PROJECT SUMMARY Obesity and other characteristics of metabolic syndrome are key underlying factors in the development of non- alcoholic fatty liver disease (NAFLD). If left unchecked, NAFLD can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Up to 60% of the 80-100 million Americans with NAFLD will progress to NASH, yet there are no FDA-approved therapeutics; the only treatment option currently available is weight loss. The overall objective of this project is to determine whether the Siege compound merits development as a NASH therapy. Recently published work demonstrates improvement of liver phenotypes in a diet-induced obesity model without toxicity in normal tissues and thus the potential to address an as-yet unmet need for NASH patients. Siege Pharmaceuticals is taking a new approach to treating this disease: correcting ROS, ER stress, and hyperleptinemia upstream of liver dysfunction, inflammation, and fibrosis instead of just targeting the pheno- types without addressing the root cause. Aim 1 will evaluate the efficacy of Siege’s compound in a mouse model that reproduces the pathological features seen in patients with NASH while Aim 2 will test SGE-893 in a liver microtissue model derived from primary human cells, allowing for dissection of liver-specific and weight loss- driven effects and validation in a human model system. These studies will establish whether development as a NASH therapeutic is merited and could support a future Phase II program. If the Siege compound performs as expected, both improving NASH phenotypes and correcting metabolic dysfunction, it could dramatically im- prove the overall health of patients who currently have no therapeutic options.

PROJECT NARRATIVE Increased prevalence of obesity and type 2 diabetes mellitus are behind the rising rate of non-alcoholic fatty liver disease (NAFLD), now the most common chronic liver disease in the United States. Siege’s compound corrects the metabolic defects that lead to the liver dysfunction, inflammation, and fibrosis characteristic of NAFLD progression to non-alcoholic steatohepatitis (NASH). This project proposes to evaluate efficacy of this compound in two clinically relevant models of the disease.