PMID- 36267872 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230308 IS - 2589-5559 (Electronic) IS - 2589-5559 (Linking) VI - 4 IP - 11 DP - 2022 Nov TI - Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis. PG - 100544 LID - 10.1016/j.jhepr.2022.100544 [doi] LID - 100544 AB - 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 mug) 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 gamma-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-mug tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-mug 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 mug doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-mug doses (p <0.001 at 60-, 90-, and 150-mug 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-mug 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). CI - (c) 2022 The Authors. FAU - Schramm, Christoph AU - Schramm C AD - Medizinische Klinik und Poliklinik Universitatsklinikum Hamburg Eppendorf, Hamburg, Germany. AD - Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Hamburg Center of Translational Immunology, Hamburg, Germany. FAU - Wedemeyer, Heiner AU - Wedemeyer H AD - Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany. FAU - Mason, Andrew AU - Mason A AD - Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada. FAU - Hirschfield, Gideon M AU - Hirschfield GM AD - Toronto Centre for Liver Disease, Department of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Levy, Cynthia AU - Levy C AD - University of Miami, Schiff Center for Liver Diseases, Miami, FL, USA. FAU - Kowdley, Kris V AU - Kowdley KV AD - Liver Institute Northwest, Washington State University, Seattle, WA, USA. FAU - Milkiewicz, Piotr AU - Milkiewicz P AD - Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland. AD - Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland. FAU - Janczewska, Ewa AU - Janczewska E AD - ID Clinic, Myslowice Poland. AD - Department of Basic Medical Sciences, School of Health Sciences in Bytom, Medical University of Silesia, Bytom, Poland. FAU - Malova, Elena Sergeevna AU - Malova ES AD - Medical Company Hepatolog, LLC, Samara, Russia. FAU - Sanni, Johanne AU - Sanni J AD - Novartis Institutes for Biomedical Research, Basel, Switzerland. AD - Sannity Consulting Ltd, Worthing, UK. FAU - Koo, Phillip AU - Koo P AD - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. FAU - Chen, Jin AU - Chen J AD - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. FAU - Choudhury, Subhajit AU - Choudhury S AD - Novartis Healthcare Pvt. Ltd., Hyderabad, India. FAU - Klickstein, Lloyd B AU - Klickstein LB AD - Novartis Institutes for Biomedical Research, Cambridge, MA, USA. FAU - Badman, Michael K AU - Badman MK AD - Novartis Institutes for Biomedical Research, Cambridge, MA, USA. FAU - Jones, David AU - Jones D AD - The Newcastle Upon Tyne Hospitals, NHS Foundation Trust, Royal Victoria Infirmary, Newcastle, UK. LA - eng SI - ClinicalTrials.gov/NCT02516605 GR - MR/L001489/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20220721 PL - Netherlands TA - JHEP Rep JT - JHEP reports : innovation in hepatology JID - 101761237 PMC - PMC9576902 OTO - NOTNLM OT - AE, adverse event OT - ALP, alkaline phosphatase OT - ALT, alanine aminotransferase OT - AUC, area under the concentration-time curve OT - C4, 7-alpha-hydroxy-4-cholesten-3-one OT - CL/F,ss, the apparent systemic clearance following oral administration at steady state OT - Cmax, maximum plasma concentration OT - FGF19, fibroblast growth factor 19 OT - FXR, farnesoid X receptor OT - Farnesoid X receptor OT - GGT, gamma-glutamyl transferase OT - HDL, high-density lipoprotein OT - LDL, low-density lipoprotein OT - NASH, non-alcoholic steatohepatitis OT - OCA, obeticholic acid OT - PBC, primary biliary cholangitis OT - PD, pharmacodynamic OT - PRO, patient-reported outcome OT - Primary biliary cholangitis OT - Proof of concept OT - Pruritus OT - QoL, quality of life OT - Racc, accumulation ratio OT - SAE, serious adverse event OT - Tmax, time to reach Cmax OT - Tropifexor OT - ULN, upper limit of normal OT - VAS, visual analogue scale OT - pBAD, primary bile acid diarrhoea OT - qd, once daily OT - gamma-Glutamyl transferase COIS- 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. EDAT- 2022/10/22 06:00 MHDA- 2022/10/22 06:01 PMCR- 2022/07/21 CRDT- 2022/10/21 03:02 PHST- 2022/07/05 00:00 [received] PHST- 2022/07/12 00:00 [accepted] PHST- 2022/10/21 03:02 [entrez] PHST- 2022/10/22 06:00 [pubmed] PHST- 2022/10/22 06:01 [medline] PHST- 2022/07/21 00:00 [pmc-release] AID - S2589-5559(22)00116-1 [pii] AID - 100544 [pii] AID - 10.1016/j.jhepr.2022.100544 [doi] PST - epublish SO - JHEP Rep. 2022 Jul 21;4(11):100544. doi: 10.1016/j.jhepr.2022.100544. eCollection 2022 Nov.