Development of TP-352 for the Treatment of Pediatric Non-alcoholic Steatohepatitis

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ABSTRACT Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of diseases related to metabolic syndrome that are characterized by steatosis, the accumulation of fat within the liver. Non-alcoholic steatohepatitis (NASH), the most aggressive NAFLD subtype, refers to the presence of inflammation and necrosis in a background of steatosis, and is associated with hepatic fibrosis. NASH is a serious health problem that can lead to serious long-term health issues, including liver fibrosis, cirrhosis and hepatocellular carcinoma. In the last few decades, NASH has emerged as one of the most common liver disorders amongst pediatric and adolescent patients. Despite affecting approximately two million children in the United States, there are currently no approved therapies for NASH. To answer this unmet medical need, Thetis Pharmaceuticals (Thetis) proposes to develop magnesium L-lysinate bis docosahexaenoate, or TP-352, as a safe, oral therapy for resolution of NASH in pediatric patients. TP-352 delivers docosahexaenoic acid, (DHA), an Omega-3 polyunsaturated fatty acid (PUFA) shown to have clinical efficacy for treatment of pediatric NASH. TP-352 overcomes the physico-chemical and commercial deficits inherent to DHA to enable development of a safe and effective treatment for NASH. In this SBIR Fast-Track project, Thetis will complete the preclinical activities required for an investigational new drug (IND) submission to the FDA and initiation of clinical studies. This goal will be achieved through the execution of five Specific Aims. The objective of Phase I is to obtain initial proof of concept by performing an efficacy studies using an established mouse model of NASH (Specific Aim #1) and characterizing TP-352 pharmacokinetics in mice (Specific Aim #2). The objective of Phase II is to complete key commercially-enabling preclinical activities required to initiate clinical studies. Initial efforts will focus on conducting a toxicological program (Specific Aim #3). Once the efficacy and acceptable toxicity profile of TP-352 are demonstrated, Thetis will manufacture good manufacturing practice (GMP) certified clinical trial material for the Phase 1 program (Specific Aim #4). Upon completion of this Fast-Track SBIR project, Thetis will have completed all requisite studies to submit an IND application and initiate Phase 1 clinical studies. As indicated by letters of support from some of the country’s leading NASH specialists, this SBIR project is critical to enabling development of the TP-352 program to address the unmet medical need in this vulnerable pediatric population.