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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

基本信息

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
项目类别：
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

项目摘要

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.

总结