Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation, and hepatocyte injury with or without fibrosis. It has emerged as the second leading indication for liver transplantation with a rising death rate in the non-transplantable population. While there are many drugs in evaluation, currently no approved therapies are on the market for this condition. Given this importance, the Food and Drug Administration has provided formal guidance regarding drug development for stopping or reversing NASH or NASH associated fibrosis. The complex pathogenesis of NASH and its bidirectional relationship with metabolic syndrome has highlighted multiple drugs of interest that address metabolic, inflammatory, and fibrotic factors. A few promising liver specific targets include farnesoid X receptor agonists and peroxisome proliferator-activated receptor agonists. Previously studied drug classes such as glucagon-like peptide-1 analogs or sodium/glucose transport protein 2 inhibitors have also demonstrated ability to improve hepatic steatosis. Here we discuss current rationale, scientific work, and preliminary data in combining multiple drugs for the purposes of a multimodal attack on the pathogenesis of NASH. We highlight multiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve a response rate higher than previously assessed monotherapies for this condition. Ultimately, one of these combination strategies may rise above in its safety and efficacy to become a part of a standardized approach to NASH.