Project Grant R44DK141341

DEVELOPMENT OF AN ORAL PILL TO MIMIC THE EFFECTS OF GASTRIC BYPASS SURGERY - PROJECT SUMMARY OBESITY IS A COMPLEX DISEASE THAT DISRUPTS HORMONAL AND METABOLIC PATHWAYS, INCREASING THE RISK OF CHRONIC CO- MORBIDITIES LIKE DIABETES, CARDIOVASCULAR DISEASE, AND CANCER. OBESITY ITSELF AFFLICTS MORE THAN 1 BILLION GLOBALLY AND, WHEN COMBINED WITH ITS ASSOCIATED RISK FACTORS, CONTRIBUTES TO OVER $480 BILLION IN DIRECT ANNUAL HEALTHCARE SPENDING. ROUX EN Y GASTRIC BYPASS SURGERY (RYGB) LEVERAGES DUODENAL NUTRIENT EXCLUSION (DNE) TO ACHIEVE BEST-IN-CLASS WEIGHT LOSS RESULTS; HOWEVER, THE HIGH COSTS, EXTENSIVE PROCEDURAL RISKS, AND LIMITED REIMBURSEMENT HAVE GREATLY LIMITED ACCESS TO CARE. FURTHER, PHARMACOTHERAPIES AND WEIGHT LOSS DEVICES HAVE FAILED TO STRIKE A BALANCE BETWEEN AFFORDABILITY AND EFFICACY, WHICH HAS BOTH LIMITED ADOPTION AND WIDENED SOCIOECONOMIC ACCESS DISPARITIES. AS SUCH, THERE IS A PRESSING NEED TO DEVELOP NOVEL WEIGHT LOSS INTERVENTIONS THAT CAN ACHIEVE BEST- IN-CLASS RESULTS WHILE MAINTAINING ATTRACTIVE SAFETY AND COST PROFILES. USING TECHNOLOGY LICENSED FROM MIT, SYNTIS BIO HAS CREATED A GASTROINTESTINAL SYNTHETIC EPITHELIAL LINING (GSEL) THAT IS ADMINISTERED ORALLY AND LEVERAGES ENDOGENOUS ENZYMES TO FORM A ROBUST MUCO-ADHESIVE COATING SPECIFIC TO THE DUODENAL EPITHELIUM. WHEN CO- FORMULATED WITH CROSS-LINKING NANOPARTICLES, GSEL CREATES A SEMI-PERMEABLE BARRIER CAPABLE OF BLOCKING NUTRIENT ABSORPTION (GSEL-BARRIER). THE GOAL OF THIS PROPOSED PROJECT IS TO CREATE A ONCE-DAILY ORAL PILL THAT BLOCKS NUTRIENT ABSORPTION IN THE DUODENUM, THEREBY MIMICKING THE EFFECTS OF RYGB. THUS FAR, GSEL-BARRIER HAS DEMONSTRATED THE ABILITY TO REDUCE GLUCOSE ABSORPTION BY 70% IN PIGS WHEN CHALLENGED WITH AN ORAL GLUCOSE TOLERANCE TEST (OGTT). IN THIS FAST-TRACK SBIR PROPOSAL, WE SEEK TO EXPAND ON THIS THIS EARLY PIG WORK TO FURTHER OPTIMIZE GSEL COMPOSITION FOR BARRIER FORMATION, ENGINEER GSEL INTO SOLID TABLET FORMULATIONS, AND TEST EFFICACY IN BEAGLES WHICH MORE CLOSELY REFLECT HUMAN GASTRIC EMPTYING TIMES. SUCCESSFUL COMPLETION OF THESE AIMS WILL YIELD OPTIMIZED SOLID DOSAGE FORM TABLETS THAT HAVE BEEN VALIDATED IN LARGE ANIMALS AND ARE READY FOR FIRST-IN-HUMAN TESTING. SYNTIS WILL THEN BE READY TO START SCALING GMP MANUFACTURING AS WELL AS INITIATE GLP PRE-IDE STUDIES IN PREPARATION FOR FIRST-IN-HUMAN TRIALS.