The US Food and Drug administration has approved resmetirom as the first drug to treat metabolic dysfunction-associated steatohepatitis (MASH)

Abstract

Diabetes, Obesity Metabolism (DOM) NOW—April 2024

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing and is fast emerging as one of the most important cause for progressive liver disease. Despite this, there has been no approved treatment until now.

Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist for the treatment of NASH with liver fibrosis. A previous phase 3 clinical trial (MAESTRO-NASH)¹ involving 966 adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 [stages range from F0 (no fibrosis) to F4 (cirrhosis)] was published in the New England Journal Medicine. Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 or 100 mg or placebo. The two primary end points at week 52 were NASH resolution [including a reduction in the nonalcoholic fatty liver disease (NAFLD) activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease] with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.

The study showed that NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group. Improvement in fibrosis was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group. The trial also met multiple secondary endpoints, including statistically significant reduction from baseline in liver enzymes (alanine transaminase, aspartate aminotransferase and gamma-glutamyl transferase) and low-density lipoprotein cholesterol with resmetirom compared with placebo.

Based on this, the US FDA has recently approved resmetirom (80-mg and 100 mg doses) to treat patients with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced liver fibrosis (consistent with stage F2 and F3 disease), along with diet and exercise. The most common adverse events included diarrhea and nausea, which typically began early in treatment and were mild to moderate in severity.

I believe that this approval for the first medication to treat MASH will form the basis for current and emerging pharmacological agents being studied as a therapeutic option to patients living with this serious liver condition. Further studies are ongoing to determine if the early beneficial effects of resmetirom could lead to reduced risk of progression to cirrhosis, liver failure and need for liver transplant.