SBIR-STTR Award

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. Public Health Relevance Statement Narrative The objective is to develop new drugs for treating diseases that lead to liver fibrosis, including nonalcoholic steato hepatitis (NASH), a significant cause of mortality.

Project Terms:
Affect ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Back ; Dorsum ; Carbohydrates ; Cells ; Cell Body ; Chemistry ; Cholesterol ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Chronic Disease ; Chronic Illness ; chronic disorder ; Cicatrix ; Scars ; Clinical Trials ; Control Groups ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Diabetic Nephropathy ; Diabetic Kidney Disease ; Diabetic Neuropathies ; diabetes-associated neuropathy ; Diet ; diets ; Disease ; Disorder ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Investigational Drugs ; Investigational New Drugs ; Fatty acid glycerol esters ; Fats ; Female ; Fibrosis ; Fructose ; Levulose ; Goals ; Grant ; Human ; Modern Man ; In Vitro ; Inflammation ; Insulin Resistance ; insulin resistant ; Kidney ; Kidney Urinary System ; renal ; Kidney Diseases ; Nephropathy ; Renal Disease ; kidney disorder ; renal disorder ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Life Style ; Lifestyle ; Liver diseases ; Hepatic Disorder ; hepatic disease ; hepatopathy ; liver disorder ; macrophage ; Mφ ; male ; Obese Mice ; ob/ob mouse ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Obesity ; adiposity ; corpulence ; Pathology ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Risk ; Toxicology ; Work ; Measures ; Investigational New Drug Application ; Lysophosphatidic Acid Receptors ; LPA Receptors ; improved ; Chronic ; Phase ; Histologic ; Histologically ; Hepatic Stellate Cell ; Ito Cell ; Individual ; Liver Fibrosis ; fibrotic liver ; hepatic fibrosis ; diabetic ; Dyslipidemias ; Therapeutic ; Hepatic Cancer ; liver cancer ; malignant liver tumor ; Malignant neoplasm of liver ; programs ; ACRP30 protein ; adipocyte complement-related protein 30-kDa ; adipocyte, C1q and collagen domain containing protein ; apM-1 protein ; apM1 (adipose-specific) protein ; adiponectin ; neuropathic ; Neuropathy ; Treatment Period ; treatment days ; treatment duration ; Source ; Cell Growth in Number ; Cell Multiplication ; Cellular Proliferation ; Cell Proliferation ; drug efficacy ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; disorder model ; Disease model ; Modeling ; Metabolic syndrome ; Sentinel ; epigen ; Liver Insufficiency ; Hepatic Insufficiency ; CCL2 ; Chemokine, CC Motif, Ligand 2 ; MCAF ; MCP-1 ; MCP1 ; Monocyte Chemoattractant Protein-1 ; Monocyte Chemotactic Protein-1 ; Monocyte Chemotactic and Activating Factor ; Monocyte Chemotactic and Activating Protein ; Monocyte Chemotactive and Activating Factor ; Monocyte Secretory Protein JE ; SCYA2 ; Small Inducible Cytokine A2 ; CCL2 gene ; Dose ; Trans Fats ; Control Animal ; Data ; Supplementation ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Wild Type Mouse ; wildtype mouse ; C57BL/6 Mouse ; trend ; Process ; Development ; developmental ; Cirrhosis ; cirrhotic ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; feeding ; Outcome ; Population ; Prevalence ; migration ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; nonalcoholic steatohepatitis ; NASH ; non-alcohol induced steatohepatitis ; non-alcoholic steato-hepatitis ; non-alcoholic steatohepatitis ; nonalcoholic steato-hepatitis ; effective therapy ; effective treatment ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; preclinical evaluation ; pre-clinical evaluation ; preclinical efficacy ; pre-clinical efficacy ; candidate identification ; efficacy testing ; treatment group ; non-alcoholic fatty liver disease ; NAFLD ; non-alcohol fatty liver disease ; non-alcoholic liver disease ; nonalcoholic fatty liver disease ; lead candidate ;

The ultimate goal of this application is to develop one of Epigen's proprietary antagonists of the lysophosphatidicacid 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 mostcommon liver disease and is associated with obesity and type-2 diabetes. There are currently no effectivetreatments available for NASH except lifestyle changes.The feasibility data presented in this application establishes the proof-of-concept of one of Epigen's LPAR1 leadantagonists, EPGN2154, in two different mouse models of NASH and liver fibrosis. In vitro mechanistic dataconfirms that LPAR1 antagonism blocks hepatic stellate cell proliferation, thus blocking an important fibroticpathway. Furthermore, LPAR1 antagonists block migration of macrophages stimulated by MCP-1 indicating ananti-inflammatory mechanism. During the course of our work, we have identified combinations of drugs withcomplementary mechanisms of action to EPGN2154, which provide superior efficacy in the preclinical modelsand may result in greater benefit to patients.In this phase 2 SBIR grant, we propose an approach involving a more detailed pre-clinical evaluation ofEPGN2154 and combinations in one translational animal model of NASH. For optimizing the dose andcombination regimen of EPGN2154, the HFHC-fed wild type mouse model of NASH is considered adequatebecause 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 efficaciousdose (MED), ii) conduct efficacy studies with the optimized dose of EPGN2154 in combination with commercialGLP-1R agonists and GIP/GLP-1R agonists, iii) complete GLP safety pharmacology studies and submit an INDto 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 attractiveasset for commercialization. The successful outcome of this work will likely trigger private investment to advancethe program towards initiation of clinical trials in humans.

Public Health Relevance Statement:
Narrative The objective is to develop new drugs for treating diseases that lead to liver fibrosis, including non- alcoholic steatohepatitis (NASH), a significant cause of mortality.

Project Terms: