维化。肺纤维化影响全世界500万人，在美国有超过20万肺纤维化患者。其中每年有4万多份过期。通常，患者在确诊时都是四五十岁。从诊断开始的中位生存期为5.5年。肺纤维化与显著的发病率和死亡率相关，并且对目前可用的治疗反应不佳。虽然类固醇和其他免疫抑制剂作为肺纤维化的标准治疗，但这些药物已被证明是不够的，并具有有害的副作用。最近的研究已经确定肝细胞生长因子（HGF）作为抗纤维化剂，其在动物模型中保护免于转化生长因子（TGF β）介导的对上皮细胞的凋亡作用和肝、肾和肺纤维化中的细胞外基质积累。为了克服蛋白质治疗的缺点和费用，我们开发了一种通过噬菌体展示和分子模拟技术的新组合来合理设计的HGF活性的小分子模拟物。在体外，我们的主要HGF模拟物Ang 1170激活HGF受体c-Met，并诱导其生物学功能，包括激活内皮和支气管上皮细胞增殖，而不刺激SMC/成纤维细胞，并抑制TGF β表达，类似于HGF。在体内，Ang 1170抑制胶原合成并减少肝和肾纤维化。我们最近的初步I期研究表明，Ang 1170治疗可降低博来霉素诱导的体内肺纤维化中的胶原含量。定量组织学评价表明，与溶剂处理组相比，Ang 1170处理的小鼠肺切片具有减少的间质纤维化、肺泡凋亡和受损组织。在拟定的研究中，我们将在三种不同的肺纤维化临床前动物模型中进一步评价Ang 1170（通过延迟治疗和口服途径）对肺纤维化的保护作用。本申请的目的是在临床相关的肺纤维化模型中评价我们的领先小分子化合物Ang 1170，以开发足够的数据，成功向FDA提交研究性新药（IND）申请，以进行我们的领先小分子抗纤维化治疗肺纤维化的临床试验。 肺纤维化影响全球500万人，美国超过20万患者。从诊断开始的中位生存期为5.5年。本申请的目的是在肺纤维化的临床相关模型中评估一种领先的小分子候选药物，以获得足够的数据，从而成功向FDA提交研究性新药（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.