Aramchol improves hepatic fibrosis in MASH: Results of multimodality assessment using both conventional and digital pathology.

ABSTRACT

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.