Clinical, safety, and patient-reported outcomes associated with second-line and later therapies in primary biliary cholangitis: A systematic review
Marco Carbone, David Jones, Oyinkan Solanke, Rikke Brandt, Taryn Krause, Darren Asquith, Alex Pashley, Sonia Shaw, Emma Worthington, Jörn M. SchattenbergBackground:
Primary biliary cholangitis (PBC) is a rare, chronic, cholestatic disease that can result in cirrhosis, liver failure, and death. While biochemical markers such as alkaline phosphatase (ALP) and total bilirubin (TB) measure disease activity and progression, definitions of biochemical response vary. This systematic literature review (SLR) identified clinical studies for investigational and approved treatments in patients with PBC with inadequate response or intolerance to ursodeoxycholic acid requiring second-line (2L) or later (2L+) therapies.
Methods:
Electronic databases were searched on August 7, 2025 (MEDLINE; Embase) or September 30, 2025 (Cochrane Database of Systematic Reviews; CENTRAL), and conference proceedings (2021–2025), bibliographies, and ClinicalTrials.gov were searched on August 15, 2025, following a pre-specified protocol (PROSPERO ID: CRD42023382262). Interventional and observational studies in the 2L/2L+ setting were prioritized for inclusion, and randomized controlled trials for extraction.
Results:
A total of 149 publications on 44 unique studies were included. Phase III trials evaluated elafibranor, seladelpar, budenoside, bezafibrate, and obeticholic acid. Various composite biochemical response endpoints were reported across 34% of studies, most frequently the POISE criteria (18%). Biochemical markers were assessed frequently (ALP: 89%; TB: 71%); however, upper limits of normal and response thresholds varied substantially. Response rates in placebo-controlled trials favored active treatment, although placebo responses were highly variable. Non-invasive fibrosis measures were reported in 16% of studies and showed small short-term changes. Patient-reported outcomes assessed pruritus (52%) and fatigue (32%) using a variety of scales.
Conclusion:
The evidence base for 2L/2L+ PBC therapies is extensive but heterogeneous in study designs, patient populations, and treatment assessment scales and outcome definitions, limiting cross-trial comparisons. This SLR provides a robust foundation for contextualizing study outcomes within the broader landscape and supporting clinical decision-making.