Candidate selection of a LPAR1 antagonist 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。 此应用程序中提供的可行性数据建立了Eigen的LPAR1引线之一的概念验证 拮抗剂EPGN2154在两种不同的NASH和肝纤维化小鼠模型中使用。体外力学数据 证实LPAR1拮抗剂阻断肝星状细胞的增殖，从而阻断一个重要的纤维化 路径。此外，LPAR1拮抗剂阻断由MCP-1刺激的巨噬细胞的迁移，表明 抗炎机制。在我们的工作过程中，我们发现了药物与 EPGN2154的补充作用机制，在临床前模型中提供更好的疗效 并可能给患者带来更大的好处。 在这个第二阶段的SBIR赠款中，我们提出了一种方法，涉及更详细的临床前评估 EPGN2154和组合在NASH的一个翻译动物模型中。用于优化剂量和 EPGN2154联合方案，HFHC喂养的野生型NASH小鼠模型被认为是合适的 因为它呈现出人类纳什的特征。在本申请中，我们寻求：i)进行详细的剂量- EPGN2154对HFHC小鼠NASH模型的疗效研究 剂量(MED)，II)使用EPGN2154的最佳剂量结合商业 GLP-1R激动剂和GIP/GLP-1R激动剂，III)完成GLP安全药理学研究并提交IND 向FDA提供支持人体第一阶段临床试验的资金。根据Pharma和投资者的反馈，Ind- 具有临床前有效性和安全性的现成资产，以及描绘的临床路径，是一种有吸引力的 商业化的资产。这项工作的成功结果可能会推动私人投资的发展 启动人体临床试验的计划。

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. The feasibility data presented in this application establishes the proof-of-concept of one of Epigen’s LPAR1 lead antagonists, EPGN2154, in two different 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, we have identified combinations of drugs with complementary mechanisms of action to EPGN2154, which provide superior efficacy in the preclinical models and may result in greater benefit to patients. In this phase 2 SBIR grant, we propose an approach involving a more detailed pre-clinical evaluation of EPGN2154 and combinations in one translational animal model of NASH. For optimizing the dose and combination regimen of EPGN2154, the HFHC-fed wild type mouse model of NASH is considered adequate because it presents with features of human NASH. In this application, we seek to: i) conduct a detailed dose- response efficacy study of EPGN2154 in the HFHC mouse model of NASH to determine the minimum efficacious dose (MED), ii) conduct efficacy studies with the optimized dose of EPGN2154 in combination with commercial GLP-1R agonists and GIP/GLP-1R agonists, iii) complete GLP safety pharmacology studies and submit an IND to the FDA to support phase 1 clinical trials in humans. Based on feedback from Pharma and investors, an IND- ready asset with preclinical efficacy and safety established along with a delineated clinical path, is an attractive asset for commercialization. The successful outcome of this work will likely trigger private investment to advance the program towards initiation of clinical trials in humans.