Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea

Abstract

Background: In primary bile acid diarrhoea (PBAD), feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired. Aims:To evaluate the safety, mechanisms and efficacy of tropifexor, a non-bile acid FXR agonist, in patients with PBAD. Methods:In this double-blind, multicentre, randomised, crossover study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of 2 treatment periods. Primary objectives included the effect of tropifexor on safety and tolerability, stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit.Results: A total of 20 patients (tropifexor 60 µg/placebo [N=10]; placebo/tropifexor 60 µg [N=10]) were enrolled. Adverse event rates were similar with tropifexor and placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. Differences in stool frequency, stool form or loperamide use between two treatments were not appreciably large.Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma concentrations of tropifexor peaked at 5 hours post-dose on days 1 and 12. At Day 12, reduction in peak total bile acid concentration (33%, P=0.032) and exposure (36%, P=0.005) was noted with tropifexor. A significant increase in ascending colonic halfemptying time was observed with tropifexor (P=0.036). Conclusions:Tropifexor 60 µg once daily had an acceptable safety and tolerability profile.

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

“…Interestingly, modified BA and non-BA FXR agonists are helpful to prevent those adverse effects. The diarrhea is associated with alteration in secretion and motility in the colon, and activation of FXR by obeticholic acid or tropifexor (non-BA FXR agonist) increases the feedback inhibition via fibroblast growth factor 19, improving diarrhea scores [ 154 , 155 ].…”

The Saga of Endocrine FGFs

“…FGF19 and FXR affect the bile acid regulation and have been known to treat primary bile acid diarrhea [ 13 , 14 ]. FXR agonists were further developed based on the relationship of FGF19 with FXR [ 226 ]. This agonist reduces the expression of FGF19 in the liver, thus, decreasing hepatic bile acid secretion for treating bile acid diarrhea [ 226 ].…”

“…FXR agonists were further developed based on the relationship of FGF19 with FXR [ 226 ]. This agonist reduces the expression of FGF19 in the liver, thus, decreasing hepatic bile acid secretion for treating bile acid diarrhea [ 226 ]. In a very recent clinical trial, Tropifexor (LJN452) a highly potent non-bile acid FXR agonist, was employed to assess the efficacy in a patient with primary acid bile diarrhea.…”

“…In a very recent clinical trial, Tropifexor (LJN452) a highly potent non-bile acid FXR agonist, was employed to assess the efficacy in a patient with primary acid bile diarrhea. Tropifexor at 60 μg once-daily dose for 14 days had an acceptable safety and tolerability profile in those patients [ 226 ].…”

Chologene Diarrhö, Stiefkind der chronischen Diarrhö – Prävalenz, Diagnostik und Therapie. Update 2021

“…Ein weiterer FXR-Agonist, Tropifexor, wurde erst 2019 in einer ersten randomisierten, kontrollierten Crossoverstudie bei insgesamt 20 Patienten mit chologener Diarrhö Typ 1 getestet. Dabei kam es, verglichen mit Placebo, zu signifikant langsameren szintigrafisch gemessenen Kolontransitzeiten; die beobachteten Symptomverbesserungen waren aber nicht signifikant [56]. Weiterhin konnte gezeigt werden, dass der Gallensäurenkomplexbildner Colesevelam zusätzlich FXR-agonistisch wirkt [57].…”