O8 Linerixibat significantly improves cholestatic pruritus in primary biliary cholangitis (PBC): results of the pivotal phase 3 GLISTEN trial

Introduction Cholestatic pruritus is common, debilitating and undertreated in patients with PBC. Here, we describe the results of GLISTEN (NCT04950127), a Phase 3 study investigating efficacy and safety of linerixibat (ileal bile acid transporter inhibitor) for pruritus in PBC. 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. 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; change). Safety endpoints included adverse event (AE) reporting. Results 238 patients were randomised (95% female); itch severity was mean (standard deviation [SD]) 7.34 (1.54), 52% had alkaline phosphatase <1.67 times upper limit of normal; 47% were receiving stable pruritus therapy. 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, observed mean (SD) difference from baseline in pruritus was -3.66 (2.50) with linerixibat and -2.82 (2.32) with placebo. Linerixibat effect was superior to placebo at Week 2: LS mean change -1.78 versus -1.07, adjusted mean difference -0.71; p<0.001. Linerixibat 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; 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%) and abdominal pain (18% vs 3%); 4% of patients in the linerixibat group discontinued treatment due to diarrhoea. Summary/Conclusion In patients with PBC and moderate-to-severe pruritus, linerixibat 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. Funding GSK [212620/NCT04950127]. Previously presented at EASL 2025 (presentation GS-011) [on behalf of the GLISTEN study group]

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