Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial

Gideon M Hirschfield ^1,2,3, Katherine Arndtz ^1,2, Amanda Kirkham ⁴

¹Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
²National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK.
³Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.
⁴Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁵Parexel International, Sheffield, UK.
⁶Liver Services, Royal Free London NHS Foundation Trust, London, UK.
⁷Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁸Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, The University of Nottingham, Nottingham, UK.
⁹NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and University of Nottingham, Nottingham, UK.
¹⁰Biotie Therapies Corp., Turku, Finland.

⁰Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

Hepatology Communications +

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April 26, 2024

View abstract on PubMed

Summary

The BUTEO trial found timolumab safe for primary sclerosing cholangitis but ineffective. This vascular adhesion protein-1 (VAP-1) blockade did not significantly reduce liver enzymes or fibrosis markers in patients.

Area Of Science

Hepatology
Immunology
Clinical Trials

Background

Primary sclerosing cholangitis (PSC) is a progressive liver disease with significant fibrosis.
Vascular adhesion protein-1 (VAP-1) plays a key role in the inflammatory pathways driving PSC.
Targeting VAP-1 with monoclonal antibodies is a potential therapeutic strategy for PSC.

Purpose Of The Study

To evaluate the safety and efficacy of VAP-1 blockade using timolumab (BTT1023) in patients with PSC.
To confirm the safety of timolumab at 8 mg/kg and achieve sufficient VAP-1 blocking levels.
To assess the impact of timolumab on serum alkaline phosphatase and fibrosis markers.

Main Methods

A prospective, single-arm, open-label, Phase II trial (BUTEO) involving 23 PSC patients.
Patients had elevated alkaline phosphatase (>1.5x ULN).
Timolumab (8 mg/kg) was administered, with primary efficacy measured by a ≥25% reduction in alkaline phosphatase at day 99.

Main Results

Timolumab (8 mg/kg) demonstrated short-term safety with adequate circulating levels for VAP-1 blockade.
Only 11.1% (2/18) of evaluable patients met the primary efficacy endpoint.
No significant changes were observed in inflammatory cell populations or fibrosis biomarkers.

Conclusions

The BUTEO trial confirmed the safety of 8 mg/kg timolumab in PSC patients.
The study was halted due to a lack of efficacy, as evidenced by no significant improvement in liver tests.
VAP-1 blockade with timolumab did not show therapeutic benefit in this PSC cohort.