MASH clinical trials and drugs pipeline: An impending Tsunami

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, Metabolic Dysfunction-Associated Steatohepatitis (MASH), may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator-activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in two primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in Phase 3 clinical trials, while alternative non-invasive endpoints are explored in Phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.