Hepatic Growth Factor Mimetic for Liver Fibrosis

描述(申请人提供)：肝纤维化是一种影响全球数千万患者的疾病，是由于乙型或丙型病毒性肝炎、过度饮酒、铁超载或肝外梗阻造成的慢性损伤导致的肝脏疤痕反应，可发展为肝硬化、肝功能衰竭和死亡。事实上，由于丙型肝炎流行和与非酒精性脂肪性肝炎相关的肝病发病率上升，预计未来十年死于肝纤维化/肝硬变并发症的人数将增加两倍。目前可用的治疗方法，包括抗病毒药物，在治疗潜在的纤维化方面基本上无效，在大多数情况下，肝移植是唯一有效的选择。散射因子(SF)，又称肝细胞生长因子(HGF)，是一种非日光性生长因子，主要通过其促有丝分裂、促运动和促形态作用诱导多种细胞类型的激活和增殖。此外，SF/HGF通过调节胶原和转化生长因子-β等关键促纤维化因子发挥抗纤维化作用。事实上，最近发表的几项研究已经证明了外源性给予SF/HGF在肾、肺和肝纤维化动物模型中的治疗潜力。Angion发现了一种SF/HGF的小分子模拟物，它概括了体内和体外的所有SF/HGF活性，并已在两个动物模型中被证明具有抗肝纤维化的作用。为了进一步开发这种有潜力的化合物作为治疗纤维化肝病的潜在药物，将在以下三个动物模型中对其进行评估：(1)从剂量、疗程和给药途径方面评价其对肝纤维化的疗效；(2)在药代动力学、毒理学和遗传毒性研究中；(3)在蛋白质组学研究中，对其作用机制进行研究。这些研究旨在为IND申请的提交收集完整的数据集。一种安全有效的抗肝纤维化药物有望延缓或阻止肝纤维化的进展，阻止终末期肝硬变的发展，并有可能逆转疾病的病理进程。

DESCRIPTION (provided by applicant): Hepatic fibrosis, a disease affecting tens of millions of patients worldwide, is the liver scarring response to chronic injury from viral hepatitis B or C, excessive alcohol use, iron overload or extrahepatic obstructions and can progress to liver cirrhosis, liver failure and death. In fact, deaths from complications of liver fibrosis/cirrhosis are expected to triple over the next decade as a result of the hepatitis C epidemic and the growing incidence of liver disease associated with non-alcoholic steatohepatitis. Currently available therapies, including antiviral, are largely ineffective in treating the underlying fibrosis, and in the majority of cases, liver transplantation is the only effective option. Scatter factor (SF), also known as hepatocyte growth factor (HGF), is a apheliotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic, motogenic and morphogenic activities. Additionally, SF/HGF exerts antifibrotic effects by modulating key profibrogenic elements including collagen and transforming growth factor-beta. In fact, several recently published studies have documented the therapeutic potential of exogenously administered SF/HGF in animal models of renal, pulmonary and liver fibrosis. A small molecule mimetic of SF/HGF has been discovered at Angion that recapitulates all in vitro and in vivo SF/HGF activities and has been shown to protect against liver fibrosis in two animal models. In order to further develop this promising compound as a potential therapeutic for fibrotic liver disease, it will be evaluated (1) in three animal models for its efficacy in liver fibrosis with respect to dose, time course of treatment, and route of administration, (2) in the studies of pharmacokinetics, toxicology and genotoxicity, (3) in the studies on its mechanism of action by proteomics. These studies are designed to collect complete data sets for the filing of an IND application. A safe and effective antifibrotic agent is expect to slow or stop the progression of liver fibrosis, prevent the development of end-stage liver cirrhosis, and possible reverse the pathological course of the diseases.