Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: open-label, multi-centre, single arm, phase II trial

Introduction: Primary sclerosing cholangitis (PSC) is a progressive inflammatory liver disease characterised 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 PSC.

Methods: BUTEO was a prospective, single arm, open-label, multi-centre, phase II trial, conducted in six centres in the UK. Patients with PSC aged 18–75 years had an alkaline phosphatase (ALP) value of greater than 1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through 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 response to timolumab at day 99, as measured by a reduction in serum ALP by 25% or more from baseline to day 99.

Results: 23 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 two of the 18 evaluable patients (11.1%) achieved a reduction in ALP levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline.

Discussion: The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and results 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.