BACKGROUND: In primary bile acid diarrhoea, 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 primary bile acid diarrhoea. 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 two treatment periods. Primary objectives included tropifexor safety and tolerability, and on 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 vs 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 a significant increase in ascending colon half-emptying time (P = 0.036). CONCLUSIONS: Tropifexor 60 µg once daily had acceptable safety and tolerability. 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 primary bile acid diarrhoea. ClinicalTrials.gov number: NCT02713243.
RCT Entities:
BACKGROUND: In primary bile aciddiarrhoea, 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 acidFXR agonist, in patients with primary bile aciddiarrhoea. 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 two treatment periods. Primary objectives included tropifexor safety and tolerability, and on 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 vs 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 a significant increase in ascending colon half-emptying time (P = 0.036). CONCLUSIONS: Tropifexor 60 µg once daily had acceptable safety and tolerability. 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 primary bile aciddiarrhoea. ClinicalTrials.gov number: NCT02713243.
Authors: Maksim Khotimchenko; Nicholas E Brunk; Mark S Hixon; Daniel M Walden; Hypatia Hou; Kaushik Chakravarty; Jyotika Varshney Journal: Pharm Res Date: 2022-03-21 Impact factor: 4.200
Authors: Stephen J Keely; Andreacarola Urso; Alexandr V Ilyaskin; Christoph Korbmacher; Nigel W Bunnett; Daniel P Poole; Simona E Carbone Journal: Am J Physiol Gastrointest Liver Physiol Date: 2021-11-10 Impact factor: 4.052
Authors: Christoph Schramm; Heiner Wedemeyer; Andrew Mason; Gideon M Hirschfield; Cynthia Levy; Kris V Kowdley; Piotr Milkiewicz; Ewa Janczewska; Elena Sergeevna Malova; Johanne Sanni; Phillip Koo; Jin Chen; Subhajit Choudhury; Lloyd B Klickstein; Michael K Badman; David Jones Journal: JHEP Rep Date: 2022-07-21