Cholestatic pruritus represents one of the most debilitating symptoms of PBC and is often progressive, sleep-disturbing, and psychologically burdensome. Since nonspecific therapies currently provide only unsatisfactory relief, the researchers tested whether pharmacologic inhibition of bile acid reabsorption would improve itch intensity directly. This global trial is the most comprehensive evidence to date for the clinical efficacy and safety profile of linerixibat.
This phase 3 trial was a multicenter, randomized, double-blind, placebo-controlled study of adults with PBC and moderate-to-severe pruritus (defined as a WI-NRS score ≥4). Patients were drawn from 115 centers across 19 countries, thus reflecting a broad geographic and clinical representation. A total of 238 patients were randomly assigned to either oral linerixibat 40 mg twice daily (n = 119) or a matched placebo (n = 119) using an interactive online system. Randomization was stratified by baseline pruritus severity (moderate or severe) and the use of concomitant treatments for pruritus (bile acid binding resins, other treatments, or none).
The primary endpoint was the change in WI-NRS score from baseline to 24 weeks. The efficacy analysis included all randomly assigned patients, whereas the safety analysis included all those who had received at least one dose of study medication. The trial was registered as NCT04950127.
Results
Least-squares mean reduction in WI-NRS:
Linerixibat: −2.86 (95% CI −3.23 to −2.50)
Placebo: −2.15 (95% CI −2.51 to −1.78)
Adjusted mean difference: −0.72 (95% CI −1.15 to −0.28), p = 0.0013
Adverse events related to the gastrointestinal system were more common with linerixibat, consistent with its mechanism of increasing bile acids in the colon.
Diarrhoea: 72/119 (61%) with linerixibat vs 21/118 (18%) with placebo
Abdominal pain: 22/119 (18%) vs 4/118 (3%)
Treatment discontinuations because of gastrointestinal events occurred in 8 patients (7%) receiving linerixibat (5) due to diarrhoea compared with (1) (<1%) on placebo.
Serious adverse events occurred in 14/119 (12%) linerixibat patients and 4/118 (3%) placebo patients. No deaths occurred during the 24-week trial.
This is a phase 3 trial that indicates linerixibat significantly improves pruritus in patients with PBC, thus confirming its potential as an effective targeted therapy. The gastrointestinal adverse events, especially diarrhoea, were more frequent, but most of them were manageable, and there were no deaths.
Reference:
Hirschfield, G. M., Bowlus, C. L., Jones, D. E. J., Kremer, A. E., Mayo, M. J., Tanaka, A., Andreone, P., Jia, J., Jin, Q., Macías-Rodríguez, R. U., Cobitz, A. R., Currie, B. M., Gorey, C., Lazic, I., Podmore, D., Ribeiro, A., Shannon, J. B., Swift, B., McLaughlin, M. M., … GLISTEN Study Group. (2025). Linerixibat in patients with primary biliary cholangitis and cholestatic pruritus (GLISTEN): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. The Lancet. Gastroenterology & Hepatology.
https://doi.org/10.1016/S2468-1253(25)00192-X
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