Evaluating the efficacy of a novel NASH therapeutic

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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.