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GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

Lookup NU author(s): Dr Stuart Kendrick, Professor David Jones

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Abstract

© 2023 The Authors. Background & Aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0–10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. Results: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Conclusions: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. ClinicalTrials.gov ID: NCT02966834.

Publication metadata

Author(s): Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, Mayo MJ, Haque N, von Maltzahn R, Allinder M, Swift B, McLaughlin MM, Hirschfield GM

Publication type: Article

Publication status: Published

Journal: Clinical Gastroenterology and Hepatology

Year: 2023

Volume: 21

Issue: 7

Pages: 1902-1912.e13

Print publication date: 01/07/2023

Online publication date: 04/11/2022

Acceptance date: 02/04/2018

Date deposited: 18/09/2024

ISSN (print): 1542-3565

ISSN (electronic): 1542-7714

Publisher: W.B. Saunders

URL: https://doi.org/10.1016/j.cgh.2022.10.032

DOI: 10.1016/j.cgh.2022.10.032

PubMed id: 36343847

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