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 countrys 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.
Public Health Relevance Statement: NARRATIVE Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive disease characterized by hepatic fat accumulation (steatosis) that is quickly becoming the most common cause of liver disease in children and adolescents in Western countries. Non alcoholic steatohepatitis (NASH), the most aggressive NAFLD subtype, refers to the presence of inflammation and necrosis in a background of steatosis. Affecting nearly two million children in the United States, NASH can lead to serious long-term health problems including liver fibrosis, cirrhosis, hepatocellular carcinoma, liver failure, liver-related death and liver transplantation. There are currently no approved therapies for adult or pediatric NASH. Thetis Pharmaceuticals proposes to develop TP- 352 as a safe, oral therapy for resolution of NASH in pediatric patients.
NIH Spending Category: Childhood Obesity; Chronic Liver Disease and Cirrhosis; Complementary and Integrative Health; Digestive Diseases; Hepatitis; Liver Disease; Nutrition; Obesity; Pediatric
Project Terms: Address; Adolescent; adolescent patient; Adult; Affect; aqueous; base; Biological Availability; cardiovascular disorder risk; Cessation of life; Chemicals; Chemistry; Child; Childhood; Chronic; chronic liver disease; Cirrhosis; clinical development; clinical efficacy; Clinical Research; Clinical Trials; Country; Data; Development; Diabetes Mellitus; diet and exercise; Disease; disorder subtype; Dissociation; Docosahexaenoic Acids; Dose; Drug Kinetics; effective therapy; efficacy study; Evaluation; Fatty acid glycerol esters; Future; General Population; Goals; Health; Hepatic; human disease; Hypertriglyceridemia; Incidence; Inflammation; innovation; Intellectual Property; Investigational Drugs; Investigational New Drug Application; Lead; Letters; Lipids; Liver; Liver diseases; Liver Failure; Liver Fibrosis; liver transplantation; Magnesium; Medical; Medical Care Costs; Metabolic; Metabolic syndrome; Molecular; mortality; mouse model; Mus; Necrosis; No-Observed-Adverse-Effect Level; non-alcoholic fatty liver disease; non-drug; nonalcoholic steatohepatitis; novel; novel strategies; Obesity; obesity in children; Omega-3 Fatty Acids; Oral; Outcome Study; Patients; pediatric non-alcoholic fatty liver disease; pediatric patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Population; pre-clinical; Primary carcinoma of the liver cells; Procedures; Production; programs; Progressive Disease; Property; randomized placebo controlled trial; Research; Resolution; Safety; scale up; sedentary lifestyle; Small Business Innovation Research Grant; small molecule; Sodium Chloride; Solid; Specialist; Sprague-Dawley Rats; Tablets; Technology; Testing; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; United States
