FDA Approves Resmetirom (Rezdiffra) for Treating MASH and Associated Fibrosis
On March 14, 2024, the United States Food and Drug Administration (FDA) approved resmetirom (Rezdiffra) for the treatment of adults with a noncirrhotic liver condition known as metabolic dysfunction-associated steatohepatitis (MASH). This condition, which falls within the spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by inflammation and hepatocyte injury, often accompanied by hepatic fibrosis. The approval of resmetirom represents a breakthrough in the treatment of MASH, especially for patients with moderate to advanced liver fibrosis, when used alongside diet and exercise.
MASH is a severe subset of non-alcoholic fatty liver disease (NAFLD), with a global prevalence of approximately 5%. However, this prevalence rises significantly among individuals with type 2 diabetes mellitus (T2DM) and those who are overweight or obese. The condition is projected to affect about 27.0 million people by 2030, highlighting the urgent need for effective treatments.
The pathophysiology of MASH involves an excessive load of free fatty acids delivered to the liver, increased lipogenesis, and the generation of lipotoxic molecules that exacerbate stress within the endoplasmic reticulum. This stress triggers the production of oxidants and activates inflammasomes, leading to apoptosis of liver cells, recruitment of inflammatory cells, and activation of hepatic stellate cells, which promote fibrosis.
Resmetirom, a liver-targeted oral agonist of thyroid hormone receptor-beta (THR-β), addresses the underlying pathophysiology of MASH by reducing hepatic fat accumulation, decreasing liver enzyme levels, enhancing non-invasive indicators of liver fibrosis, and reducing liver stiffness. It also demonstrates positive cardio-metabolic effects by decreasing low-density lipoprotein (LDL) cholesterol levels.
The safety and efficacy of resmetirom were demonstrated in clinical trials, with significant improvements observed in liver enzymes, fibrosis biomarkers, and imaging tests compared to placebo. The drug was well tolerated, with no significant increases in serious treatment-emergent adverse events (TEAEs).
The recommended dosage of resmetirom depends on the patient’s weight, with 80 mg daily for those under 100 kg and 100 mg daily for those at or above 100 kg. The drug's pharmacokinetics remain consistent with a high-fat meal, and it has a plasma half-life of 4.5 hours.
Resmetirom's approval opens new avenues for the treatment of MASH and associated fibrosis, offering hope to millions of patients worldwide. Further research is needed to explore its use in treating secondary NAFLD or MASH in conjunction with primary endocrine diseases and lifestyle modifications.