What is the mechanism of action of resmetirom?

Mechanism of Action of Resmetirom

Resmetirom is a selective thyroid hormone receptor-beta (THR-β) agonist that acts primarily in the liver to reduce hepatic steatosis and improve metabolic dysfunction-associated steatotic liver disease (MASLD/MASH). 1

Primary Mechanism

Resmetirom functions through the following specific mechanisms:

• Selective THR-β Activation: Resmetirom is a partial agonist of the thyroid hormone receptor-beta with high selectivity for the β1 receptor that is predominantly expressed in the liver 2, 1

  • Produces 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 μM for THR-β activation
  • Shows limited activity at thyroid hormone receptor-alpha (THR-α), with only 48.6% efficacy relative to T3 and a much higher EC50 of 3.74 μM 1

• Liver-Directed Action: THR-β is the major form of thyroid hormone receptor in the liver, allowing resmetirom to target hepatic metabolism while minimizing systemic thyroid effects 1

Metabolic Effects

Resmetirom's activation of hepatic THR-β leads to several beneficial metabolic changes:

• Reduction of hepatic steatosis through:

  • Stimulation of hepatic lipophagy (breakdown of lipid droplets)
  • Enhancement of mitochondrial biogenesis
  • Inhibition of hepatic lipogenesis (fat production in the liver) 2

• Anti-fibrotic activity via:

  • Inhibition of TGF-β signaling, a key pathway in fibrogenesis 2
  • Downregulation of genes involved in fibrogenesis 3

• Lipid metabolism improvements:

  • Significant reduction in serum lipids, particularly LDL cholesterol
  • In clinical trials, resmetirom reduced LDL-cholesterol by 14-20% compared to placebo 2

Pharmacodynamic Effects

Resmetirom treatment produces several measurable pharmacodynamic effects:

• Decreased liver fat content as measured by:

  • MRI-proton density fat fraction (MRI-PDFF)
  • FibroScan controlled attenuation parameter (CAP) 1

• Altered thyroid hormone parameters:

  • Decreased concentrations of prohormone free T4 (FT4) by approximately 16-19%
  • No clinically significant changes in thyroid-stimulating hormone (TSH) or T3/free T3 levels 2, 1

• Increased sex hormone binding globulin (SHBG):

  • SHBG elevation is observed as early as 4 weeks after treatment initiation
  • This serves as a biomarker of target engagement
  • Despite SHBG elevation, free testosterone levels typically remain unchanged 2, 4, 1

Clinical Significance

Resmetirom is the first FDA-approved medication specifically for MASH (metabolic dysfunction-associated steatohepatitis), approved in March 2024 for:

• Non-cirrhotic MASH with moderate to advanced liver fibrosis (stages F2-F3)
• Used in conjunction with diet and exercise 5

The drug's unique mechanism of action provides targeted hepatic effects while minimizing systemic thyroid hormone effects, making it particularly valuable for patients with MASH and significant fibrosis who are at risk of progressing to cirrhosis 6.

Pharmacokinetic Considerations

• Reaches steady state within 3-6 days of daily dosing
• Median time to maximum plasma concentration is approximately 4 hours
• Exposure increases in a dose-proportional manner between 40-100 mg 1

Potential Pitfalls and Monitoring

• Thyroid function: While resmetirom reduces FT4 levels, this occurs through liver-specific upregulation of type 1 deiodinase (DIO1) without affecting the central hypothalamic-pituitary-thyroid axis 2

• Sex hormone changes: SHBG elevation is expected and confirms target engagement, but monitoring may be warranted in certain patients 4

• Drug interactions: Caution with statins (dose limitations may apply) and moderate CYP2C8 inhibitors like clopidogrel (may require dose reduction) 2

Resmetirom's selective THR-β agonism represents a significant advancement in the targeted treatment of MASH by addressing the underlying hepatic metabolic dysfunction while minimizing systemic thyroid effects.