NASH and Type 2 Diabetes

Non-alcoholic fatty liver disease or NAFLD is not one disease, but a continuum ranging from simple fat accumulation in the liver also referred to as steatosis or NAFL, progressing to steatosis with inflammation and fibrosis, the definition of NASH  (non-alcoholic steatohepatitis). Unchecked, NASH can further progress to cirrhosis and hepatocellular carcinoma.

NASH is associated with a two-fold increase in cardiovascular mortality and a 10-fold increase in hepatic failure and death. As NASH further progresses to cirrhosis and liver cancer, patients may require liver transplantation.  The prevalence of NASH is staggering as is the cost to society.  It is estimated that one billion people have hepatic steatosis or fatty liver disease worldwide. In the US, ~30% of adults and ~10% of children (81 million) are afflicted by fatty liver, and some 16 million progress to NASH. It is estimated that in the next 10 years, the healthcare burden will reach $35 billion in the US. NASH was first described 35 years ago. To date, no FDA-approved drug for NASH is available, although the development pipeline of new drug candidates has significantly expanded. A most critical hurdle is meeting the current surrogate endpoints established by the FDA, either resolution of steatosis with no worsening of fibrosis, or reduction in fibrosis. Clinical trials of several experimental drugs have failed at various stages. Therein, the probability of success of most of the current drug candidates remains low, and this provides an opportunity for new mechanisms for the treatment of NASH.

Abnormal lipid accumulation inside liver cells is one of the most important causal factors of NASH and type 2 diabetes. On the one hand, lipid accumulation in the liver increases insulin resistance, which is the root cause of type 2 diabetes; on the other hand, abnormal lipid accumulation in liver cells causes liver damage, triggering inflammation and subsequent fibrosis, which drive the progress of NASH.  The intertwining of fatty liver disease, type 2 diabetes, and NASH is evident as over 80% of type 2 diabetes patients have fatty liver disease, of which some 20-50% progress to NASH. Reducing or depleting hepatic lipid load would thus greatly improve type 2 diabetic symptoms or even provide a cure in some patients. Similarly, effective depletion of cellular lipid content would decrease liver damage and reduce inflammation and fibrosis, providing effective treatment for NASH.  

In cells, lipid is oxidized in mitochondria. Mito Biopharma has developed proprietary platform technology and lead compounds that dissipate abnormal liver lipid accumulation by modulating mitochondrial function via safely uncoupling mitochondrial respiration. Proof-of-concept studies in various diabetes and NASH mouse models demonstrated efficacy in dissipation of steatosis, reduction in insulin resistance, decrease of liver damage and inflammation, and reduction in fibrosis. Moreover, toxicology studies indicate competitive therapeutic index. Lead compounds are selected for NASH and type 2 diabetes respectively with the goal of initiating IND enabling studies in 2021 and initial clinical trials in 2023.