Quantitative regression of qFibrosis with resmetirom: Exploratory histologic endpoints from the MAESTRO-NASH phase III clinical trial.

In the phase III MAESTRO-NASH trial, the impact of resmetirom compared with placebo on histologic fibrosis features was evaluated using artificial intelligence (AI)-based digital pathology (qFibrosis).

在III期MAESTRO-NASH试验中，使用基于人工智能（AI）的数字病理学（qFibrosis）评估了Resmetirom与安慰剂相比对组织学纤维化特征的影响。

Methods

qFibrosis was a secondary analysis of liver biopsies from 966 patients with biopsy-confirmed MASH and fibrosis stages F1B, F2, or F3 enrolled in the multicenter, double-blind, placebo-controlled, phase III MAESTRO-NASH trial. Biopsies from baseline and week 52 were assessed using second harmonic generation (SHG) and two-photon excitation fluorescence microscopy.

qFibrosis 是 MAESTRO-NASH 试验中 966 名经活检确认患有 MASH 且纤维化分期为 F1B、F2 或 F3 的患者肝活检的二次分析。该试验是一项多中心、双盲、安慰剂对照的 III 期临床试验。使用二次谐波生成（SHG）和双光子激发荧光显微镜对基线和第 52 周的活检样本进行了评估。

Pre-specified assessments by treatment group included qFibrosis continuous values (qFC), categorical stages (qFS), and qSteatosis.

治疗组的预先指定评估包括 qFibrosis 连续值（qFC）、分类分期（qFS）和 qSteatosis。

Post hoc analyses evaluated regional qFibrosis features and 30 clinical outcome-associated qFibrosis features, including correlations of these features with pathologist-assessed fibrosis improvement and non-invasive tests.

事后分析评估了区域定量纤维化特征以及与30个临床结果相关的定量纤维化特征，包括这些特征与病理学家评估的纤维化改善和非侵入性测试的相关性。

Results

Resmetirom 80 mg and 100 mg resulted in qFS improvement (≥1-stage decrease) in 24.4% and 22.3% more patients than placebo, respectively, and reduced qFS worsening (≥1-stage increase) relative to placebo (nominal p ≤0.001 for both doses).

Resmetirom 80 mg和100 mg分别使24.4%和22.3%的患者相对于安慰剂实现了qFS改善（≥1级下降），并且相对于安慰剂减少了qFS恶化（≥1级增加）（两剂量的名义p ≤0.001）。

Mean placebo-corrected reductions in qFC were -0.95 (95% CI -1.22 to -0.69) and -1.08 (95% CI -1.34 to -0.81) for the 80 mg and 100 mg doses, respectively.

平均安慰剂校正的qFC降低值分别为80毫克剂量的-0.95（95%置信区间-1.22至-0.69）和100毫克剂量的-1.08（95%置信区间-1.34至-0.81）。

Six of the 30 clinical outcome-associated qFibrosis features, primarily from the portal tract and Zone 2 regions, showed the strongest positive correlations with pathologist-assessed fibrosis stage and biomarkers, including liver stiffness measures.

在30个与临床结果相关的qFibrosis特征中，有6个主要来自门静脉区和区域2的特征显示出与病理学家评估的纤维化阶段以及包括肝脏硬度测量在内的生物标志物最强的正相关性。

Individual fibrosis features in the portal region and chicken wire fibrosis showed the greatest reductions with resmetirom treatment.

门静脉区域的个体纤维化特征和鸡丝样纤维化在 resmetirom 治疗后显示出最大的减少。

Conclusions

Resmetirom treatment led to significant improvements in qFC, qFS, and individual collagen features associated with fibrosis progression.

Resmetirom 治疗使得 qFC、qFS 以及与纤维化进展相关的个体胶原蛋白特征显著改善。

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.

这些数字病理学发现支持 resmetirom 的抗纤维化效果，并展示了基于 AI 的量化技术在定义 MASH 中纤维化反应的潜力。

impact_and_implications

This study provides the first evidence from a pivotal phase III trial that AI-based digital pathology, including qFibrosis and region-specific collagen features, can sensitively detect the antifibrotic effects of resmetirom in MASH beyond conventional ordinal staging.

这项研究提供了首个来自关键的第三阶段试验的证据，表明基于 AI 的数字病理学，包括 qFibrosis 和区域特异性胶原特征，能够敏感地检测到 resmetirom 在 MASH 中的抗纤维化效果，这超出了传统序数分期的范围。

These continuous metrics offer deeper insight into the pathophysiological mechanisms underlying fibrosis progression and reversal in MASLD, including early matrix remodeling, while enabling more granular, reproducible, and biologically plausible analyses.

这些连续的度量指标为MASLD（代谢相关脂肪性肝病）中纤维化进展和逆转的病理生理机制提供了更深入的见解，包括早期基质重塑，同时使得分析更加细致、可重复且生物学上更为合理。

The ability to quantify spatially distinct patterns of collagen remodeling - particularly in the portal tract and Zone 2 regions - may refine understanding of treatment-related antifibrotic effects in MASH and help clarify how such changes may reduce progression to cirrhosis and improve clinical outcomes.

能够量化空间上不同的胶原蛋白重塑模式 - 特别是在门静脉道和区域2 - 可能会深化对MASH（代谢相关脂肪性肝硬化）治疗相关抗纤维化效果的理解，并帮助阐明这些变化如何可能减缓肝硬化进展并改善临床结果。

clinical_trial_number

NCT03900429.

NCT03900429。