Hepatology Communications (May 2024)

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

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

DOI
https://doi.org/10.1097/HC9.0000000000000426
Journal volume & issue
Vol. 8, no. 5

Abstract

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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.