Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD). NAFLD is caused by a buildup of fat in the liver and is the most common form of liver disease in the United States. It affects patients who drink little to no alcohol. The fatty deposits occur when the liver can no longer break down fats easily, causing them to accumulate in the liver. In severe cases, these deposits will cause inflammation and damage to the liver, leading to the more severe form of this condition NASH which can lead to cirrhosis of the liver, a life-threatening condition.
The most common risk factor for both forms of the disease is obesity. It is the most frequent liver disease, affecting a quarter of the global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. It’s undergone a recent name change to Metabolic dysfunction–associated fatty liver disease (MAFLD). The new definition of MAFLD refers to hepatic steatosis in addition to one of the following three criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation.
MAFLD is defined as the presence of steatosis in > 5% of hepatocytes in the absence of other competing chronic liver diseases and without significant alcohol consumption (< 20 g/day in women and < 30 g/day in men). NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), the latter being more severe as it includes hepatocyte damage with the risk of subsequent development of significant fibrosis, cirrhosis, and/or hepatocellular carcinoma. In this context, NASH has become one of the leading causes of cirrhosis in adults in the USA and NASH-related cirrhosis is currently the second leading cause of liver transplantation in the USA. See Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment.
The disease has had no effective drug therapy. However on March 14 the the U.S. Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. The full text of the FDA’s approval notice is here. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist.
The approval followed the publication of a study A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis in the NEJM. It found that both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.
The FDA approved Rezdiffra under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious conditions and address an unmet medical need, based on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. A 54-month study, which is ongoing, will assess clinical benefit after 54 months of Rezdiffra treatment. Thus, this drug’s safety and long-term efficacy is yet to be determined. Yet, some hope for patients afflicted with a serious disease being recognized with increasing frequency.
