GLISTEN: Linerixibat Improves Biomarkers and Itch in Patients With PBC, With Andreas Kremer, MD, PhD, MHBA

Results from GLISTEN, the largest investigational study of pruritus in primary biliary cholangitis (PBC), highlight the effects of linerixibat on pharmacodynamic biomarkers of bile acid metabolism and mediators of cholestatic pruritus in this patient population.1

Andreas Kremer, MD, PhD, MHBA, the head of hepatology in the department of gastroenterology at the University Hospital Zurich, presented the data at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. The findings hold important implications for PBC management, showing increases in serum C4 and reductions in FGF-19, total serum bile acids (TSBA), autotaxin (ATX), and interleukin-31 (IL-31), validating the biologic mechanism of linerixibat and its impact on cholestatic pruritus in PBC.

“If you look carefully at the baseline characteristics, 50% of patients were on guideline-recommended therapy yet continued to experience mostly severe itch, clearly illustrating a significant unmet clinical need,” Kremer said in an interview with HCPLive. “Linerixibat, an ileal bile acid transport inhibitor, demonstrated significant improvement in itch over 24 weeks of therapy, as well as in sleep interference and other related parameters.”

Cholestatic pruritus refers to the bile flow impairment caused by PBC, which creates symptoms of itch, and has an 89% occurrence in the patient population. Linerixibat, an ileal bile acid transporter inhibitor, blocks bile acid reabsorption in the terminal ileum, targeting a root cause of cholestatic pruritus. Prior investigation of the novel therapy addressed an unmet need for symptom-specific therapy targeting pruritus.2,3

GLISTEN was a phase 3, randomized, double-blind, placebo-controlled study evaluating pruritus symptoms and pharmacodynamic biomarkers in 238 patients with PBC and moderate-to-severe pruritus. During the 24-week primary intervention period, patients received linerixibat 40 mg twice daily (n = 119) or placebo (n = 119). In the subsequent 8-week crossover period, patients either maintained or switched treatment. Biomarkers were assessed at baseline and every 4 weeks through week 32. A post hoc analysis evaluated correlations between changes from baseline in biomarker levels and weekly itch scores.

The phase 3 findings presented at AASLD aligned with the pharmacology of linerixibat, showing changes in key pharmacodynamic biomarkers reflecting bile acid synthesis and feedback regulation with significant increases in serum C4 (95% confidence interval [CI], 2.22-2.93; P <.001) and decreases in FGF-19 (95% CI, 0.51-0.65; P <.001) through week 24. Additionally, investigators noted significant reductions in pruritus mediators TSBA (95% CI, 0.66-0.85; P <.001), ATX (95% CI, 0.82-0.95; P <.001), and IL-31 (95% CI, 0.44-0.65; P <.001).

The crossover period demonstrated reduced C4 levels and increases in FGF-19, TSBA, ATX, and IL-31 in patients who switched from linerixibat to placebo.

In the post hoc analysis, investigators observed a weak correlation between reductions in TSBA (r = .20, P = .04) and IL-31 (r = .24, P = .05) with reductions in pruritus at week 4. Additionally, they noted a weak but statistically significant correlation between changes in C4 (r = -.289, P < .0001), FGF-19 (r = .205, P <.0001), and ATX (r = .093, P = .028) with reductions in pruritus over time.

Kremer and colleagues noted the recorded changes in biomarkers and itch scores from baseline were reversible upon linerixibat treatment discontinuation.

“We gained more insights into how [linerixibat] works and are very happy to see these developments," said Kremer. "Hopefully, in the near future, we will have an in-label drug to treat pruritus in PBC.”

Editor’s Note: Kremer reports relevant disclosures with Gilead, Intercept, Roche, AbbVie, and others.

References

1. Kremer A, Bowlus C, Lennie J, et al. Impact of linerixibat on pharmacodynamic biomarkers and mediators of cholestatic pruritus in primary biliary cholangitis (PBC) in the Phase 3 GLISTEN study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Hirschfield GM, Bowlus CL, Jones DEJ, et al. 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. Published online October 1, 2025. doi:https://doi.org/10.1016/s2468-1253(25)00192-x

3. GSK. Linerixibat shows positive Phase III results in cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC). Published 2024. Accessed November 12, 2025. https://www.gsk.com/en-gb/media/press-releases/linerixibat-shows-positive-phase-iii-results-in-cholestatic-pruritus/