DISCUSSION
nausea, fatigue, fibrosis, liver fibrosis stage, NASH, pruritus, steatosis
REGRESSION, STEATOSIS, PATHOLOGY, FIBROSIS
This study was a 48-week, randomized, double-blind, multicenter trial with the primary objective to evaluate the safety and tolerability of TXR + CVC in patients with NASH and fibrosis as compared with TXR and CVC monotherapy. The safety profiles of the combination therapies of TXROverall, pruritus, nausea, and fatigue were the most frequently experienced AEs, with the highest incidence of pruritus observed in the TXR monotherapy group and notably lower with TXRThere was a decrease in ALT, AST, and GGT in the TXR monotherapy and combination groups from baseline during the 48-week period, while in the CVC monotherapy group, no such reduction was observed. A similar decrease in ALT from baseline with TXR was observed in the FLIGHT-FXR study.Although the observed fibrosis improvement was in the same range as in other placebo-controlled monotherapy studies with CVC or TXR,Although we did not see synergistic efficacy with these therapies when used in combination, this does not exclude such an effect in other combinations. As the effects of CVC on metabolic components of NASH are thought to be limitedThe post hoc digital pathology and AI analyses provided useful mechanistic details in the evaluation of NASH treatment with compounds of different mechanisms of action. TXR alone was shown to have greater impact in reducing steatosis than CVC monotherapy, consistent with TXR effects in reducing liver enzymes and HFF; the antifibrotic activity of TXR monotherapy was seen mainly in zone 1 and zone 2 of the liver lobule, while CVC showed antifibrotic effects uniformly in all 3 zones of the liver lobule. Although no significant difference in liver fibrosis stage was observed between the 4 treatment groups over the study period using conventional microscopy, digital quantitation analysis of fibrosis changes in different zones of the liver lobule revealed that the combination of TXR and CVC had an additive effect, achieving the greatest fibrosis reduction near steatosis in all 3 zones of the liver lobule, compared with each monotherapy group, with the TXRThe colocalization analyses assessing treatment-induced changes of fibrosis in relation to steatosis or hepatocyte ballooning, in the 4 treatment arms, confirmed the association that fibrosis regression occurs in cases with reduction of steatosis and hepatocyte ballooning, as described.The treatment effect on changes in lipid levels related to TXR treatment was apparent by week 4, near maximum by week 12, and with little change thereafter. This was similar to the stabilization of changes in lipid levels after week 12 in the FLIGHT-FXR study.PK data from this study confirm a similar predose exposure between TXRLimitations of this study include a small number of patients, limiting the power to address histological change, with the COVID-19 pandemic effect further decreasing effective sample size, and leading to missed visits and central laboratory assessments.