Candidate selection of a LPAR1 antagonist 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。 本申请中提供的可行性数据确立了Epigen的一种LPAR 1电极导线的概念验证 在NASH和肝纤维化的两种不同的小鼠模型中，使用拮抗剂EPGN 2154。体外机制数据 证实了LPAR 1拮抗作用阻断肝星状细胞增殖，从而阻断一种重要的纤维化 通路此外，LPAR 1拮抗剂阻断MCP-1刺激的巨噬细胞迁移，表明LPAR 1拮抗剂对巨噬细胞的增殖有抑制作用。 抗炎机制在我们的工作过程中，我们已经确定了药物的组合， 与EPGN 2154互补的作用机制，在临床前模型中提供上级疗效 并且可以对患者产生更大的益处。 在SBIR第2阶段拨款中，我们提出了一种方法，涉及更详细的临床前评估， EPGN 2154和组合在NASH的一个转化动物模型中的应用。为了优化剂量， 在EPGN 2154的组合方案中，HFHC喂养的NASH野生型小鼠模型被认为是足够的 因为它具有人类NASH的特征。在本申请中，我们寻求：i）进行详细的剂量- EPGN 2154在NASH的HFHC小鼠模型中的响应功效研究，以确定EPGN 2154的最小有效剂量。 ii）用最佳剂量的EPGN 2154与市售药物组合进行功效研究， GLP-1 R激动剂和GIP/GLP-1 R激动剂，iii）完成GLP安全药理学研究并提交IND 用于支持人类的第一阶段临床试验。根据制药公司和投资者的反馈，一项IND- 具有临床前有效性和安全性的现成资产，沿着划定的临床路径建立，是一种有吸引力的 商业化的资产。这项工作的成功结果将可能引发私人投资的推进 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.