What are the outcomes of the Maestro (Non-Alcoholic Steatohepatitis) NASH study on Resmetirom?

MAESTRO-NASH Trial Outcomes for Resmetirom in NASH/MASH

Resmetirom demonstrated significant efficacy in the MAESTRO-NASH phase 3 trial, showing superior rates of NASH resolution (29.9% with 100mg dose vs 9.7% with placebo) and fibrosis improvement (25.9% with 100mg dose vs 14.2% with placebo) at 52 weeks, leading to FDA conditional approval for non-cirrhotic NASH/MASH with moderate to advanced fibrosis (F2-F3). 1

Key Efficacy Outcomes

• The MAESTRO-NASH phase 3 trial evaluated resmetirom in adults with biopsy-confirmed NASH and fibrosis stages F1B-F3 1
• Primary endpoints at 52 weeks showed:
  • NASH resolution with no worsening of fibrosis: 25.9% (80mg) and 29.9% (100mg) vs 9.7% (placebo), p<0.001 1
  • Fibrosis improvement by ≥1 stage with no worsening of NAFLD activity score: 24.2% (80mg) and 25.9% (100mg) vs 14.2% (placebo), p<0.001 1
• Significant reduction in hepatic fat content:
  • MRI-PDFF relative reduction of 32.9% (resmetirom) vs 10.4% (placebo) at week 12 2
  • MRI-PDFF relative reduction of 37.3% (resmetirom) vs 8.5% (placebo) at week 36 2

Non-Invasive Markers Improvement

• Significant improvements in liver enzymes and lipid parameters 1, 3
• Reduction in markers of fibrosis:
  • Liver stiffness measured by transient elastography decreased by 2.1 kPa (p=0.015) 4
  • PRO-C3 (fibrosis marker) reduced by 9.8 ng/mL (p=0.0004) 4
  • PRO-C3/C3M ratio (marker of net fibrosis formation) decreased significantly 4
• LDL cholesterol reduction of 13.6% (80mg) and 16.3% (100mg) vs 0.1% (placebo) at week 24 1

Safety Profile

• Most common adverse events were gastrointestinal:
  • Diarrhea (up to 33%) 5
  • Nausea (up to 22%) 5
  • Pruritus (up to 11%) 5
  • Vomiting (up to 11%) 5
• Serious adverse events were similar across groups: 10.9% (80mg), 12.7% (100mg), and 11.5% (placebo) 1
• No significant impact on thyroid function was observed 3

FDA Approval and Treatment Recommendations

• In March 2024, resmetirom received conditional FDA approval for non-cirrhotic NASH/MASH with moderate to advanced fibrosis (F2-F3) 5
• Weight-based dosing is recommended:
  • 80mg for patients <100kg
  • 100mg for patients >100kg 5
• The drug is not approved for patients with cirrhosis or early fibrosis (F0-F1) 5

Long-Term Outcomes and Monitoring

• The MAESTRO-NASH trial is continuing to evaluate longer-term outcomes at 54 months to determine if treatment prevents progression to cirrhosis 5
• A separate trial (MAESTRO-NASH-OUTCOMES) is evaluating resmetirom in patients with compensated NASH cirrhosis 6
• Treatment monitoring recommendations:
  • Initial assessment at 12 weeks for safety and tolerability 5
  • Assessment at 6 months for disease monitoring 5
  • Full efficacy assessment at 12 months and annually thereafter 5
  • Treatment response indicators include:
    • ALT improvement (>17 IU/L or >20% reduction) 5
    • MRI-PDFF reduction of ≥30% 5
    • Reduction in liver stiffness by VCTE (>30% drop) 5

Limitations and Ongoing Research

• Current evidence is limited to 52-week histological outcomes 5
• Long-term sustainability of histological benefits is not yet established 5
• Predictive criteria for response and optimal duration of therapy remain unknown 5
• The 54-month assessment will provide critical data on prevention of progression to cirrhosis 5
• Treatment is expected to be long-term, similar to management of other metabolic conditions 5

Clinical Implications

• Resmetirom represents the first liver-directed therapy with FDA approval for NASH/MASH 5
• Non-invasive tests can be used for patient selection and monitoring, without requiring liver biopsy 5
• Treatment should be used in conjunction with diet and exercise 5
• Patients should be monitored for gastrointestinal side effects and thyroid hormone function 5