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

Gideon M Hirschfield; Kris V Kowdley; Palak J Trivedi; Bertus Eksteen; Bilal Hameed; Catherine Vincent; Tianyan Chen; Aparna Goel; K Gautham Reddy; Eric Orman; Deepak Joshi; Éric A Lefebvre; Johanna R Schaub; Mahru C An; Annie Clark; Chris N Barnes; Richard Pencek; Douglas Thorburn; Aldo J Montano-Loza; Christoph Schramm; Christopher L Bowlus; Michael Trauner; Cynthia Levy

doi:10.1016/j.jhep.2025.09.016

Phase II INTEGRIS-PSC trial of bexotegrast, an α_vβ₆/α_vβ₁ integrin inhibitor, in primary sclerosing cholangitis

J Hepatol. 2026 Jan;84(1):86-98. doi: 10.1016/j.jhep.2025.09.016. Epub 2025 Sep 26.

Authors

Gideon M Hirschfield¹, Kris V Kowdley², Palak J Trivedi³, Bertus Eksteen⁴, Bilal Hameed⁵, Catherine Vincent⁶, Tianyan Chen⁷, Aparna Goel⁸, K Gautham Reddy⁹, Eric Orman¹⁰, Deepak Joshi¹¹, Éric A Lefebvre¹², Johanna R Schaub¹², Mahru C An¹³, Annie Clark¹³, Chris N Barnes¹², Richard Pencek¹³, Douglas Thorburn¹⁴, Aldo J Montano-Loza¹⁵, Christoph Schramm¹⁶, Christopher L Bowlus¹⁷, Michael Trauner¹⁸, Cynthia Levy¹⁹

Affiliations

¹ The Autoimmune and Rare Liver Disease Programme, Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada. Electronic address: Gideon.Hirschfield@uhn.ca.
² Liver Institute Northwest, Seattle, WA, USA; Elson S. Floyd College of Medicine, Washington State University, Seattle, WA, USA.
³ NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK.
⁴ Aspen Woods Clinic, Calgary, AB, Canada.
⁵ University of California San Francisco School of Medicine, San Francisco, CA, USA.
⁶ Liver Unit, Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
⁷ Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
⁸ Stanford University, Palo Alto, CA, USA.
⁹ Department of Medicine, University of Chicago, Chicago, IL, USA.
¹⁰ Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
¹² Pliant Therapeutics, Inc, South San Francisco, CA, USA.
¹³ Former employees of Pliant Therapeutics, Inc, South San Francisco, CA, USA.
¹⁴ Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, London, UK.
¹⁵ Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
¹⁶ University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ University of California, Davis, Sacramento, CA, USA.
¹⁸ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
¹⁹ Schiff Center for Liver Diseases, University of Miami, Miami, FL, USA.

PMID: 41016442
DOI: 10.1016/j.jhep.2025.09.016

Abstract

Background & aims: Transforming growth factor-β signaling activated by α_vβ₆ and α_vβ₁ 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_vβ₆ and α_vβ₁ 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 α_vβ₆ and α_vβ₁ 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.

Keywords: PSC; bexotegrast; integrin; liver fibrosis; safety.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial
Multicenter Study

MeSH terms

Adult
Antigens, Neoplasm*
Cholangitis, Sclerosing* / complications
Cholangitis, Sclerosing* / drug therapy
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Integrins* / antagonists & inhibitors
Liver Cirrhosis* / drug therapy
Liver Cirrhosis* / etiology
Male
Middle Aged
Receptors, Vitronectin
Treatment Outcome

Substances

integrin alphavbeta6
Integrins
integrin alphavbeta1
Antigens, Neoplasm
Receptors, Vitronectin

Associated data

ClinicalTrials.gov/NCT04480840