Background and Aims: Antifibrotic trials rely on conventional pathology (CP) despite recognized limitations. We compared single fiber digital image analysis (DIA) with CP to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic-dysfunction associated steatohepatitis (MASH). Approach and Results: 51 MASH patients enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among three hepatopathologists, and separately assessed by a DIA platform (PharmaNest®) that generates a continuous phenotypic Fibrosis Composite Severity Score (Ph-FCS). Fibrosis improvement was defined as: >1 NASH-CRN stage reduction; “improved” by ranked pair assessment (RPA); reduction in Ph-FCS (“any” for >0.3 absolute reduction, “substantial” for >25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (RPA), 74.5% (any Ph-FCS reduction) and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or RPA had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for <48 weeks vs. 39% for >48 weeks by NASH-CRN; 43% vs. 61% by RPA, mean Ph-FCS reduction -0.54 (sd 1.22) vs. -1.72 (sd 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3 and ELF. Changes in Ph-FCS were positively correlated with changes in liver stiffness. Conclusions: Continuous fibrosis scores generated in antifibrotic trials by DIA quantify antifibrotic effects with greater sensitivity and larger dynamic range than CP.

中文翻译：

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Aramchol 改善 MASH 中的肝纤维化：使用传统病理学和数字病理学的多模态评估结果


背景和目的：抗纤维化试验依赖于传统病理学 (CP)，尽管存在公认的局限性。我们将单纤维数字图像分析 (DIA) 与 CP 进行比较，以量化 Aramchol 的抗纤维化作用，Aramchol 是一种正在开发用于治疗代谢功能障碍相关脂肪性肝炎 (MASH) 的硬脂酰辅酶 A 去饱和酶 1 抑制剂。方法和结果：参加 ARMOR 试验开放标签部分的 51 名 MASH 患者接受了 Aramchol 300 mg BID，并进行了配对的治疗前肝活检，经三位肝病理学家一致评分，并通过 DIA 平台 (PharmaNest®) 分别进行评估生成连续表型纤维化综合严重程度评分 (Ph-FCS)。纤维化改善定义为：>1 NASH-CRN 阶段降低；通过排名配对评估（RPA）“改进”； Ph-FCS 减少（“任意”表示 >0.3 绝对减少，“大量”表示 >25% 相对减少）。 31% 的患者 (NASH-CRN)、51% (RPA)、74.5%（任何 Ph-FCS 减少）和 41%（Ph-FCS 大幅减少）的纤维化得到改善。大多数通过 NASH-CRN 或 RPA 获得稳定纤维化的患者的 Ph-FCS 减少（三分之一大幅减少）。纤维化改善随着治疗时间的延长而增加：根据 NASH-CRN，<48 周为 25%，>48 周为 39%； RPA 为 43% vs. 61%，平均 Ph-FCS 减少 -0.54 (sd 1.22) vs. -1.72 (sd 1.02)； Ph-FCS 减少（54% 对比 100%，显着降低 21% 对比 65%）。 Aramchol 的抗纤维化作用通过肝脏硬度、Pro-C3 和 ELF 的降低得到证实。 Ph-FCS 的变化与肝脏硬度的变化呈正相关。结论：DIA 在抗纤维化试验中生成的连续纤维化评分量化抗纤维化效果，比 CP 具有更高的敏感性和更大的动态范围。