Lead candidate identification of LPAR1 antagonists for therapeutic application in NASH

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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. Preliminary data presented in this application establishes the proof-of-concept of one of Epigen’s LPAR1 lead antagonists, EPGN696, in three 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 in kidney disease, we have identified EPGN2154, an improved LPAR1 antagonist, that has proven safe and more efficacious than EPGN696 in kidney disease models. In this phase 1 SBIR grant, we propose an approach which will involve the pre-clinical evaluation of EPGN2154 in two translational animal models of NASH. The disease will be induced for a longer period and chronic therapeutic treatment with the LPAR1 antagonists will be extended. EPGN696 will be used as a comparator in these studies. We expect that this will allow characterization of a minimum efficacious dose of EPGN2154 in NASH relevant endpoints. The successful outcome of this work will lauch efforts in toxicology and chemistry, manufacturing and controls (CMC) work to support filing of an investigational new drug (IND) application and eventually initiation of clinical trials in humans.