A novel approach to treat non-alcoholic steatohepatitis (NASH)

Abstract The goal of this SBIR fast-track application is to carry out a number of IND enabling studies on our siRNA drug candidate, which is designed to treat non-alcohol steatohepatitis (NASH). NASH is a form of non-alcohol fatty liver disease (NAFLD) and results from a pathological accumulation of fat in the liver. Approximately 5 million people have been diagnosed with NASH in the US alone. NASH can lead to cirrhosis, followed by liver failure or hepatocellular carcinoma. The projected number of diagnosed NASH patients worldwide is about 16 million. The current primary treatment for NASH is lifestyle change. However, few patients remain adherent for extended periods of time. No drugs have been approved in the US or other countries for treating NASH. To address this unmet medical need, we are taking the innovative approach of treating NASH by increasing mitochondrial metabolism in the liver. Fatty acids are transported to the liver where they are metabolized in mitochondria through ?-oxidation, which is coupled to the electron transport chain (ETC) and mitochondrial respiration. Increasing the activity of the ETC in the liver could therefore speed up the degradation of fatty acids and prevent their accumulation in the liver. A key endogenous negative regulator of the ETC is the MCJ protein (MCJ/DnaJC15 or Methylation-Controlled J protein). MCJ is a mitochondrial protein that acts as a brake on the ETC (“internal mitochondrial brake”). We have demonstrated that removal of MCJ is safe and results in increased mitochondrial respiration without increasing the generation of reactive oxygen species. This is because removal of MCJ minimizes electron leak by promoting the formation of respiratory supercomplexes. In preliminary studies, we used mouse specific siRNAs to show safety of our approach and efficacy for reversal and prevention of pathologies that are associated with NASH, using multiple mouse models of NASH. siRNA has been validated as a drug for a number of diseases, with two siRNA drugs recently approved by FDA for treatment of liver diseases (Patisiran and Givosiran). In addition, GalNAc (N-acetylgalactosamine) has been used clinically to direct siRNA to liver hepatocytes. We have identified a lead siRNA that is cross-reactive for human, NHP, and mouse MCJ. We have also developed proprietary GalNAc vectors and a lead siRNA-GalNAc formulation (MITO-1041), but that formulation has not yet been tested in NASH models or for the rare occurrence of polynucleotide liver toxicity. In Phase I, we will test for toxicity and efficacy. Back-up compounds have also been identified to de-risk the program. Upon success of Phase I, we will apply to the NIH for Phase II funding. In Phase II, we will carry out a number of IND enabling studies, as suggested by NIDDK. Following the success of these studies, we will submit an SBIR Phase IIb proposal to manufacture GMP material, carry out the final GLP tox studies in rat and NHPs, submit an IND, and carry out a first in human Phase I clinical study.