Introduction
Resmetirom is the first drug approved to treat non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring. It is an orally administered thyroid hormone receptor beta (THR-β) agonist designed to treat noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (F2-F3). NASH, previously categorized under non-alcoholic fatty liver disease (NAFLD), is now referred to as metabolic dysfunction-associated steatohepatitis (MASH). If left untreated, NASH can progress to cirrhosis, liver failure and death.
This treatment received accelerated FDA approval on March 14, 2024 based on its ability to improve NASH and fibrosis, with full approval contingent on confirmatory clinical trials.
About NASH and Liver Fibrosis
NASH is a severe form of fatty liver disease characterized by hepatocyte ballooning, lobular inflammation and fibrosis. In some patients, fibrosis progresses to cirrhosis and liver failure.
Risk Factors: NASH is associated with obesity, insulin resistance, type 2 diabetes and metabolic syndrome.
Progression: Unlike simple steatosis, NASH leads to lipotoxic lipid accumulation, hepatocyte injury, inflammation and stellate cell activation, resulting in fibrosis and increased risk of hepatocellular carcinoma (HCC).
Age of Onset: It typically occurs in the fifth and sixth decades of life.
Mechanism of Action
The image illustrates the molecular mechanism of Resmetirom (Rezdiffra), a THR-β agonist, in treating non-alcoholic steatohepatitis (NASH). It highlights two thyroid hormone receptor (THR) isoforms: THR-α found in the heart, brown adipose tissue (BAT), white adipose tissue (WAT) and THR-β primarily expressed in the liver. The systemic effects of thyroid hormones in hepatocytes include gene expression regulation, fatty acid mobilization, mitochondrial biogenesis, and glucose metabolism. Resmetirom selectively activates THR-β in the liver, promoting fatty acid oxidation (FAO), mitochondrial biogenesis, and bile acid synthesis, while reducing lipid accumulation, cholesterol synthesis, and steatosis. This action helps lower VLDL and LDL levels, making Resmetirom the first FDA-approved drug for NASH, addressing both liver fibrosis and metabolic dysfunction.
An Overview of Mechanism of Action:
1. Lipid Metabolism Regulation:
o THR-β activation promotes mitochondrial function, increasing lipophagy and hepatic fatty acid β-oxidation.
o Reduces intrahepatic triglyceride levels, lowering the liver’s fat burden.
2. Hepatic Inflammation and Fibrosis Reduction:
o Improves mitochondrial biogenesis and function, decreasing lipotoxicity-induced hepatocyte injury.
o Inhibits hepatic stellate cell activation, reducing collagen deposition and fibrosis.
3. Thyroid Hormone Role in NASH:
o Many patients with NASH exhibit impaired thyroid function (hypothyroidism), which contributes to hepatic fat accumulation.
o Hypothyroidism increases pro-inflammatory adipokines, worsening inflammation and fibrosis.
o It mimics the liver-specific effects of thyroid hormones, improving lipid metabolism and reducing insulin resistance. Pharmacodynamics
· THR-β Selectivity:
o Resmetirom is 28 times more selective for THR-β than for thyroid hormone receptor-alpha (THR-α), reducing off-target effects in the heart and bones.
o Produces 83.8% of the maximum THR-β response compared to triiodothyronine (T3) and has an EC50 of 0.21 µM in vitro.
· Half-Life:
o The median terminal plasma half-life is 4.5 hours, allowing for once-daily dosing.
· Lipid Profile Improvement: o Reduces LDL cholesterol and promotes low-density lipoprotein (LDL) uptake, providing cardiovascular benefits.
Clinical Efficacy
It has been evaluated in clinical trials, including the MAESTRO-NASH and MAESTRO-NASH OUTCOMES studies.
· Fat Reduction:
o MRI-derived proton density fat fraction (MRI-PDFF) confirmed significant hepatic fat reduction.
· Fibrosis Improvement:
o Phase III biopsy data showed NASH resolution and fibrosis improvement after 52 weeks.
· Liver Function:
o Improved non-invasive markers of liver fibrogenesis and liver stiffness.
Serious Adverse Reactions
1. Liver Damage (Hepatotoxicity)
Signs of liver damage include: Jaundice (yellowing of skin/eyes), dark urine or light-coloured stool, unexplained fatigue or weakness and loss of appetite.
2. Gallbladder Problems
It may cause cholelithiasis (gallstones) or cholecystitis, leading to pancreatitis. Symptoms include: Upper stomach pain, clay-coloured stool, vomiting and fever.
Caution of use in Specific Populations
Drug Interactions
Resmetirom metabolism is affected by several drugs some of them are:
Conclusion
Resmetirom represents a promising first-in-class THR-β agonist for the treatment of noncirrhotic NASH with moderate to advanced fibrosis. By directly targeting lipid metabolism and inflammation, it reduces hepatic fat, improves fibrosis, and offers potential cardiovascular benefits.
While long-term efficacy is being further evaluated in MAESTRO-NASH trials, current data supports Resmetirom as a transformative treatment option for patients with limited therapeutic alternatives.
References
1. Karim G, Bansal MB: Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, beta-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60. Epub 2023 May 1. [Article]
-By Juhi Chakraborty
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