Key points are not available for this paper at this time.
BACKGROUND & AIMS: Resmetirom, a thyroid hormone beta (THR-β) agonist, has been shown to improve metabolic-dysfunction associated steatohepatitis (MASH) and fibrosis in patients with non-cirrhotic MASH in a Phase 3 serial liver biopsy study. The impact of resmetirom compared with placebo on histologic fibrosis features was evaluated using artificial intelligence (AI)-based digital pathology (qFibrosis) in the phase 3 MAESTRO-NASH trial. METHODS: q-Fibrosis was a secondary analysis of liver biopsies from 966 patients with biopsy-confirmed MASH and fibrosis stages F1B, F2, or F3 enrolled in the multicentre, double-blind, placebo-controlled, phase 3 MAESTRO-NASH trial. Biopsies from baseline and Week 52 were assessed using second harmonic generation (SHG) and two-photon excitation fluorescence microscopy. Pre-specified assessment according to treatment was conducted of qFibrosis continuous values (qFC), categorical stages (qFS), and qSteatosis. Posthoc assessments were conducted of regional qFibrosis features and 30 clinical outcome-associated qFibrosis features including correlations of the 30 features with pathologist-assessed fibrosis improvement and non-invasive tests. RESULTS: Resmetirom 80 mg and 100 mg led to qFS improvement (decrease by ≥1) in 24.4% and 22.3% more patients than placebo, respectively, and reduced qFS worsening (increase by ≥1) relative to placebo, respectively (nominal, p≤0.001 for both doses). Mean placebo-corrected reductions in qFC were -0.95 (95% CI: -1.22, -0.69) and -1.08 (95% CI: -1.34, -0.81) for 80 mg and 100 mg, respectively. Six of the 30 clinical-outcome associated qFibrosis features from the portal tract and Zone 2 regions showed the highest positive correlations with pathologist-assessed fibrosis stage, and biomarkers including liver stiffness measures. Individual fibrosis features from the portal region and chicken wire fibrosis showed the strongest reduction by resmetirom. CONCLUSIONS: Resmetirom treatment led to significant improvements in qFC, qFS, and individual collagen features associated with fibrosis progression. These digital pathology findings support the antifibrotic efficacy of resmetirom and demonstrate the potential of AI-based quantification to help define the fibrogenic response in MASH. IMPACT AND IMPLICATIONS: This study provides the first evidence that AI-based digital pathology, including qFibrosis and region-specific collagen features, sensitively detects antifibrotic treatment effects of resmetirom in MASH beyond the conventional ordinal staging based on a phase 3 pivotal trial. These continuous metrics highlight nuanced pathophysiological mechanisms of fibrosis progression and reversal in MASLD including early matrix remodeling and allowing for more granular, reproducible, and biologically plausible analysis. The ability to quantify spatially distinct collagen remodeling patterns, especially in portal tract and Zone 2 regions, could help refine the understanding of the anti-fibrotic effects of treatment for MASH including the impact to reduce fibrosis progression to cirrhosis and clinical outcomes. CLINICAL TRIAL NUMBER: NCT03900429.
Schattenberg et al. (Sun,) studied this question.