Camilleri, Michael, Linker Nord, Sara, Burton, Duane , Oduyebo, Ibironke , Zhang, Yiming, Chen, Jin, Im, Koeun, Bhad, Prafulla, Badman, Michael, 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