Expanding the armamentarium for metabolic dysfunction-associated steatohepatitis

Abstract

The treatment of metabolic dysfunction-associated steatohepatitis (MASH) has proven challenging, with many compounds failing during development for various reasons. However, with the recent accelerated approval of resmetirom by the US Food and Drug Administration for the treatment of individuals with fibrotic MASH,¹ there is renewed enthusiasm in the field. MASH pathophysiology is complex, and progressive disease results from an imbalance between the driving metabolic inflammatory mechanisms (many of which are extrahepatic; eg, the dysfunctional adipose tissue) and intrahepatic defence and repair mechanisms.² Many of the compounds currently considered to be the most promising mainly improve the cardiometabolic environment, subsequently (with or without additional direct intrahepatic effects) improving MASH. Many drugs targeting specific intrahepatic metabolic or fibroinflammatory mechanisms have proven unsuccessful in clinical trials, despite preclinical evidence.³ Resmetirom, a liver-targeted thyroid hormone β receptor agonist, showed that a more isolated liver-directed approach, with little or no effect on the extrahepatic drivers of MASH, is also capable of not only improving MASH but inducing the regression of fibrosis.¹