Lead candidate identification of LPAR1 antagonists for therapeutic application in NASH

摘要 该应用的最终目标是开发一种epigen的溶血磷脂的专有拮抗剂 酸性受体1(LPAR1)用于有效治疗与慢性疾病相关的肝纤维化 酒精性脂肪性肝炎(NASH)，一种严重的非酒精性脂肪性肝病(NAFLD)。NAFLD是最多的 这是一种常见的肝病，与肥胖和2型糖尿病有关。目前还没有有效的 除了改变生活方式外，NASH还可进行治疗。本申请中提供的初步数据 在三种小鼠模型上建立了EPIGEN的LPAR1先导拮抗剂之一EPGN696的概念验证 非酒精性脂肪肝和肝纤维化。体外机制数据证实LPAR1拮抗剂阻断肝星状细胞 增殖，从而阻断一条重要的纤维化途径。此外，LPAR1拮抗剂可阻断血管的迁移 巨噬细胞受单核细胞趋化蛋白-1刺激，提示其具有抗炎机制。在我们工作的过程中 在肾脏疾病方面，我们已经确定了EPGN2154，一种改进的LPAR1拮抗剂，已被证明是安全和 在肾病模型中比EPGN696更有效。 在这一阶段的SBIR赠款中，我们提出了一种方法，该方法将涉及EPGN2154的临床前评估 在纳什的两个动物模型中。这种疾病会诱发较长的时间和慢性 LPAR1拮抗剂的治疗将延长。EPGN696将用作比较器 这些研究。我们预计，这将使表征EPGN2154的最低有效剂量在 NASH相关端点。这项工作的成功结果将推动毒物学和化学方面的努力， 制造和控制(CMC)工作，以支持研究新药(IND)申请的提交和 最终开始在人体上进行临床试验。

Summary The ultimate goal of this application is to develop one of Epigen’s proprietary antagonists of the lysophosphatidic acid receptor 1 (LPAR1) for the effective treatment of liver fibrosis associated with chronic diseases such as non- alcoholic steatohepatitis (NASH), a severe type of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disease and is associated with obesity and type-2 diabetes. There are currently no effective treatments available for NASH except lifestyle changes. Preliminary data presented in this application establishes the proof-of-concept of one of Epigen’s LPAR1 lead antagonists, EPGN696, in three mouse models of NASH and liver fibrosis. In vitro mechanistic data confirms that LPAR1 antagonism blocks hepatic stellate cell proliferation, thus blocking an important fibrotic pathway. Furthermore, LPAR1 antagonists block migration of macrophages stimulated by MCP-1 indicating an anti-inflammatory mechanism. During the course of our work in kidney disease, we have identified EPGN2154, an improved LPAR1 antagonist, that has proven safe and more efficacious than EPGN696 in kidney disease models. In this phase 1 SBIR grant, we propose an approach which will involve the pre-clinical evaluation of EPGN2154 in two translational animal models of NASH. The disease will be induced for a longer period and chronic therapeutic treatment with the LPAR1 antagonists will be extended. EPGN696 will be used as a comparator in these studies. We expect that this will allow characterization of a minimum efficacious dose of EPGN2154 in NASH relevant endpoints. The successful outcome of this work will lauch efforts in toxicology and chemistry, manufacturing and controls (CMC) work to support filing of an investigational new drug (IND) application and eventually initiation of clinical trials in humans.