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.