IND Enabling Studies for the Development of NASH Therapeutic TB-019

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SUMMARY Nonalcoholic steatohepatitis (NASH) is a significant, worldwide health problem affecting an estimated 14 million people in the US. It is characterized by hepatic inflammation and injury and fibrosis. Subjects diagnosed with NASH are at significantly increased risk of morbidity and mortality due to cirrhosis, and hepatocellular carcinoma. Without any currently available FDA approved treatments, NASH has become a significant unmet medical need. In NASH patients, lipid accumulation along with generation of lipotoxic intermediates leads to the induction of cell stress triggering apoptotic, inflammatory, and fibrotic signaling pathways. Reactive aldehydes, the product of oxidative modification (i.e. peroxidation) of polyunsaturated fatty acids (PUFA), can bind proteins by indirect or secondary protein modification, resulting in an increased risk for aggregation, loss of function, and cell damage. Published evidence points to the critical role of 4-Hydroxynonenal (4-HNE), the most abundant reactive aldehyde, contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and NASH. 4-HNE has been implicated as a specific driver of multiple pathways in NASH etiology including: a) loss of insulin inhibition of adipocyte lipolytic activity leading to increased fatty acid flux to the liver and generation of lipotoxic products, b) direct activation of inflammatory pathways, and c) as the direct driver of hepatic stellate cell activation and liver fibrosis. While 4-HNE production results from lipid peroxidation, the ability to control its levels by endogenous or exogenous antioxidants is limited; lipophilic reservoirs can provide a long-lasting discharge of 4- HNE beyond the temporal source of oxidant generation. Therefore, controlling 4-HNE levels represents a unique and novel therapeutic approach for the treatment of NASH. TamuroBio has synthesized a new chemical entity, TB-019, that is able to act as a nucleophilic scavenger. TB- 019 binds to 4-HNE, thereby reducing its levels in cells and has been shown in two rodent models of NASH to be effective in reducing liver fat, inflammation, and fibrosis progression. TB-019 has favorable physicochemical and ADME properties, as well as a preliminary good safety profile. This proposal aims to complete IND-enabling GLP safety and toxicology studies and to produce drug supply for the Phase I first-in human trial. This work will be performed by high quality contract research organizations in the US, overseen by the experienced team at TamuroBio. In summary, the overall goal of TamuroBio is to develop TB-019 as a novel therapeutic for the treatment of NASH and to mitigate the progression of fibrosis.