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Clinical Trial
. 2024 Apr 26;8(5):e0426.
doi: 10.1097/HC9.0000000000000426. eCollection 2024 May 1.

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 , Yung-Yi Chen  1   2 , Richard Fox  4   5 , Anna Rowe  2   4 , Jessica Douglas-Pugh  4 , Douglas Thorburn  6 , Eleanor Barnes  7 , Guruprasad P Aithal  8   9 , Diana Hull  2 , Khushpreet Bhandal  2 , Kathryn Olsen  2 , Paul Woodward  2 , Siân Lax  4 , Philip Newsome  1   2 , David J Smith  10 , Antero Kallio  10 , David H Adams  1   2 , Victoria Homer  2   4 , Chris J Weston  1   2
Affiliations
Clinical Trial

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

Gideon M Hirschfield et al. Hepatol Commun. .

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.

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Conflict of interest statement

David J. Smith was employed by Biotie Therapies, a company engaged in the development of therapies targeting VAP-1. Antero Kallio was employed by Biotie Therapies, a company engaged in the development of therapies targeting VAP-1. Douglas Thorburn advises, is on the speakers' bureau, and received grants from Ipsen. He consults for Engitix. He advises Pliant. He is on the speakers' bureau for Advanz and Falk. Eleanor Barnes consults and received grants from Roche and Vaccitech. She consults for AstraZeneca. Guruprasad P. Aithal consults and advises Abbott, Albireo, AstraZeneca, BenevolentAI, Clinipace, DNDi, GlaxoSmithKline, Merck, Pfizer, PureTech, and Servier. Philip Newsome consults, advises, is on the speakers' bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Intercept, Madrigal, Pfizer, and Poxel. He is on the speakers' bureau for AiCME. David H. Adams consults for Faron. Chris J. Weston received grants from Novo Nordisk and Regeneron. The remaining authors have no conflicts to report.

Figures

FIGURE 1
FIGURE 1
BUTEO trial profile. CONSORT diagram of the BUTEO trial. One patient was registered and then found to be ineligible; they are therefore counted as both a screen failure and as a patient recruited. Abbreviations: ALP, alkaline phosphatase; mITT, modified intention-to-treat.
FIGURE 2
FIGURE 2
Liver biochemistry pre-timolumab, during and post-timolumab treatment. (A) Median with IQRs of ALP (IU/L) in all evaluable patients during the BUTEO trial. Percentage change of ALP (B), ALT (C), GGT (D), and bilirubin (E) levels comparing pretreatment and posttreatment in all evaluable patients. Abbreviations: ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase.
FIGURE 3
FIGURE 3
Concentration and enzymatic activity of circulating sVAP-1. (A) Concentration of sVAP-1 in patient serum was measured before each infusion of timolumab and during the posttreatment phase (n=21). (B) Amine oxidase activity of patient serum was determined by Amplex UltraRed assay. Data were background-corrected using the VAP-1 inhibitor LJP1586 (1 μM). Data for 13 patients shown with enzyme activity determined at each visit and then averages taken for pretreatment, treatment, and posttreatment (follow-up visits 10–11: days 99 and 120). Mean±IQR are shown. Kruskal-Wallis test with Dunn multiple comparison test vs. pretreatment group (ns, not significant, ****p<0.001). Abbreviation: sVAP-1, soluble vascular adhesion protein-1.
FIGURE 4
FIGURE 4
Proportions of circulating inflammatory cell populations that have been shown to be recruited into vascular beds by VAP-1. Cryopreserved peripheral blood mononuclear cells were thawed and immunophenotyped using flow cytometry for (A) CD3+, (B) CD4+, and (C) CD8+ T cells, (D) CD3-CD56+ NK cells, (E) regulatory T cells (Treg), and (F) classical (CD14+CD16−), (G) intermediate (CD14+CD16+), and (H) nonclassical (CD14−CD16+) monocyte populations. Aggregated data collected during pretreatment (visits 1–3: screening visits 1 and 2, pre-first infusion visit 3 [day 1]), treatment (infusion visits 4–9: days 8, 22, 36, 50, 64, and 78), and posttreatment (follow-up visits 10–11: days 99 and 120) groups. There were no significant differences between groups (Kruskal-Wallis test with Dunn multiple comparison test). Median±IQR. Abbreviation: VAP-1, vascular adhesion protein-1.
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