Treatment with the thyroid hormone beta agonist resmetirom significantly improves qFibrosis continuous values (qFC), categorical stages (qFS), and individual collagen features associated with fibrosis progression at week 52 compared with placebo in patients with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH), as shown in the phase III MAESTRO-NASH trial.
“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,” said the investigators, who assessed the impact of resmetirom on histologic fibrosis features using qFibrosis, an artificial intelligence (AI)-based digital pathology.
The MAESTRO-NASH trial enrolled 966 patients with MASH and fibrosis stages F1B, F2, or F3. Liver biopsies from baseline and week 52 were examined using second harmonic generation (SHG) and two-photon excitation fluorescence microscopy.
The investigators performed prespecified assessments by treatment group using qFC, qFS, and qSteatosis. They also conducted post hoc analyses to assess regional qFibrosis features and 30 clinical outcome-related qFibrosis features, including the associations of these features with pathologist-assessed fibrosis improvement and noninvasive tests.
Resmetirom 80 and 100 mg improved qFS (≥1-stage decrease) in 24.4 percent and 22.3 percent more patients than those treated with placebo, respectively. The study drug also reduced qFS worsening (≥1-stage increase) compared with placebo (nominal p≤0.001 for both doses). [J Hepatol 2026;85:202-211]
The mean placebo-corrected reductions in qFS were ‒0.95 (95 percent confidence interval [CI], ‒1.22 to ‒0.69) for resmetirom 80 mg and ‒1.08 (95 percent CI, ‒1.34 to ‒0.81) for the 100-mg dose.
Of the 30 clinical outcome-associated qFibrosis features, six (primarily from the portal tract and Zone 2 regions) exhibited the most robust associations with pathologist-assessed fibrosis stage and biomarkers, including liver stiffness measures. Resmetirom treatment produced the greatest reductions in individual fibrosis features in the portal region and chicken wire fibrosis.
In a post hoc analysis, resmetirom also resulted in improvements in qFibrosis features on liver biopsies that have been shown to contribute to liver-related outcomes and death. [Liver Int 2024;44:2511-2516]
Reference standard
The reference standard for MASH staging is histological assessment of liver biopsy samples based on ordinal scoring of fibrosis stage. This reference is also used for diagnostic sub-phenotyping, risk stratification, disease monitoring, and evaluation of treatment response in clinical trials. [Hepatology 2023;77:1797-1835]
“Fibrosis is a dynamic process: fibrogenesis and collagen turnover are higher in patients with more advanced stages of MASH,” the investigators said. [Hepatology 2017;65:78-88]
“The limited range of measurement of ordinal scoring does not allow for assessment of nuances in fibrosis progression and regression,” they added. [Hepatology 2017;65:78-88]
Digital pathology, however, enables the assessment of liver features that are typically challenging to quantify by traditional microscopy and assessment. SHG imaging makes use of the physical properties of collagen filaments and tissue. This allows the analysis of the three-dimensional architecture of fibrillar collagen and its inherent physician features. [Anal Chem 2011;83:3224-3231; J Hepatol 2010;52:398-406]
Ongoing study
“The ongoing outcome portion of the MAESTRO-NASH study evaluates liver-related outcomes including histological conversion to cirrhosis, all-cause mortality, and hepatic decompensation at month 54,” the investigators said.
“Evaluation of the qFibrosis findings on the month 54 biopsies will lead to additional insights and may further improve the ability to discriminate resmetirom-induced improvements in biopsy fibrosis features that are associated with liver-related outcomes,” they added.