1Medizinische Klinik und Poliklinik Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.
2Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3Hamburg Center of Translational Immunology, Hamburg, Germany.
4Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
5Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada.
6Toronto Centre for Liver Disease, Department of Medicine, University of Toronto, Toronto, ON, Canada.
7University of Miami, Schiff Center for Liver Diseases, Miami, FL, USA.
8Liver Institute Northwest, Washington State University, Seattle, WA, USA.
9Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.
10Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland.
11ID Clinic, Myslowice Poland.
12Department of Basic Medical Sciences, School of Health Sciences in Bytom, Medical University of Silesia, Bytom, Poland.
13Medical Company Hepatolog, LLC, Samara, Russia.
14Novartis Institutes for Biomedical Research, Basel, Switzerland.
15Sannity Consulting Ltd, Worthing, UK.
16Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
17Novartis Healthcare Pvt. Ltd., Hyderabad, India.
18Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
19The Newcastle Upon Tyne Hospitals, NHS Foundation Trust, Royal Victoria Infirmary, Newcastle, UK.
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 AUC0-8h and Cmaxbetween 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).