Phase II INTEGRIS-PSC trial of bexotegrast, an αvβ6/αvβ1 integrin inhibitor, in primary sclerosing cholangitis

作者：Gideon M. Hirschfield, Kris V. Kowdley, Palak Trivedi, Bertus Eksteen, Bilal Hameed, Catherine Vincent, Tianyan Chen, Aparna Goel, K. Gautham Reddy, Eric S. Orman, Deepak Joshi, Éric Lefebvre, Johanna Schaub, Mahru C. An, Annie Clark, Chris N. Barnes, Richard Pencek, Douglas Thorburn, Aldo J. Montaño‐Loza, Christoph Schramm, Christopher L. Bowlus, Michael Trauner, Cynthia Levy · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.09.016 · 被引用次数：9 · 研究领域：Liver Diseases and Immunity、Inflammatory Bowel Disease、Rheumatoid Arthritis Research and Therapies

Background & Aims Transforming growth factor-β signaling activated by α v β 6 and α v β 1 integrins drives liver fibrosis in primary sclerosing cholangitis (PSC). The aim of this study was to investigate the safety and exploratory pharmacodynamics of bexotegrast (PLN-74809), an oral, once-daily inhibitor of α v β 6 and α v β 1 integrins, in participants with PSC and liver fibrosis. Methods In this phase II, double-blind, dose-ranging study, 117 participants with PSC were randomized 3:1 to receive once-daily oral bexotegrast or placebo in three cohorts: 40 mg or placebo for 12 weeks (part 1); 80 mg, 160 mg, or placebo for 12 weeks (part 2); and 320 mg or placebo for up to 40 weeks (part 3). The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Exploratory pharmacodynamic endpoints included changes in alkaline phosphatase values, enhanced liver fibrosis (ELF) scores, neoepitope-specific N-terminal pro-peptide of type III collagen (PRO-C3) levels, liver stiffness measurements, gadoxetate-enhanced MRI measures, and the Itch Numeric Rating Scale. Results A total of 117 participants received bexotegrast (40 mg [n = 22], 80 mg [n = 21], 160 mg [n = 21], 320 mg [n = 27]) or placebo (n = 30). Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (72.7% and 70.0%). TEAEs were mild to moderate, and no serious TEAEs related to study drug were observed. Numerically less pharmacodynamic progression was observ...