Linerixibat in patients with primary biliary cholangitis and cholestatic pruritus (GLISTEN): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

backgroundCholestatic pruritus is common and undertreated in primary biliary cholangitis (PBC) and negatively affects patients' lives. We aimed to evaluate the safety and efficacy of linerixibat, an ileal bile acid transporter inhibitor, as a specific antipruritic therapy in patients with PBC.

methodsWe conducted a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Patients with PBC and moderate-to-severe pruritus (Worst Itch Numerical Rating Scale [WI-NRS] ≥4) were recruited at 115 centres in 19 countries. Patients were randomly assigned to receive either oral linerixibat 40 mg twice a day or a matching placebo through an interactive online response system, with pruritus severity (moderate or severe) and concomitant pruritus treatment (bile acid binding resins, other treatments, or none) as stratification factors. The primary endpoint was change in pruritus over 24 weeks assessed using the WI-NRS, ranging from 0 (no itching) to 10 (worst imaginable itching). Efficacy analyses included all randomly allocated patients; safety analyses included all randomly allocated patients who received one dose of study treatment or more. This study is registered with ClinicalTrials.gov, number NCT04950127.

findingsFrom Dec 1, 2021, to May 13, 2024, a total of 238 patients were randomly assigned to receive either linerixibat (n=119) or placebo (n=119). One (<1%) of 119 patients randomly allocated to receive placebo withdrew before receiving treatment. Patients receiving linerixibat experienced significant improvement in pruritus over 24 weeks compared with placebo (least-squares mean change from baseline -2·86 [95% CI -3·23 to -2·50] for linerixibat vs -2·15 [-2·51 to -1·78] for placebo; adjusted mean difference -0·72 [95% CI -1·15 to -0·28]; p=0·0013). Gastrointestinal adverse events were more frequent in patients treated with linerixibat than with placebo (72 [61%] of 119 vs 21 [18%] of 118 had diarrhoea; 22 [18%] vs four [3%] had abdominal pain). Treatment discontinuations due to gastrointestinal adverse events occurred in eight (7%) of 119 patients in the linerixibat group (of which five were due to diarrhoea) and one (<1%) of 118 in the placebo group. Serious adverse events were reported in 14 (12%) of 119 patients receiving linerixibat and four (3%) of 118 receiving placebo. No deaths were reported during the study.

interpretationLinerixibat significantly improved pruritus versus placebo, supporting its potential to address a major symptom of PBC. An expected increase in diarrhoea in linerixibat-treated patients was observed.

fundingGSK.