Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis.

Background & Aims: The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response.
Methods: Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 μg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics.
Results: Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-μg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-μg tropifexor group. Pruritus was the most frequent AE in the study (52.5% [tropifexor] vs . 28.6% [placebo]), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 μg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-μg doses ( p <0.001 at 60-, 90-, and 150-μg tropifexor vs . placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC _0-8h and C _max between 30- and 150-μg doses.
Conclusions: Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety-tolerability profile, thereby supporting its potential further clinical development for PBC.
Lay Summary: The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose.
Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02516605).
Competing Interests: CS is a consultant for Novartis and BiomX and has received honoraria from Falk Pharma and research funding from Galapagos and BiomX. HW is a consultant for or has received speaker fees from Falk Foundation, BMS, AbbVie, Norgine, Merz, Mallinckrodt, MYR GmbH, Gilead, MSD, and Intercept. AM has research grants from Merck and Intercept and has received speaker’s and teaching honoraria from Intercept. GMH has consulted for Intercept, Genfit, Cymabay, GSK, Novartis, Pliant, Falk Pharma. CL has research grants from Novartis, Gilead, Intercept, Enanta, NGM, Genfit, Cara Therapeutics, CymaBay, Target PharmaSolutions, Genkyotex, GSK, Durect, Pliant, High Tide and Zydus, and is a consultant for Genfit, GSK, CymaBay, Mirum, Cara therapeutics, Pliant, Shire, Target PharmaSolutions, Calliditas, and Escient. KVK is on the Advisory Committee or Review Panel of 89Bio, Gilead, CymaBay, Intercept, Genfit, and Madrigal; is a consultant for Calliditas, Intercept, HighTide, Mirum, and Novo Nordisk; has received grant/research support from Allergan, Gilead, Intercept, Genfit, Novartis, Enanta, HighTide, CymaBay, GSK, Pfizer, Madrigal, Viking, Metacrine, Pliant, and Hanmi; has received speaker’s and teaching honoraria from AbbVie, Gilead, and Intercept; and is a stock shareholder of Inipharm. PM has received speaker’s honoraria from Alfa Wasserman and Chiesi. EJ is an investigator in clinical trials sponsored by Allergan, BMS, Celgene, CymaBay, Dr Falk, Gilead, GSK, Janssen, Pfizer, MSD, Novartis, and Roche; has received speaker’s honoraria from AbbVie, BMS, Gilead, Janssen, MSD, and Roche. ESM has no conflicts of interest to disclose. LBK was an employee of Novartis until study completion and is a stockholder of Novartis. DJ has received grant funding from Intercept and Pfizer; is a consultant for Abbott, Genkyotex, GSK and Intercept; and has received speaker fees from Falk, Abbott, and Intercept. JS is a contractor with Novartis. PK, SC, and JC were employees of Novartis until manuscript finalisation. MKB is an employee and stockholder of Novartis. Please refer to the accompanying ICMJE disclosure forms for further details.
(© 2022 The Authors.)