Lead candidate identification of LPAR1 antagonists for therapeutic application in NASH

总结 该申请的最终目标是开发Epigen专有的溶血磷脂拮抗剂之一， 酸受体1（LPAR 1）用于有效治疗与慢性疾病如非肝性肝纤维化相关的肝纤维化。 酒精性脂肪性肝炎（NASH），一种严重类型的非酒精性脂肪性肝病（NAFLD）。NAFLD是最 常见的肝脏疾病，并与肥胖和2型糖尿病有关。目前还没有有效 治疗NASH，除了改变生活方式。本申请中提供的初步数据 在三种小鼠模型中建立了Epigen的LPAR 1先导拮抗剂EPGN 696的概念验证 NASH和肝纤维化体外机制数据证实，LPAR 1拮抗作用阻断肝星状细胞 增殖，从而阻断重要的纤维化途径。此外，LPAR 1拮抗剂阻断了 MCP-1刺激的巨噬细胞，表明抗炎机制。在我们工作的过程中， 在肾脏疾病中，我们已经确定了EPGN 2154，一种改进的LPAR 1拮抗剂，已被证明是安全的， 在肾脏疾病模型中比EPGN 696更有效。 在第一阶段SBIR资助中，我们提出了一种方法，该方法将涉及EPGN 2154的临床前评估 在NASH的两个转化动物模型中。诱发本病的时间较长，且呈慢性化 将延长使用LPAR 1拮抗剂的治疗。EPGN 696将用作对照品， 这些研究。我们预期这将允许表征在小鼠中EPGN 2154的最小有效剂量。 NASH相关终点。这项工作的成功结果将在毒理学和化学方面做出努力， 生产和控制（CMC）工作，以支持研究性新药（IND）申请的提交， 最终开始人体临床试验。

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.