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

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

Free article

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

Gideon M Hirschfield et al. J Hepatol. 2025.

Free article

. 2025 Sep 26:S0168-8278(25)02498-5.

doi: 10.1016/j.jhep.2025.09.016. Online ahead of print.

Authors

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.

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Conflict of interest statement

Conflict of interest GM Hirschfield was a consultant for Advanz, CymaBay, Ipsen, Gilead, Intercept, Mirum, Kowa, GSK, Pliant Therapeutics, and Escient. KV Kowdley received grants from Boston Scientific, Corcept, CymaBay, Genfit, Gilead, GSK, Hanmi, Intercept, Ipsen, Janssen, Madrigal, Mirum, Novo Nordisk, NGM, Pfizer, Pliant Therapeutics, Terns, Viking, Zydus, and 89bio Inc.; received royalties or licenses from UpToDate; received consulting fees from CymaBay, Enanta, Genfit, Gilead, HighTide, Inipharm, Intercept, Ipsen, Madrigal, Mirum, NGM, Pliant Therapeutics, Pfizer, Protagonist, Zydus, and 89bio Inc.; received payment or honoraria from AbbVie, Gilead, and Intercept; received payment for expert testimony from the US Department of Justice; participated on a data safety monitoring board or advisory board for CTI, Medpace, Labcorp, and Worldwide Clinical Trials; holds stock in Inipharm; and received equipment, materials, drugs, medical writing, gifts, or other services from Velacur. PJ Trivedi received institutional salary support from the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC); received grant support from the Wellcome Trust, the Medical Research Foundation, the NIHR, LifeArc, Regeneron, Albireo/Ipsen, Mirum, GSK, Guts UK, PSC Support, Intercept, Dr Falk Pharma, Gilead Sciences, and BMS; received speaker fees from Advanz/Intercept, Albireo/Ipsen, and Dr Falk Pharma; and received advisory board/consultancy fees from Advanz/Intercept, GSK, CymaBay, Pliant Therapeutics, and Dr Falk Pharma. B Eksteen has served on a scientific board for Pliant Therapeutics and has consulted for Jansen, Pfizer, and AbbVie. B Hameed has received grant support from Gilead, Intercept, Pliant Therapeutics, Novo Nordisk, Madrigal, and Salix; has served on an advisory board for Mallinckrodt, Pleiogenix, CLDF, and Madrigal; has served as a consultant for Gilead, Pioneering Medicine VII, Inc., and Surrozen; holds stock options in Pleiogenix; and has served as a speaker for Scholars in Medicine. C Vincent has nothing to disclose. T Chen received advisory board/consultancy fees from Advanz/Intercept and Pliant Therapeutics. A Goel has nothing to disclose. KG Reddy has received grant support from Pliant Therapeutics, COUR, Gilead, and CymaBay; has served as a consultant for CymaBay; and has served in a speaking/teaching role for Mallinckrodt and Gilead. E Orman received consulting fees from BioVie and Sitero. D Joshi received advisory board/consultancy fees from Advanz/Intercept, Boston Scientific, Cook Medical, Gilead, Ipsen Pharmaceuticals, Mirum Pharmaceuticals, Q3 Medical, and Dr Falk Pharma. ÉA Lefebvre, JR Schaub, and CN Barnes are employees and shareholders of Pliant Therapeutics, Inc. M An, A Clark, and R Pencek are former employees and shareholders of Pliant Therapeutics, Inc. D Thorburn served as an advisor to Pliant Therapeutics. AJ Montano-Loza served on advisory boards for Intercept and Pliant Therapeutics. C Schramm served as an advisor to Pliant Therapeutics, Chemomab, and Agomab; and has received travel grants from Dr. Falk Pharma. CL Bowlus advised for Chemomab, Ipsen, NGM Bio, and Pliant Therapeutics; and received grants from Calliditas Therapeutics, Chemomab, COUR Therapeutics, CymaBay, Gilead, GSK, Hanmi, Intercept, Ipsen, Mirum, Novartis, Novo Nordisk, Pliant Therapeutics, TARGET, Viking, and Zydus. M Trauner received consulting fees from AbbVie, Albireo, Agomab, BiomX, Boehringer Ingelheim, Chemomab, Dr Falk Pharma, Gilead, Genfit, HighTide, Intercept, Ipsen, Janssen, MSD, Mirum, Novartis, Phenex, Pliant Therapeutics, ProQR Therapeutics, Regulus, Siemens, and Shire; served on speakers bureaus for Albireo, BMS, Dr Falk Pharma, Gilead, Intercept, Ipsen, Madrigal, Mirum, and MSD; received travel grants from AbbVie, Dr Falk Pharma, Gilead, Intercept, and Janssen; received unrestricted contract grants from Albireo, Alnylam, CymaBay, Genentech, Dr Falk Pharma, Gilead, Intercept, MSD, Takeda, and Ultragenyx; and is listed as co-inventor (service inventions) on patents on medical use of nor-UDCA filed by the Medical University of Graz. C Levy received consulting fees from Calliditas, Chemomab, CymaBay, Gilead, GSK, Intercept, Ipsen, Kowa, Mirum, and Pliant Therapeutics; and received institutional research grants from Calliditas, CymaBay, Escient, Gilead, GSK, Intercept, Ipsen, Kowa, Mirum, Pliant Therapeutics, and Zydus.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous