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

Hirschfield, Gideon M.; Arndtz, Katherine; Kirkham, Amanda; Chen, Yung-Yi; Fox, Richard; Rowe, Anna; Douglas-Pugh, Jessica; Thorburn, Douglas; Barnes, Eleanor; Aithal, Guruprasad P.; Hull, Diana; Bhandal, Khushpreet; Olsen, Kathryn; Woodward, Paul; Lax, Siân; Newsome, Philip; Smith, David J.; Kallio, Antero; Adams, David H.; Homer, Victoria; Weston, Chris J.

Abstract

Background:
Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis.

Methods:
BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18–75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient’s response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99.

Results:
Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline.

Conclusions:
The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Citation

Hirschfield, G. M., Arndtz, K., Kirkham, A., Chen, Y.-Y., Fox, R., Rowe, A., Douglas-Pugh, J., Thorburn, D., Barnes, E., Aithal, G. P., Hull, D., Bhandal, K., Olsen, K., Woodward, P., Lax, S., Newsome, P., Smith, D. J., Kallio, A., Adams, D. H., Homer, V., & Weston, C. J. (2024). Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial. Hepatology Communications, 8(5), Article e0426. https://doi.org/10.1097/hc9.0000000000000426

• Journal Article Type: Article
• Acceptance Date: Jan 23, 2024
• Online Publication Date: May 5, 2024
• Publication Date: 2024-05
• Deposit Date: Jul 24, 2024
• Publicly Available Date: Jul 26, 2024
• Journal: Hepatology Communications
• Electronic ISSN: 2471-254X
• Publisher: Wiley Open Access
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 5
• Article Number: e0426
• DOI: https://doi.org/10.1097/hc9.0000000000000426
• Public URL: https://nottingham-repository.worktribe.com/output/34619030
• Publisher URL: https://journals.lww.com/hepcomm/fulltext/2024/05010/vascular_adhesion_protein_1_blockade_in_primary.8.aspx