GLISTEN phase 3 trial: Linerixibat in cholestatic pruritus of primary biliary cholangitis

Cholestatic pruritus is a distressing and debilitating symptom which affects a substantial proportion of individuals living with primary biliary cholangitis (PBC). The GLISTEN phase 3 trial (NCT04950127) investigated linerixibat, a minimally absorbed ileal bile acid transporter (IBAT) inhibitor, for the treatment of moderate-to-severe cholestatic pruritus in adults with PBC.

In this interview, Dr Andreas Kremer (University Hospital Zurich, Zurich, Switzerland) discusses the clinical burden of cholestatic pruritus, the mechanism of action of linerixibat, and the design and key outcomes of the pivotal GLISTEN trial.

The abstract “LINERIXIBAT SIGNIFICANTLY IMPROVES CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS: RESULTS OF THE PIVOTAL PHASE 3 GLISTEN TRIAL” was presented at UEG Week, 4–7 October, Berlin, Germany.

touchIMMUNOLOGY coverage of UEG Week 2025:

I’m Andreas Kremer, a gastroenterologist and hepatologist by training, and I’m currently the Head of Hepatology at the University Hospital in Zurich with a long-lasting interest in immune-mediated and cholestatic liver diseases.

What impact does cholestatic pruritus have on the quality-of-life of patients living with PBC?

Pruritus is a common yet very burdensome symptom for patients with PBC and other cholestatic liver diseases, particularly when of moderate-to-severe intensity. Its impact extends far beyond the physical sensation of itching. Using the EQ-5D quality-of-life instrument, we have previously demonstrated that overall health-related quality of life (HRQoL) in PBC is relatively preserved; however, in those experiencing severe pruritus, HRQoL scores decline dramatically – even below those people living with chronic heart failure and to levels comparable to patients with severe Parkinson’s disease. Severe itch disrupts sleep, impairs daytime functioning and cognition, and contributes to fatigue, mood disorders, and even suicidal ideation, underscoring that cholestatic pruritus represents a systemic and multidimensional health burden.

What is the mechanism of action of linerixibat, and the rationale for investigating the therapy in this indication?

Linerixibat is a highly selective and minimally absorbed inhibitor of the ileal bile acid transporter (IBAT). By blocking the reuptake of bile acids in the terminal ileum, linerixibat interrupts the enterohepatic circulation of bile acids, thereby reducing systemic bile acid levels and potentially lowering pruritogenic mediators derived from this pool.

Similar pharmacological approaches have demonstrated efficacy in paediatric cholestatic disorders – notably maralixibat and odevixibat, which are approved for Alagille syndrome and progressive familial intrahepatic cholestasis, respectively. The GLISTEN trial represents the largest phase 3 investigation of an IBAT inhibitor in adults with PBC, aiming to translate this mechanism to an adult cholestatic population.

What were the aims, design and inclusion criteria of the phase 3 GLISTEN trial?

GLISTEN was a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and safety of linerixibat in adults with PBC-associated moderate-to-severe pruritus, defined as a worst itch numeric rating scale (WI-NRS) score ≥4 at screening. Participants were randomized to receive linerixibat 40mg twice daily or matching placebo for 24 weeks.

Concomitant antipruritic therapies such as bile acid sequestrants, rifampicin, naltrexone, or selective serotonin reuptake inhibitors were permitted if stable for at least 8 weeks before randomization and prohibited medication was obeticholic acid or other IBAT inhibitors. This design ensured evaluation of linerixibat’s effect under real-world therapeutic conditions while minimizing confounding by recent or unstable treatment changes.

What were the clinical endpoints of the study and how well were they met?

The primary endpoint was the change from baseline in mean monthly WI-NRS over 24 weeks. Linerixibat demonstrated a statistically significant improvement vs placebo. Importantly, symptom relief was evident as early as week 2, underscoring the rapid onset of action. Key secondary endpoints including changes in itch-related sleep interference and the proportion of participants achieving a ≥3-point WI-NRS reduction were also met. These findings confirm that linerixibat provides clinically meaningful and sustained improvement in pruritus and related quality-of-life measures.

What was the safety profile of linerixibat?

The safety profile of linerixibat was consistent with its mechanism of action. The most frequently reported treatment-emergent adverse event was diarrhoea, occurring in approximately 61% of participants receiving linerixibat versus 18% on placebo. In most cases, diarrhoea was mild, transient, and resolved with continued therapy or symptomatic management; only about 4% of participants discontinued treatment due to gastrointestinal adverse events. No new or unexpected safety signals were observed, and laboratory parameters remained stable, supporting a favourable overall benefit–risk profile.

What will be the impact of these findings for clinical practice?

If approved, linerixibat could become the first therapy specifically indicated for pruritus associated with PBC, addressing a long-standing unmet need in hepatology. Beyond providing an effective treatment option, these results emphasize the importance of actively screening for pruritus in patients with PBC, since it is often underrecognized yet profoundly affects well-being. The findings also extend the evidence base for IBAT inhibition as a therapeutic strategy across cholestatic liver diseases, demonstrating its relevance not only in paediatric but also in adult populations.