Biomarkers, Imaging, and Safety in a Well-compensated NASH Cirrhotic Cohort Treated With Resmetirom, a Thyroid Hormone Receptor-beta Selective Agonist, for 52 Weeks

MAESTRO-NAFLD-1 is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating resmetirom, a thyroid hormone receptor-beta selective agonist, in NASH patients identified using noninvasive biomarkers and imaging (NCT04197479). MAESTRO-NAFLD-1 includes an open-label resmetirom arm in well-compensated NASH cirrhotic patients. Eligibility required≥3 metabolic risk factors and NASH cirrhosis (diagnosed by biopsy or accepted criteria). Primary and key secondary endpoints include safety, relative percent reduction in MRI-PDFF (Week 16), LDL-C, apoB, and triglycerides (Week 24), and fibrosis markers. All patients received 80 or 100mg resmetirom daily for 52 weeks. Cohort 1 (n=105) has completed 52 weeks of treatment. Cirrhosis stage inversely correlated with baseline MRI-PDFF. At Week 52, resmetirom reduced FibroScan CAP by 42dB/m (p<0.0001) and FibroScan VCTE (LSM) by 7.6kPa (p=0.02). In patients with baseline MRI-PDFF>5% (5%=ULN), resmetirom reduced MRI-PDFF by 37% (p<0.0057). At Week 52, resmetirom reduced MRE by 0.68kPa; 34% of patients achieved an MRE reduction≥15%. GGT and ALP were reduced with resmetirom (by 27% and 18%, respectively; p=0.04 for both). Liver volume, which was elevated at baseline, was reduced by 15.9% at Week 16 (p<0.0001), independent of baseline MRI-PDFF. Liver volume reduction correlated with reduction in MRE, MRI-PDFF, TIMP, P3NP, and SHBG. Resmetirom reduced LDL-C (20%), apoB (20%), triglycerides (21%), and Lp(a) (30%), independent of cirrhosis stage. Resmetirom was well tolerated. BP decreased by 4-5mmHg. Overall, resmetirom reduced markers of cardiovascular risk and fibrosis in NASH cirrhotic patients.