Can GC-1 (thyroid hormone receptor beta agonist) be used to treat stage 3 liver fibrosis?

Can GC-1 (Thyroid Hormone Receptor Beta Agonist) Be Used to Treat Stage 3 Liver Fibrosis?

Yes, resmetirom (a thyroid hormone receptor beta agonist similar to GC-1) is FDA-approved and strongly recommended for treatment of stage 3 (F3) liver fibrosis in the context of metabolic dysfunction-associated steatohepatitis (MASH), but only in non-cirrhotic patients with active "at-risk MASH." 1

FDA Approval and Guideline Recommendations

Resmetirom received FDA approval in March 2024 specifically for patients with MASH and stage 2 or stage 3 fibrosis (F2-F3). 1 This represents the only liver-directed therapy currently approved by the FDA for this indication. 1

The 2024 EASL-EASD-EASO guidelines provide a strong recommendation (88% consensus) that adults with non-cirrhotic MASH with significant liver fibrosis (stage ≥2) should be considered for treatment with resmetirom, as it demonstrated histological efficacy on both steatohepatitis and fibrosis in large phase III registrational trials with acceptable safety and tolerability. 1

Critical Eligibility Criteria

Who Should Be Treated:

• Non-cirrhotic patients with F2 or F3 fibrosis and active "at-risk MASH" 1
• Patients can be identified by liver biopsy or noninvasive tests (NITs) showing disease consistent with moderate to advanced fibrosis 1

Who Should NOT Be Treated:

• Patients with cirrhosis (F4 fibrosis) are explicitly excluded - resmetirom should not be used in cirrhotic patients at this time 1
• Patients with early fibrosis (F0-F1) are not indicated for treatment 1

Evidence of Efficacy in Stage 3 Fibrosis

The MAESTRO-NASH phase 3 trial (n=966 patients with F2-F3 fibrosis) demonstrated that resmetirom achieved:

• Fibrosis improvement by at least one stage with no worsening of disease activity in 24.2% (80mg dose) and 25.9% (100mg dose) versus 14.2% with placebo (P<0.001) 2
• MASH resolution with no worsening of fibrosis in 25.9% (80mg) and 29.9% (100mg) versus 9.7% with placebo (P<0.001) 2
• Additional metabolic benefits including 13.6-16.3% reduction in LDL cholesterol 2

These results represent body weight-independent improvements in hepatic metabolism and fibrosis. 3

Practical Patient Selection Algorithm

Step 1: Confirm Non-Cirrhotic Status

• Rule out cirrhosis using imaging, liver stiffness measurement, or biopsy 1
• If cirrhosis is present, do not initiate resmetirom 1

Step 2: Identify F2-F3 Fibrosis Using NITs

When liver biopsy is not available, use the following thresholds to identify stage 2-3 fibrosis: 1

• Vibration-controlled transient elastography (VCTE/FibroScan): 10-15 kPa suggests F2-F3 1
• MR elastography (MRE): 3.3-4.2 kPa suggests F2-F3 1
• Enhanced Liver Fibrosis (ELF) score: ≥9.8 when used in isolation, or 9.2-9.7 with confirmatory testing 1

Important caveat: FIB-4 score is NOT reliable for treatment decisions in this population (median FIB-4 was only 1.3 in MAESTRO-NASH patients with F2-F3), so do not use FIB-4 alone to exclude patients from treatment. 1

Step 3: Confirm Active "At-Risk MASH"

• Ideally confirmed by liver biopsy showing NAFLD Activity Score ≥4 2
• If biopsy performed within 12 months shows MASH with F2-F3, can proceed regardless of NIT values 1
• In absence of biopsy, use combination of elevated liver enzymes, metabolic risk factors, and imaging evidence of steatosis 1

Concomitant Therapy Considerations

GLP-1 Receptor Agonists:

• For patients already on GLP-1 therapy with residual F2-F3 fibrosis, add resmetirom - existing GLP-1 therapy (present in ~14% of MAESTRO-NASH patients) did not affect tolerability or efficacy 1
• Do not initiate GLP-1 and resmetirom simultaneously due to lack of safety data for concomitant initiation 1
• In GLP-1-naive patients, prioritize resmetirom as it is the only therapy demonstrating both MASH resolution AND fibrosis regression in phase 3 trials 1

Other Medications:

• Resmetirom can be coadministered with thyroid hormone replacement therapy without interference 1
• Continue statins, SGLT2 inhibitors, and metformin for their respective indications as they are safe in MASLD 1, 4

Safety Profile and Monitoring

Common Adverse Effects:

• Diarrhea and nausea were more frequent than placebo 2
• Serious adverse events occurred at similar rates to placebo (10.9-12.7% vs 11.5%) 2

Thyroid-Related Effects:

• Free T4 levels decreased by 16-19% but T3, free T3, and TSH remained normal 1
• No increase in endocrine adverse events 1
• No central hypothalamic-pituitary-thyroid axis dysregulation 1

Hormonal Effects:

• Sex hormone-binding globulin levels increased (reflecting target engagement) 1
• Free testosterone remained unchanged and no change in bone mineral density occurred 1

Critical Limitations and Unknowns

The guidelines explicitly acknowledge that for patients treated with resmetirom: 1

• Long-term sustainability of histological benefits is unknown
• Individual prediction of response is not yet established
• Liver-related clinical outcomes data are not available
• Long-term safety beyond 52 weeks is not established

These limitations should be discussed with patients when initiating therapy, but do not negate the strong evidence supporting use in appropriate candidates with F3 fibrosis.

Comparison to Other Therapies

Resmetirom is the ONLY pharmacotherapy with demonstrated efficacy in both MASH resolution AND fibrosis regression in large phase 3 trials. 1 Other agents have limitations:

• Vitamin E: Cannot be recommended due to lack of robust phase 3 data and potential long-term risks 1
• Pioglitazone: Cannot be recommended as MASH-targeted therapy despite some histological benefits 1
• GLP-1 receptor agonists: Cannot be recommended as MASH-targeted therapy absent phase 3 histological data, though safe for diabetes/obesity indications 1, 4