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LINERIXIBAT SIGNIFICANTLY IMPROVES CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS: RESULTS OF THE PIVOTAL PHASE 3 GLISTEN TRIAL

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LINERIXIBAT SIGNIFICANTLY IMPROVES CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS: RESULTS OF THE PIVOTAL PHASE 3 GLISTEN TRIAL

Gideon M. Hirschfield 1, Christopher L. Bowlus 2, David Jones 3, Andreas E. Kremer 4, Marlyn J. Mayo 5, Atsushi Tanaka 6, Pietro Andreone 7, Jidong Jia 8, Qinglong Jin 9, Ricardo Macias-Rodriguez 10, Alexander R. Cobitz 11, Brooke M. Currie 11, Ciara Gorey 12, Ivana Lazic 12, Danielle J. Podmore 12, Andrea Ribiero 13, Jennifer B. Shannon 14, Brandon Swift 14, Megan M. McLaughlin 11, Cynthia Levy 15

Affiliations

1 Toronto General Hospital, Toronto, Canada

2 University of California Davis School of Medicine, Sacramento, United States

3 Newcastle University, Newcastle Upon Tyne, United Kingdom

4 University Hospital Zurich, Zurich, Switzerland

5 University of Texas Southwestern Medical School, Dallas, United States

6 Teikyo University School of Medicine, Tokyo, Japan

7 Azienda Ospedaliero-Universitaria di Modena and Università di Modena e Reggio Emilia, Modena, Italy

8 Capital Medical University, Beijing, China

9 The First Hospital of Jilin University, Changchun, China

10 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

11 GSK, Collegeville, United States

12 GSK, London, United Kingdom

13 GSK, Madrid, Spain

14 GSK, Durham, United States

15 University of Miami, Miami, United States

Summary

AI Generated

GLISTEN, a Phase 3 trial in 238 PBC patients with moderate-to-severe pruritus, showed that linerixibat 40 mg twice daily significantly improved worst itch over 24 weeks compared to placebo (LS mean change -2.86 vs -2.15, adjusted difference -0.72, p=0.001).

Linerixibat produced rapid pruritus improvement, demonstrating superiority over placebo as early as Week 2 (LS mean change -1.78 vs -1.07, adjusted difference -0.71, p<0.001).
At Week 24, 56% of linerixibat-treated patients achieved a ≥3-point reduction in pruritus versus 43% on placebo, and 21% reported absent pruritus versus 9% on placebo.
Linerixibat significantly improved pruritus-related sleep interference over 24 weeks versus placebo (LS mean change -2.77 vs -2.24, adjusted difference -0.53, p=0.024).
Diarrhoea was the most common adverse event, occurring in 61% of linerixibat-treated patients versus 18% on placebo, but only 4% discontinued treatment due to diarrhoea.
The study enrolled 238 patients, 95% female, with baseline mean itch severity 7.34, of whom 47% were receiving stable antipruritic therapy and 52% had alkaline phosphatase <1.67 times upper limit of normal.

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Abstract

Introduction

Cholestatic pruritus is common, debilitating and undertreated in patients with primary biliary cholangitis (PBC). Here, we describe the results of GLISTEN (NCT04950127), a Phase 3 study investigating the efficacy and safety of the ileal bile acid transporter inhibitor linerixibat for pruritus in PBC.

Aims & Methods

In this double-blind, randomised, placebo-controlled study, patients with PBC and moderate-to-severe pruritus received oral linerixibat 40 mg or placebo twice daily. Pruritus severity and pruritus-related sleep interference were assessed using a 0–10 numerical rating scale. The primary endpoint was change from baseline in worst itch over 24 weeks. Secondary endpoints included: at Week 2, change in worst itch; over 24 weeks, change in sleep interference; at Week 24, proportion of responders (≥ 2-, ≥ 3-, ≥ 4-point reduction in worst itch) and analysis of responses to 2 patient global impression items (itch severity and change). Safety endpoints included adverse event (AE) reporting.

Results

238 patients were randomised; 95% were female, itch severity was mean (standard deviation [SD]) 7.34 (1.54), 52% had alkaline phosphatase < 1.67 times upper limit of normal, and 47% were receiving stable therapy for pruritus. Pruritus improvement over 24 weeks was significantly greater with linerixibat than placebo: least-squares (LS) mean change -2.86 versus -2.15, adjusted mean difference -0.72; p = 0.001. At Week 24, the observed mean (SD) difference from baseline in pruritus was -3.66 (2.50) with linerixibat and -2.82 (2.32) with placebo. The effect of linerixibat was rapid and superior to placebo at Week 2: LS mean change -1.78 versus -1.07, adjusted mean difference -0.71; p < 0.001. Linerixibat also significantly improved pruritus-related sleep interference over 24 weeks versus placebo: LS mean change ‑2.77 versus -2.24, adjusted mean difference -0.53; p = 0.024. At Week 24, more patients on linerixibat than placebo achieved a ≥ 2-point (68% vs 64%), ≥ 3-point (56% vs 43%) or ≥ 4-point (41% vs 29%) reduction in pruritus and a higher proportion of linerixibat than placebo-treated patients reported their pruritus was very much improved (55% vs 37%) or absent (21% vs 9%). AEs reported more frequently with linerixibat than placebo were predominantly gastrointestinal (GI), including diarrhoea (61% vs 18% of patients) and abdominal pain (18% vs 3% of patients); 4% of patients in the linerixibat group discontinued treatment due to diarrhoea.

Conclusion

In patients with PBC and moderate-to-severe pruritus, linerixibat rapidly and significantly improved pruritus and pruritus-related sleep interference versus placebo. While GI AEs were more common with linerixibat than placebo, they rarely led to treatment discontinuation.

Disclosure

Funded by GSK. Various authors declare conflicts of interest as consultants, employee, recipients of grants and stockholders. These will be reported in full during the presentation.

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Advances in management of immune-mediated biliary disease

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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