Resmetirom is the first medication approved by the U.S. Food and Drug Administration (FDA2024) for the treatment of adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis (stages F2–F3). It represents a major milestone in the management of MASH, as previous treatment strategies primarily focused on lifestyle modification and management of metabolic comorbidities.

Mechanism of Action

Resmetirom is an orally administered, selective thyroid hormone receptor-beta (THR-β) agonist. THR-β is predominantly expressed in the liver and plays a central role in regulating lipid metabolism, fatty acid oxidation, and energy homeostasis.

Activation of hepatic THR-β by resmetirom:

• Increases mitochondrial β-oxidation of fatty acids
• Reduces hepatic fat accumulation
• Improves lipid metabolism
• Lowers serum LDL cholesterol and triglyceride levels
• Reduces hepatic inflammation
• May slow or reverse the progression of liver fibrosis

Because resmetirom selectively targets THR-β in the liver, it minimizes the systemic cardiovascular and skeletal effects associated with non-selective thyroid hormone stimulation.

Clinical Efficacy

The efficacy of resmetirom was demonstrated in the phase 3 MAESTRO-NASH trial involving patients with biopsy-confirmed MASH and fibrosis stages F1B–F3.

After 52 weeks of treatment:

• Approximately 26–30% of patients achieved resolution of MASH without worsening of fibrosis, compared with approximately 10% in the placebo group.
• Approximately 24–26% of patients achieved at least a one-stage improvement in fibrosis without worsening of MASH, compared with approximately 14% in the placebo group.
• Significant reductions in liver fat content were observed by magnetic resonance imaging (MRI-PDFF).
• Resmetirom also produced clinically meaningful reductions in LDL cholesterol, apolipoprotein B, and triglycerides.

The most commonly reported adverse effects were mild to moderate gastrointestinal symptoms, including diarrhea and nausea.

Clinical Perspective

Although lifestyle intervention and sustained weight loss remain the cornerstone of MASH management, resmetirom provides the first approved disease-targeted pharmacological option for patients with fibrosis. Ongoing studies are evaluating its long-term impact on cirrhosis, liver-related outcomes, and overall mortality.