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

BACKGROUND & AIMS: Transforming growth factor-β signaling activated by αβ and αβ 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 αβ and αβ 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 observed with bexotegrast in ELF score, PRO-C3, and MRI assessments at Week 12 compared with placebo. Pharmacodynamic results at Week 24 showed limited change from Week 12 except in MRI parameters which continued to improve. CONCLUSIONS: Bexotegrast was well tolerated for up to 40 weeks in participants with PSC and liver fibrosis and was associated with numerically less progression in exploratory pharmacodynamic markers. IMPACT AND IMPLICATIONS: Primary sclerosing cholangitis (PSC) is a rare cholestatic disease of unknown etiology. Currently, there is an unmet medical need for safe and effective therapies capable of halting or reversing progression of PSC. In this phase II study in participants with PSC and suspected liver fibrosis, bexotegrast, an oral, once-daily, dual selective inhibitor of αβ and αβ integrins, had a favorable safety and tolerability profile. This study supports targeting integrin-mediated transforming growth factor-β activation as a potential therapeutic approach for PSC. TRIAL REGISTRATION NUMBER: NCT04480840.

Citation

Hirschfield GM, Kowdley KV, Trivedi PJ, Eksteen B, Hameed B, Vincent C, Chen T, Goel A, Reddy KG, Orman E, Joshi D, Lefebvre ÉA, Schaub JR, An MC, Clark A, Barnes CN, Pencek R, Thorburn D, Montano-Loza AJ, Schramm C, Bowlus CL, Trauner M, Levy C. Phase II INTEGRIS-PSC trial of bexotegrast, an αvβ6/αvβ1 integrin inhibitor, in primary sclerosing cholangitis. J Hepatol. 2025 Sep 26:S0168-8278(25)02498-5. doi: 10.1016/j.jhep.2025.09.016. Epub ahead of print.

Type

Article