Linerixibat reduces cholestatic pruritus in patients with primary biliary cholangitis

Primary biliary cholangitis (PBC) is one of the chronic cholestatic liver diseases, and patients with PBC exhibit pruritus and/or fatigue (1). In addition, an association exists between pruritus severity and sleep disturbance (1). Patients with PBC frequently report sleep disturbances, which contribute to their symptoms, including fatigue (2). Therefore, patients with PBC should receive treatment for their pruritus to improve their quality of life (3).

Pruritus is sensitized by the peripheral or the central nervous system (3). In patients with cholestatic liver disease, such as PBC and primary sclerosing cholangitis (PSC), multiple factors, including high serum/plasma concentrations of bile salts, bilirubin, endogenous opioids, etc., affect mediators of pruritus in the skin and sensory nerves as well as those in the spinal cord (3). Therefore, both peripheral and/or central nervous systems are also involved in the pruritus of patients with PBC.

Ileal bile acid transporter (IBAT) is overexpressed in the terminal ileum, which is the primary site of bile acid reabsorption (3). IBAT is a bile sodium symporter protein and cotransports actively conjugated bile acids into the cytosol by using the natural osmotic sodium gradient. As IBAT inhibitors have been approved for use to improve pruritus in patients with pediatric cholestatic diseases, such as Alagille syndrome and progressive familial intrahepatic cholestasis, IBAT inhibition appears to be a useful treatment for chronic intractable pruritus in patients with PBC or PSC (Table 1) (3).

We would like to congratulate Hirschfield et al. for their recent publication in Lancet Gastroenterol Hepatol; this study provides important findings, which demonstrate that linerixibat, an IBAT inhibitor, significantly improved cholestatic pruritus in patients with PBC in a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial (GLISTEN) (4).

From December 1, 2021 to May 13, 2024, a total of 238 patients with PBC and moderate to severe pruritus [Worst Itch Numerical Rating Scale (WI-NRS) ≥4] were included at 115 centers in 19 countries (4). The WI-NRS ranged from 0 (no itching) to 10 (worst imaginable itching). They were randomly assigned to receive either linerixibat (40 mg twice a day) (n=119) or a matching placebo (n=119).

GLISTEN consists of two parts: Parts A and B. In Part A, patients received oral linerixibat (40 mg twice a day) or a matching placebo for 24 weeks. In Part B, patients either received the same treatment or crossed over to the other treatment group (time was blinded to each patient) for an additional 8 weeks (4). Of the 119 patients in the placebo group, one patient (<1%) withdrew before the treatment. Of the 238 patients, 211 (89%) completed Part A; of these 211 patients, 206 (98%) completed Part B. Concomitant pruritus treatment and fibrate use were slightly more common in the placebo group than in the linerixibat group (4). Bezafibrate was the most commonly used concomitant fibrate (5).

In Part A, the linerixibat group experienced significant improvement in pruritus (WI-NRS) over 24 weeks [least-square (LS) mean −2.86; 95% confidence interval (CI), −3.23 to −2.50] compared with the placebo group (LS mean -2.15; 95% CI, −2.51 to −1.78); the adjusted mean difference was −0.72 (95% CI, −1.15 to −0.28; P=0.0013) (4). At week 2, improvement in pruritus (WI-NRS) was significantly greater in the linerixibat group (LS mean −1.78; 95% CI, −2.08 to −1.48) than in the placebo group (LS mean −1.07; 95% CI, −1.37 to −0.77); the adjusted mean difference was −0.71 (95% CI, −1.07 to −0.34; P=0.0002) (4). When the effect of linerixibat on sleep interference was examined, the linerixibat group reported significantly reduced sleep interference over 24 weeks (LS mean −2.77; 95% CI, −3.15 to −2.38) compared with the placebo group (LS mean −2.44; 95% CI, −2.62 to −1.86); the adjusted mean difference was −0.53 (95% CI, −0.98 to −0.07; P=0.024) (4).

In Part B, pruritus improved in patients who switched to linerixibat but pruritus worsened in patients who switched to placebo; patients who remained on their Part A assigned treatments experienced no marked change (4). These results indicated that linerixibat is effective in treating chronic pruritus in patients with PBC.

No deaths were observed during this study (4). In the linerixibat group, treatment discontinuation due to adverse events was due mainly to gastrointestinal adverse events: diarrhea, 8 (7%) of 119; abdominal pain, 5 (4%); and both, 2 (2%). Increased alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) levels were more commonly reported in the linerixibat group than in the placebo group (4). Elobixibat, a minimally absorbed IBAT inhibitor, is safely used in Japan as a laxative for the treatment of chronic constipation (6), although diarrhea and abdominal pain were observed as adverse events similar to those associated with linerixibat in the present study. Interruption of the enterohepatic circulation of essential fat-soluble molecules and/or bile acids may lead to alterations in membrane integrity and/or compensatory increases in bile acid synthesis (7). Several animal models and in vitro studies have shown that the extent of hepatic ALT release correlates with the movement of hepatic cholesterol into the blood (8). It has been proposed that increases in ALT/AST levels are transient and might result from hepatic cholesterol depletion affecting membrane integrity or initial compensatory increases in bile acid synthesis (7,8).

Janus kinase (JAK) inhibition, which is a broader immunemodulator, may be effective for chronic pruritus with PBC (9). PBC patient was treated with upadacitinib, a JAK1 inhibitor, resulting in the improvement of her pruritus (10). Dupilumab, an anti-interleukin (IL)-4/IL-13 receptor humanized monoclonal antibody, and nemolizumab, an anti-IL-31 receptor A humanized monoclonal antibody, were also effective for the refractory pruritic in chronic cholestasis (11,12). Further studies are needed for the mechanism of chronic pruritus in patients with PBC.

In conclusion, linerixibat reduced pruritus as well as sleep disturbance in patients with PBC and moderate to severe pruritus. Although diarrhea and abdominal pain were observed in the linerixibat treatment group, the long-term safety and tolerability of linerixibat for patients with PBC are currently being investigated in clinical trials.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0020/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0020/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. von Maltzahn R, Mayo MJ, Smith HT, et al. Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial. J Patient Rep Outcomes 2024;8:60. [Crossref] [PubMed]
2. Newton JL, Gibson GJ, Tomlinson M, et al. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 2006;44:91-8. [Crossref] [PubMed]
3. Kanda T, Sasaki-Tanaka R, Kimura N, et al. Pruritus in Chronic Cholestatic Liver Diseases, Especially in Primary Biliary Cholangitis: A Narrative Review. Int J Mol Sci 2025;26:1883. [Crossref] [PubMed]
4. 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. Lancet Gastroenterol Hepatol 2026;11:22-33. [Crossref] [PubMed]
5. Kanda T, Yokosuka O, Imazeki F, et al. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol 2003;38:573-8. [Crossref] [PubMed]
6. Nakajima A, Seki M, Taniguchi S, et al. Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:537-47. [Crossref] [PubMed]
7. Singhal R, Harrill AH, Menguy-Vacheron F, et al. Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine. BMC Pharmacol Toxicol 2014;15:42. [Crossref] [PubMed]
8. Herzog E, Pragst I, Waelchli M, et al. Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component. J Appl Toxicol 2016;36:1038-47. [Crossref] [PubMed]
9. Kolev M, Möller B, Berzigotti A, et al. Upadacitinib for refractory primary biliary cholangitis. J Hepatol 2025;83:e16-8. [Crossref] [PubMed]
10. Zhou AE, Ravi S, Murphy M, et al. Treatment of Refractory Pruritic Dermatitis in the Setting of Primary Biliary Cholangitis and CREST Syndrome With Upadacitinib. J Drugs Dermatol 2025;24:1138-40. [Crossref] [PubMed]
11. Chovatiya R, Brieva J, Hung A. Dupilumab treatment for cholestatic pruritus. Dermatol Ther 2022;35:e15296. [Crossref] [PubMed]
12. Masukane S, Taketani T. Effectiveness of Nemolizumab for Refractory Pruritus in a Pediatric Patient With Atopic Dermatitis After Biliary Atresia Surgery. Cureus 2025;17:e83810. [Crossref] [PubMed]