Candidate selection of a LPAR1 antagonist for therapeutic application in NASH

用于 NASH 治疗应用的 LPAR1 拮抗剂的候选选择

• 批准号: 10760130
• 负责人: Rohit Kohli
• 金额: $ 97.17万
• 依托单位: EPIGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760130
• 关键词: Acute; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Authorization documentation; Biological Assay; C57BL/6 Mouse; CCL2 gene; Carbohydrates; Cardiovascular Physiology; Cardiovascular system; Cell Proliferation; Cells; Chronic; Chronic Disease; Cicatrix; Cirrhosis; Clinic; Clinical Data; Clinical Paths; Clinical Trials; Data; Deposition; Diabetic Nephropathy; Diabetic Neuropathies; Diet; Disease; Dose; Drug Combinations; Dyslipidemias; Fatty acid glycerol esters; Feedback; Female; Fibrosis; Fructose; Goals; Grant; Hepatic Insufficiency; Hepatic Stellate Cell; Histologic; Human; In Vitro; Individual; Infiltration; Inflammation; Insulin Resistance; Investigational New Drug Application; Investments; Lead; Life Style; Liver; Liver Fibrosis; Liver diseases; Lysophosphatidic Acid Receptors; Macrophage; Malignant neoplasm of liver; Metabolic syndrome; Modeling; Monkeys; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Preparation; Prevalence; Privatization; Process; Rattus; Regimen; Research; Respiratory System; Risk; Safety; Small Business Innovation Research Grant; Supplementation; Therapeutic; United States Food and Drug Administration; Wild Type Mouse; Work; antagonist; authority; candidate selection; clinical efficacy; commercialization; effective therapy; efficacy study; epigen; feeding; human disease; improved; in vivo; liver biopsy; male; meetings; migration; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; patch clamp; phase III trial; preclinical efficacy; preclinical evaluation; preclinical safety; programs; response; safety assessment; safety study; standard measure; telemetering

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.

概括 该应用的最终目的是发展溶物磷脂的专有拮抗剂之一 酸受体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肝病（NAFLD）。 NAFLD是最大的 常见的肝病，与肥胖和2型糖尿病有关。目前没有效力 除了改变生活方式外，可用于NASH的治疗。 本应用程序中介绍的可行性数据建立了Epigen LPAR1铅之一的概念证明 拮抗剂EPGN2154在NASH和肝纤维化的两种不同小鼠模型中。体外机械数据 确认LPAR1拮抗作用会阻止肝星状细胞增殖，从而阻止重要的纤维化 路径。此外，LPAR1拮抗剂阻止了MCP-1刺激的巨噬细胞的迁移，表明 抗炎机制。在工作过程中，我们已经确定了药物的组合 完全在EPGN2154的作用机理，在临床前模型中提供了较高的效率 并可能对患者带来更大的好处。 在此阶段2 SBIR赠款中，我们提出了一种涉及更详细的临床前评估的方法 EPGN2154和一种纳什转化动物模型中的组合。优化剂量和 EPGN2154的组合方案，HFHC喂养的野生型小鼠模型被认为是足够的 因为它具有人类纳什的特征。在此应用中，我们寻求：i）进行详细的剂量 - NASH的HFHC小鼠模型中EPGN2154的响应效率研究，以确定最低效率 剂量（MED），ii）通过优化EPGN2154的剂量与商业结合进行效率研究 GLP-1R激动剂和GIP/GLP-1R激动剂，iii）完整的GLP安全药理学研究并提交IND 向FDA支持人类的1阶段临床试验。根据Pharma和Investors的反馈 与临床前效率和安全性以及与划定的临床路径一起建立的临床前效率和安全性的现成资产，是一个有吸引力的 用于商业化的资产。这项工作的成功结果可能会触发私人投资以促进 启动人类临床试验的计划。