Project Grant R44DK129071

CANDIDATE SELECTION OF A LPAR1 ANTAGONIST FOR THERAPEUTIC APPLICATION IN NASH - 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.