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A Randomized Controlled Trial of a Farnesoid X Receptor Agonist, Tropifexor, in Patients with Primary Bile Acid Diarrhea

Camilleri, Michael and Linker Nord, Sara and Burton, Duane and Oduyebo, Ibironke and Zhang, Yiming and Chen, Jin and Im, Koeun and Bhad, Prafulla and Badman, Michael and Sanders, David and Walters, Julian (2020) A Randomized Controlled Trial of a Farnesoid X Receptor Agonist, Tropifexor, in Patients with Primary Bile Acid Diarrhea. Alimentary pharmacology & therapeutics, 52 (5). pp. 808-820. ISSN 02692813

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 negative feedback by FXR activation with tropifexor, a non-bile acid FXR agonist, in patients with PBAD.
Methods: In this double-blind, multicentre, randomised, cross-over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of 2 treatment periods. Primary objectives included tropifexor effect on safety, tolerability, stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers, and gastrointestinal transit.
Results: Twenty patients (tropifexor 60 µg/placebo [N=10]; placebo/tropifexor 60 µg [N=10]) were enrolled. Adverse event rates were lower with tropifexor versus placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post-dose on Days 1 and 12. At Day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P=0.032) and exposure (36%, P=0.005). Moreover, tropifexor showed significant increase in ascending colonic half-emptying time (P=0.036).
Conclusions: Tropifexor 60 µg once daily had an acceptable safety and tolerability profile. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with PBAD.

Item Type: Article
Date Deposited: 27 Oct 2020 00:45
Last Modified: 27 Oct 2020 00:45
URI: https://oak.novartis.com/id/eprint/42902

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