Liver 3D model in the foreground, with a doctor speaking to a patient holding their painful stomach in the background

A clinical trial led by Birmingham researchers investigated targeting a molecule causing liver inflammation and fibrosis to treat patients with Primary sclerosing cholangitis (PSC) – a debilitating liver disease for which there is currently no treatment.

The findings, published in Hepatology Communications, highlight how the therapeutic agent timolumab was able to safely block the molecule of interest, a vascular adhesion protein called VAP-1, without causing significant adverse effects. However, it did not produce significant change in the levels of alkaline phosphatase (ALP), an enzyme associated with liver disease, which meant the trial was stopped due to lack of treatment efficacy.

Our findings may well help guide other studies using monotherapy or combined therapy with VAP-1, both in the liver and in other sites of inflammation and fibrosis.

Dr Chris Weston, University of Birmingham

Nevertheless, researchers remain hopeful about the potential of VAP-1 as a target in inflammatory diseases – also thanks to the breadth of previous evidence gained in previous studies led by Professor David Adams at the University of Birmingham – and believe these findings may help guide future research focusing on this protein.

Dr Chris Weston, Associate Professor at the University of Birmingham’s Institute of Immunology and Immunotherapy, member of the NIHR Birmingham Biomedical Research Centre’s Inflammatory Liver Disease theme, and co-author of the study said: “We believe that VAP-1 remains a viable target in inflammatory and fibrotic disease given the wealth of evidence in other preclinical models, and the use of small molecule inhibitors of VAP-1 that have been developed may provide an alternative means to target VAP-1. Our findings may well help guide other studies using monotherapy or combined therapy with VAP-1, both in the liver and in other sites of inflammation and fibrosis.”

Lead Clinical Investigator for the trial Professor Gideon Hirschfield, Chair in Autoimmune Liver Disease Research at the Toronto Centre for Liver Disease and Honorary Professor at the University of Birmingham, added: “Primary sclerosing cholangitis can be a very debilitating chronic disease, which most often affects people of working age. It is key that we continue to investigate this condition, its causes and potential avenues for treatment, to find effective ways to improve the lives of patients in the UK and across the globe.”

Primary sclerosing cholangitis (PSC) is a progressive inflammatory liver disease where the body’s immune attacks its own liver. It affects people of all ages, frequently in association with inflammatory bowel disease (IBD).

The BUTEO trial was sponsored by the University of Birmingham and run by the Birmingham Cancer Research UK Clinical Trials unit, with patients recruited from six hospitals in the UK. The project was funded by the NIHR Efficacy and Mechanism Evaluation Scheme in partnership with Biotie Therapies (now a part of Acorda Therapeutics).