An itch finally addressed: linerixibat and the promise of targeted antipruritic therapy in primary biliary cholangitis

Pruritus is among the most burdensome and undertreated symptoms in primary biliary cholangitis (PBC). The majority of patients with PBC endorse itch to some degree, with over a third meeting criteria for clinically significant itch associated with impaired sleep, mental health, and a diminished quality of life (1,2). Therefore, disease control and symptom-targeted therapy are complementary but distinct treatment goals. The pathophysiology of cholestatic pruritus is multimodal and incompletely understood, involving bile acid accumulation, endogenous opioid dysregulation, and lysophosphatidic acid signaling, among other mechanisms, making it inherently difficult to manage with a single therapeutic approach (3). Nevertheless, ileal bile acid transporter (IBAT) inhibitors have emerged as a promising mechanistic strategy, interrupting the enterohepatic circulation of bile acids and thereby reducing their systemic accumulation. While they have already demonstrated efficacy and earned regulatory approval for pruritus in Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), their role in PBC remains unestablished in large-scale trials (4-7). The study by Hirschfield et al., GLISTEN trial, now addresses this gap directly (8).

In this multicenter, randomized, double-blind, controlled trial, 238 patients with PBC and moderate-to-severe pruritus, defined as worst-itch numerical rating scale (WI-NRS) values ≥4, were enrolled (8). Linerixibat 40 mg twice daily was associated with an average reduction in WI-NRS by 2.86 points at 24 weeks, demonstrating a clinically significant improvement in itch with benefits occurring as early as two weeks (8). The GLISTEN trial met its primary endpoint with a statistically significant placebo-corrected change of –0.72 (95% confidence interval: –1.15 to –0.28) (8). While this difference might seem modest at first glance, it is important to recognize that this mean difference is at the study group level. At the individual patient level, the absolute treatment benefit (clinically meaningful ≥3-point reduction in WI-NRS) was 13 percentage points higher in those receiving linerixibat than in those receiving placebo (8). The high placebo response of 43% observed in this study is similar to other pruritus trials reported in the literature (7-10). Lastly, diarrhea occurred in 61% of patients and abdominal pain in 18%. These are expected side effects given the drug’s mechanism of action, as IBAT inhibition increases bile acid delivery to the colon. Importantly, diarrhea-related discontinuation happened in only 4% of patients treated with linerixibat (7). However, this trade-off between itch reduction and treatment-related symptoms, and the possibility that trial discontinuation rates may not be fully reflective of real-world tolerability. Overall, adverse events were frequent, and serious adverse events were numerically higher in the treatment arm.

These adverse effects may lead to real-world discontinuation, and the LLSAT extension study (https://clinicaltrials.gov/study/NCT04167358), an ongoing phase 3 study, is designed to assess the long-term tolerability and safety of linerixibat and better characterize discontinuation rates. The GLISTEN trial demonstrates efficacy but is limited by its pronounced placebo effect, subjective itch measures, and a modest average effect relative to placebo.

The recent approval of second-line agents such as seladelpar and elafibranor has marked a significant advance in PBC management, offering not only meaningful biochemical improvement but also associated reductions in pruritus severity (11,12). The management of pruritus in PBC is nonetheless complex, following a stepwise, algorithm-driven approach that integrates both biochemical response and itch severity to guide therapeutic decisions. All treatment-naïve patients are started on ursodeoxycholic acid as the mainstay of PBC therapy, with subsequent treatment adjustments based on whether an adequate biochemical response is achieved and if clinically significant pruritus persists. Figure 1 proposes a framework for the management of pruritus in PBC based on our expert opinion. Currently, linerixibat 40 mg taken orally twice daily is positioned as an additional treatment option that can be incorporated at various points in the algorithm, reflecting its potential as a targeted antipruritic agent regardless of the underlying biochemical response. At this time, there is no data evaluating the role of IBAT inhibitors in patients with persistent itch despite using second-line agents. Nevertheless, mechanistically, there does not appear to be any contraindication for concomitant use, as IBAT inhibitors are not absorbed.

Figure 1 Proposed algorithm for the potential use of linerixibat in patients with primary biliary cholangitis and moderate-to-severe pruritus after initiation of first-line therapy with ursodiol. Subsequent management may be individualized according to biochemical response and itch burden. Depending on the clinical scenario, treatment options may include second-line disease-modifying agents, such as elafibranor or seladelpar, established stepwise antipruritic pharmacotherapy, or linerixibat. Conventional stepwise therapies for cholestatic pruritus include cholestyramine, rifampicin, naltrexone, and sertraline, among others. PO BID, oral twice a day; UDCA, ursodeoxycholic acid.

While biochemical response remains the cornerstone of PBC management, it does not fully capture the day-to-day burden of disease, as pruritus can persist despite biochemical response, profoundly impairing quality of life. As such, the management of PBC should simultaneously but independently address biochemical remission and its associated symptoms. Linerixibat represents a welcome and targeted addition to the therapeutic armamentarium, offering clinicians a dedicated option to address this prominent yet historically undertreated symptom in patients with PBC.

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.

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0052/coif). R.V. reports consulting fee from GSK. The other author has no conflicts of interest to declare.

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