Resmetirom Drug Information
Resmetirom is the first and only FDA-approved medication for treating non-cirrhotic NASH/MASH with moderate to advanced fibrosis (stages F2-F3), administered at weight-based dosing of 80 mg daily for patients <100 kg or 100 mg daily for patients ≥100 kg, in conjunction with diet and exercise. 1
FDA Approval and Indication
Resmetirom received accelerated FDA approval in March 2024 for adults with noncirrhotic nonalcoholic steatohepatitis (NASH/MASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). 2, 1 This approval is based on improvement of NASH and fibrosis, with continued approval contingent upon verification of clinical benefit in confirmatory trials. 1
The drug is contraindicated in patients with decompensated cirrhosis and should be avoided in those with moderate to severe hepatic impairment (Child-Pugh Class B or C). 1 Patients with early fibrosis (F0-F1) and those with cirrhosis should not be treated with resmetirom. 2
Mechanism of Action
Resmetirom is an oral, liver-directed thyroid hormone receptor-beta (THR-β) selective agonist that acts as a partial agonist producing 83.8% of the maximum response compared to triiodothyronine (T3). 1 It demonstrates high selectivity for THR-β (EC50 of 0.21 µM) over THR-α (EC50 of 3.74 µM), which is critical because THR-β is the major form in the liver while THR-α mediates effects in heart and bone. 1 The drug reduces hepatic steatosis by stimulating hepatic lipophagy and mitochondrial biogenesis, inhibiting hepatic lipogenesis, and interfering with fibrogenesis through TGF-β signaling inhibition. 2
Dosing and Administration
Standard Dosing
- Patients weighing <100 kg: 80 mg orally once daily 1
- Patients weighing ≥100 kg: 100 mg orally once daily 1
- Administration: With or without food (food decreases Cmax by 33% and AUC by 11% but is not clinically significant) 1
Dose Modifications
When using moderate CYP2C8 inhibitors (e.g., clopidogrel), reduce resmetirom dosage. 2, 1 Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. 2 Additionally, concomitant use with OATP1B1 and OATP1B3 inhibitors (e.g., cyclosporine) is not recommended. 1
Patient Selection Criteria
Histological Criteria
The MAESTRO-NASH trial included patients with at-risk MASH defined by active steatohepatitis (NAS>4) and significant fibrosis (stage 2 or 3). 2 While liver biopsy provides the gold standard for diagnosis, it is not required by the FDA label. 2
Non-Invasive Testing Options
Alternative non-invasive panels with high predictive value can be used for patient selection, including: 2
- NIS2+ score
- FAST score
- MRI-based panels (MRI-PDFF)
- Elastography-defined thresholds
These non-invasive tests should demonstrate documentation of either advanced fibrosis, at-risk steatohepatitis with significant fibrosis, or risk of adverse liver-related outcomes. 2
Clinical Efficacy
Histological Outcomes at 52 Weeks
NASH resolution (≥2-point NAS reduction) with no worsening of fibrosis: 3
- 80 mg resmetirom: 25.9% vs. placebo 9.7% (P<0.001)
- 100 mg resmetirom: 29.9% vs. placebo 9.7% (P<0.001)
Fibrosis improvement by ≥1 stage with no worsening of NAS: 3
- 80 mg resmetirom: 24.2% vs. placebo 14.2% (P<0.001)
- 100 mg resmetirom: 25.9% vs. placebo 14.2% (P<0.001)
Hepatic Fat Reduction
Resmetirom achieved significant reductions in hepatic fat content assessed by MRI-PDFF: 4
- 80 mg: -27.76% mean difference vs. placebo (P<0.00001)
- 100 mg: -36.01% mean difference vs. placebo (P<0.00001)
Lipid Effects
LDL cholesterol reduction from baseline to week 24: 3
- 80 mg: -13.6% vs. placebo 0.1% (P<0.001)
- 100 mg: -16.3% vs. placebo 0.1% (P<0.001)
Additional benefits included reductions in apolipoprotein B (-23.8%) and triglycerides (-19.6%). 5
Monitoring and Treatment Response
Initial Assessment Timeline
The American Association for the Study of Liver Diseases recommends: 6
- 12 weeks: Safety and tolerability assessment
- 6 months: Disease monitoring
- 12 months and annually thereafter: Full efficacy assessment
Treatment Response Indicators
Clinicians should monitor the following markers to assess treatment response: 6
- ALT improvement: >17 IU/L or >20% reduction
- MRI-PDFF reduction: ≥30% decrease
- Liver stiffness by VCTE: >30% reduction
Reductions in liver stiffness by transient elastography (-2.1 mean kilopascals) and PRO-C3 levels (-9.8 ng/mL in patients with baseline ≥10 ng/mL) were observed at 36 weeks. 5
Adverse Events and Safety Profile
Common Adverse Events
The most common adverse reactions (occurring in ≥5% of patients and higher than placebo) include: 1
- Diarrhea: up to 33% 2, 6
- Nausea: up to 22% 2, 6
- Pruritus: up to 11% 2, 6
- Vomiting: up to 11% 2, 6
- Constipation 1
- Abdominal pain 1
- Dizziness 1
These gastrointestinal side effects were mostly mild to moderate with good overall tolerability. 2
Serious Adverse Events
The incidence of serious adverse events was similar across groups: 10.9% (80 mg), 12.7% (100 mg), and 11.5% (placebo). 3
Specific Safety Concerns
Hepatotoxicity: Monitor patients for elevations in liver tests and liver-related adverse reactions; discontinue resmetirom if hepatotoxicity is suspected. 1
Gallbladder-related events: Cholelithiasis and cholecystitis were observed more frequently in resmetirom-treated patients. If acute cholecystitis is suspected, interrupt treatment until resolved. 1
Thyroid function: Resmetirom decreased free T4 levels by approximately 16-19% at 52 weeks, but thyroid-stimulating hormone and T3/free T3 remained within normal physiological limits with no increase in endocrine adverse events. 2 The drug upregulates T4 to T3 conversion by type 1 deiodinase (DIO1) exclusively within the liver through THR-β, without central hypothalamic-pituitary-thyroid axis regulation. 2 Patients should be monitored for thyroid hormone function during treatment. 2, 1
Sex hormone-binding globulin (SHBG): SHBG levels were elevated as a reflection of target engagement, resulting in slight changes in sex hormone levels, though free testosterone remained unchanged and there was no change in bone mineral density. 2
Drug Interactions
Statins
Limit the daily dosage of the following statins when used concomitantly with resmetirom: 1
- Atorvastatin
- Pravastatin
- Rosuvastatin
- Simvastatin
CYP2C8 Substrates
Monitor patients more frequently for substrate-related adverse reactions when resmetirom is used with CYP2C8 substrates. 1
Concomitant Use with GLP-1 Agonists
For patients currently on GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists, initiate resmetirom if residual active MASH with stage 2 or 3 fibrosis persists. 2 Existing GLP-1 therapy (present in ~14% of MAESTRO-NASH patients at baseline) did not affect tolerability or efficacy of resmetirom. 2 However, concomitant initiation of both GLP-1-based therapy and resmetirom is not recommended due to lack of evidence. 2
Important Limitations and Ongoing Research
Critical data gaps currently exist: 2, 6
- Sustainability of histological benefits beyond 52 weeks
- Individual prediction of response criteria
- Long-term safety data
- Impact on liver-related clinical outcomes (cirrhosis progression, hepatocellular carcinoma, liver-related mortality)
The MAESTRO-NASH trial is continuing with a 54-month assessment that will provide critical data on prevention of progression to cirrhosis. 2, 6 A separate trial exploring clinical outcomes in cirrhotic populations is also ongoing. 2
Clinical Practice Considerations
Resmetirom represents a paradigm shift as the first liver-directed therapy with FDA approval for NASH/MASH. 2, 6 The drug should be used in conjunction with diet and exercise as part of comprehensive metabolic management. 1 Non-invasive tests can facilitate patient selection and monitoring without requiring liver biopsy in routine clinical practice. 2, 6