Discussion
Pruritus, fibrosis, liver injury, NASH, pruritus, T2DM, liver fat reduction
PRURITUS, LIVER FIBROSIS, FIBROSIS, SECONDARY, EVENTS, PATHOLOGY, TYPE 2 DIABETES MELLITUS
In this phase 2, randomized, multicenter, double-blind, three-part study, pruritus was the most commonly reported AE with tropifexor, with an incidence that was dose-dependent. Events were generally of mild severity and led to low treatment discontinuation rates. Pruritus has been noted in other FXR studiesAssessment of the secondary objectives of the study revealed that these reductions in ALT and HFF were sustained up to 48 weeks of treatment with tropifexor. Sustained reductions in GGT were also observed. Results with AST remained inconclusive up to week 48. In addition, a greater proportion of patients attained a ≥30% relative reduction in HFF at week 48 with tropifexor versus placebo. A ≥30% relative reduction in HFF has been associated with histologic improvements in NASH in several trials and has been proposed as a potential future surrogate marker for evaluating therapeutic effect in early NASH trials instead of invasive biopsiesDespite improvement in biomarkers of liver injury and indirect indicators of histologic improvement after 48 weeks of tropifexor treatment, greater histologic improvement of fibrosis or resolution of NASH relative to placebo was not observed, based on the central pathologist’s assessment using the traditional semiquantitative NASH CRN scoring system. In a post hoc analysis, the use of second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) analyses of the same liver biopsies showed that tropifexor treatment resulted in marked liver fat reduction (qSteatosis), which correlated well with the quantitative MRI-based evaluation of fat reduction and improvement of liver fibrosis (qFibrosis). Further insights into this analysis have been recently publishedFLIGHT-FXR Part C study limitations include a shorter therapy duration (48 weeks) than some previous FXR trialsAt baseline, the majority of patients had markers of progressive NASH, with stage 3 fibrosis and type 2 diabetes mellitus (T2DM). Nonetheless, tropifexor demonstrated sustained improvement in liver enzymes and HFF versus placebo, with a safety profile consistent with other FXR agonists. The histologic improvements observed with tropifexor when biopsies were assessed using AI-based digital pathology offer an interesting insight into fibrosis evolution and resolution as highly dynamic processes. The dissonance between the results from traditional histologic assessments and AI-based digital pathology may be due to the latter having a greater ability to detect fibrosis changes that are not readily apparent with traditional histological assessments, or perhaps the decreased variability when using machine-based quantitative algorithms. However, in the real world, both patients and clinicians still rely on histologic results through traditional reading and the exploratory nature of the AI-based digital pathology analysis means that the results should be interpreted with caution.In summary, treatment with tropifexor resulted in sustained decreases in ALT and HFF versus placebo. As with other FXR agonists, dose-related pruritus was frequently observed. Results from the histologic post hoc analysis support a rationale for further exploring the anti-fibrotic effects of tropifexor, either alone or in combination with other agents. Further studies are needed to characterize treatment-related changes beyond conventional histologic assessments.