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 该应用的最终目标是开发 Epigen 的溶血磷脂专有拮抗剂之一 酸性受体 1 (LPAR1) 可有效治疗与慢性疾病相关的肝纤维化，例如非 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 常见的肝脏疾病，与肥胖和 2 型糖尿病有关。目前还没有有效的 NASH 可用的治疗方法（生活方式改变除外）。 本申请中提供的可行性数据确立了 Epigen 的 LPAR1 领先产品之一的概念验证 拮抗剂 EPGN2154，在两种不同的 NASH 和肝纤维化小鼠模型中。体外机械数据 证实 LPAR1 拮抗作用可阻断肝星状细胞增殖，从而阻断重要的纤维化 途径。此外，LPAR1 拮抗剂可阻断 MCP-1 刺激的巨噬细胞迁移，表明 抗炎机制。在我们的工作过程中，我们已经确定了药物组合 EPGN2154 的补充作用机制，在临床前模型中提供卓越的功效 并可能给患者带来更大的益处。 在第二阶段 SBIR 资助中，我们提出了一种方法，涉及更详细的临床前评估 一种 NASH 转化动物模型中的 EPGN2154 及其组合。为了优化剂量和 EPGN2154 的联合方案（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。在此应用中，我们寻求：i) 进行详细的剂量- EPGN2154 在 NASH HFHC 小鼠模型中的反应疗效研究，以确定最低有效 剂量（MED），ii) 使用 EPGN2154 的优化剂量与商业药物相结合进行功效研究 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 申请支持人体 1 期临床试验。根据制药公司和投资者的反馈， IND- 具有临床前疗效和安全性以及指定的临床路径的现成资产是一项有吸引力的资产 用于商业化的资产。这项工作的成功结果可能会引发私人投资的推进 启动人体临床试验的计划。