Introduction
Resmetirom, a selective thyroid hormone receptor beta agonist, is an approved therapy for metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis based on improvement in both NASH and fibrosis. MASH cirrhosis with clinically significant portal hypertension (CSPH) leads to major adverse liver outcomes. This analysis aimed to assess the effect of resmetirom over two years of treatment in 122 patients with MASH cirrhosis, with and without CSPH, as defined by Baveno VII criteria.
Aims & Methods
A total of 122 patients with Child Pugh A MASH cirrhosis (based on MASH F4 on historic biopsy >66% or clinical diagnosis) were treated with 80 mg resmetirom for up to 2 years (MAESTRO-NAFLD-
1 (NCT04197479) year 1; open-label extension trial [NCT04951219) (year 2)]. Patients were assessed for baseline CSPH (Baveno VII) with FibroScan vibration-controlled transient elastography
(VCTE), platelet count and confirmed using magnetic resonance elastography (MRE). Non-invasive biomarkers and imaging were analysed at baseline and out to 2 years. Results are presented as mean
change or % change from baseline.
Results
Baseline characteristics included age 61.3 (9.1) [mean (SD)], female 56%, Hispanic 27%, BMI 35.3 (7.6) kg/m2, T2D 65%. Median, (Q1, Q3): VCTE, 20.1 (17.1,31.3) kPa; CAP, 327 (292,370) dB/m;
FIB-4, 2.4 (1.7, 3.8), MRE, 5.2 (4.4, 6.3) kPa; ELF, 10.7 (10.0, 11.5); MRI-PDFF, 8.6% (6, 11.5); Agile3+, 0.96 (0.89, 0.93); Agile 4, 0.64 (0.40,0.84). Resmetirom statistically significantly improved the following:
mean change from baseline: VCTE, -6.1(1.4) kPa at year 1; -6.7(1.3) kPa at year 2; at year 2: MRE -0.57 (0.14) kPa; procollagen-3 N-terminal peptide (P3NP), -1.6(0.57) ng/ml; Agile3+, -.06(0.01);
Agile4, -.09(.02); % change from baseline: MRI-PDFF -33%; ALT, -25%; AST, -21%; GGT, -45%; LDL, -20%, ApoB, -22%, triglycerides, -30%. At year 1 and 2, respectively, 46% and 52% had a ≥25% decrease in VCTE; 12% and 9% had ≥25% increase in VCTE. At baseline, 63% of patients were categorized as probable/definitive CSPH (Baveno VII), and at 1 and 2 years, respectively, 20% and 28% of CSPH
positive patients no longer met criteria for CSPH. 35% of patients with confirmed F4 at baseline (liver biopsy F4 and/or platelets <140/MRE ≥5 with VCTE ≥15) showed a transition from F4 to F3 at year 2
(VCTE <15 and ≥25% decrease from baseline). Discontinuation rate was 8%. Mild gastrointestinal disorders were the most common adverse events.
Conclusion
At 2 years of treatment, resmetirom demonstrated significant improvements in noninvasive
biomarkers, liver stiffness on imaging and portal hypertension risk in patients with MASH
cirrhosis. Resmetirom was safe and well-tolerated in this population. These findings highlight the
potential of resmetirom to demonstrate clinical benefit in MAESTRO-NASH OUTCOMES, an ongoing,
845 MASH cirrhosis patient clinical outcome study.
Disclosure
This study was funded by Madrigal Pharmaceuticals, Inc.