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

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.

Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism.

Metabolic dysfunction-associated steatohepatitis (MASH) can progress to cirrhosis and liver cancer. There are no approved medical therapies to prevent or reverse disease progression. Fructose and its metabolism in the liver play integral roles in MASH pathogenesis and progression. Here we focus on mannose, a simple sugar, which dampens hepatic stellate cell activation and mitigates alcoholic liver disease in vitro and in vivo . In the well-validated FAT-MASH murine model, oral mannose supplementation improved both liver steatosis and fibrosis at low and high doses, whether administered either at the onset of the model ("Prevention") or at week 6 of the 12-week MASH regimen ("Reversal"). The in vivo anti-fibrotic effects of mannose supplementation were validated in a second model of carbon tetrachloride-induced liver fibrosis. In vitro human and mouse primary hepatocytes revealed that the anti-steatotic effects of mannose are dependent on the presence of fructose, which attenuates expression of ketohexokinase (KHK), the main enzyme in fructolysis. KHK is decreased with mannose supplementation in vivo and in vitro, and overexpression of KHK abrogated the anti-steatotic effects of mannose. Our study identifies mannose as a simple, novel therapeutic candidate for MASH that mitigates metabolic dysregulation and exerts anti-fibrotic effects.