Is Resmetirom (a thyroid hormone receptor beta agonist) effective for treating liver fibrosis associated with Non-Alcoholic Steatohepatitis (NASH)?

Resmetirom for Liver Fibrosis in NASH/MASH

Resmetirom is FDA-approved and effective for treating liver fibrosis in patients with non-cirrhotic NASH/MASH who have moderate to advanced fibrosis (stages F2-F3), demonstrating both NASH resolution and fibrosis regression superior to placebo. 1

FDA Approval and Indication

Resmetirom received FDA approval on March 14,2024, as the first and only liver-directed pharmacotherapy for NASH/MASH. 1 The approved indication is for adults with non-cirrhotic NASH/MASH with moderate to advanced liver fibrosis (F2-F3 stages), used in conjunction with diet and exercise. 1

The approval specifically excludes patients with cirrhosis (F4) and those with early fibrosis (F0-F1). 1

Efficacy for Fibrosis Regression

The MAESTRO-NASH phase 3 trial demonstrated robust efficacy for fibrosis improvement:

• Fibrosis improvement by ≥1 stage with no worsening of NAFLD activity score occurred in 24.2% of patients on 80 mg resmetirom and 25.9% on 100 mg, compared to only 14.2% with placebo (P<0.001 for both doses). 2

• NASH resolution without worsening fibrosis was achieved in 25.9% (80 mg) and 29.9% (100 mg) versus 9.7% with placebo (P<0.001). 2

• Hepatic fat content reduction was substantial: -32.9% at 12 weeks and -37.3% at 36 weeks with resmetirom versus -10.4% and -8.5% with placebo (P<0.0001). 3

Dosing Algorithm

Weight-based dosing is recommended by the FDA label:

• 80 mg once daily for patients <100 kg body weight 1
• 100 mg once daily for patients ≥100 kg body weight 1

Patient Selection Criteria

Who Should Receive Resmetirom

Target patients with "at-risk MASH" defined as active steatohepatitis with F2 or F3 fibrosis. 1 Diagnosis can be established through:

• Liver biopsy showing F2 or F3 fibrosis (overrides non-invasive test parameters if no clinical/imaging evidence of portal hypertension) 1
• Non-invasive tests (NITs) showing concordant results suggesting F2-F3 disease 1

Who Should NOT Receive Resmetirom

Absolute exclusions include: 1

• History of F4 fibrosis on liver biopsy
• Imaging signs of portal hypertension (ascites, portosystemic collaterals, varices)
• Clinical manifestations of hepatic decompensation (ascites, varices, hepatic encephalopathy)
• VCTE liver stiffness >20 kPa or MRE >5 kPa (suggests cirrhosis) 1
• ELF score >11.3 (suggests cirrhosis) 1

Common pitfall: The distinction between F3 and early F4 is challenging with NITs, so err on the side of not treating patients who may have early cirrhosis until the MAESTRO-OUTCOMES trial data in cirrhotic patients becomes available. 1

Monitoring Treatment Response

Assessment schedule: 4, 5

• 12 weeks: Safety and tolerability assessment
• 6 months: Disease monitoring
• 12 months and annually thereafter: Full efficacy evaluation

Treatment response indicators include: 5

• ALT improvement (>17 IU/L or >20% reduction)
• MRI-PDFF reduction of ≥30%
• Liver stiffness reduction by VCTE (>30% drop)

Concomitant Medications

GLP-1 Receptor Agonists

For patients already on GLP-1 receptor agonists or dual GIP/GLP-1 agonists, resmetirom can be initiated if residual active MASH with F2-F3 fibrosis persists. 1 Existing GLP-1 therapy (present in ~14% of MAESTRO-NASH patients) did not affect resmetirom's tolerability or efficacy. 1

However, concomitant initiation of both GLP-1-based therapy and resmetirom is NOT recommended due to lack of evidence. 1, 4 In GLP-1 and resmetirom-naive patients, only resmetirom has demonstrated effects on both MASH resolution and fibrosis regression in a large phase 3 trial. 1

Drug Interactions

Reduce resmetirom dosage when used with moderate CYP2C8 inhibitors, and avoid concomitant use with strong CYP2C8 inhibitors or OATP1B1/OATP1B3 inhibitors. 4

Limit daily statin dosages when used concomitantly with resmetirom. 4

Safety Profile

Common adverse events are predominantly gastrointestinal and mild-to-moderate: 5, 6, 2

• Diarrhea (up to 33%)
• Nausea (up to 22%)
• Pruritus (up to 11%)
• Vomiting (up to 11%)

Serious adverse events were similar across groups (10.9-12.7% with resmetirom vs 11.5% with placebo). 2

Monitor thyroid hormone function during treatment, as resmetirom decreases free T4 levels. 4, 5 However, resmetirom does not interfere with thyroid hormone replacement therapy and can be coadministered. 1

Monitor for hepatotoxicity and discontinue resmetirom if suspected. 4

Additional Benefits Beyond Fibrosis

Resmetirom significantly improved lipid profiles: 2

• LDL cholesterol reduction: -13.6% (80 mg) and -16.3% (100 mg) versus 0.1% with placebo at 24 weeks (P<0.001)
• Apolipoprotein B reduction: -23.8% 7
• Triglyceride reduction: -19.6% 7

Noninvasive fibrosis markers improved: 7

• Liver stiffness by transient elastography: -2.1 kPa reduction (P=0.015)
• PRO-C3 (marker of fibrosis formation): -9.8 ng/mL reduction (P=0.0004)

Limitations and Future Data

Current evidence is limited to 52-week histological outcomes; long-term sustainability of histological benefits is not yet established. 5 The 54-month assessment from the ongoing MAESTRO-OUTCOMES trial will provide critical data on prevention of progression to cirrhosis and efficacy in compensated cirrhotic patients. 1, 5