Title: Targeting vascular adhesion protein-1 (VAP-1) for the treatment of liver fibrosis: a study of efficacy and mechanisms in patients with primary sclerosing cholangitis (PSC)
Funder: Department of Health and Social Care

Abstract: We have compelling evidence that the endothelial adhesion receptor VAP-1, an ectoenzyme with semicarbazide sensitive amine oxidase (SSAO) activity, is involved in the progression of fibrotic liver disease. Treatment with an antibody against VAP-1 prevents fibrosis in murine models of liver injury and in patients with cirrhosis VAP-1 is increased in the hepatic scar and circulating levels correlate with histological fibrosis. These results led University of Birmingham and Biotie Therapies to file patents covering the potential of VAP-1 as a therapeutic target and biomarker in liver disease. We now have the opportunity to carry out the first clinical study inhibiting VAP-1 in patients with liver disease using a fully human anti-VAP-1 antibody (BTT1023) for which Biotie has previously demonstrated efficacy and safety in early clinical studies in rheumatoid arthritis and psoriasis. We will study patients with the fibrotic liver disease primary sclerosing cholangitis (PSC) for which there is currently no effective therapy. We have shown in patients with PSC 1) strong staining of VAP-1 at sites of hepatic fibrosis 2) increased SSAO activity in liver tissue 3) elevated circulating levels of soluble VAP-1. This programme is a collaboration between two centres with major PSC clinical programmes, Universities of Birmingham and Oxford and Biotie Therapies. Patients will receive intravenous BTT1023 every 2 weeks for 3 months. The primary endpoint for response will be a fall in serum alkaline phosphatase, an accepted end point for trials in PSC. In addition we will look for changes in disease activity as measured by a novel MRI imaging test developed in Oxford, the model for end-stage liver disease (MELD) and the Mayo clinic PSC score and fibrosis using the ELF™ test, FibroTest and Fibroscan elastography. The trial was designed by the Birmingham NIHR Liver BRU trials team. The MR imaging test is established in the Birmingham NIHR BRU MR facility allowing us to quantify liver fibrosis and changes in bile duct lesions after therapy. This study will determine whether inhibiting VAP-1 is likely to be effective in PSC and thus other fibrotic liver diseases and provide data on the potential of a new imaging test for fibrotic liver disease. The mechanisms of action of antibodies against VAP-1 will be studied by investigating whether treatment reduces total sVAP-1 and blocks SSAO activity in patients. It is unclear whether SSAO activity is required for the fibrogenic effects of VAP-1 and we will investigate whether clinical efficacy is linked to reduction in SSAO enzyme activity mediated either by antibody-VAP-1 complex clearance mechanisms or enzyme inhibition in vivo. In addition we will test the effect of antibody blockade on the function of leucocytes that use VAP-1 to enter the liver. These experiments will elucidate the mechanisms of action of VAP-1 and its SSAO function in disease. We will investigate the clinical utility of measuring sVAP-1 in patients with PSC. We have access to a large cohort of serum samples from PSC patients including longitudinal samples over 5 years in more than 100 patients. We will correlate sVAP-1 levels and SSAO activity with clinical events and conventional tests of liver dysfunction to determine whether sVAP-1 predicts the clinical course. This evaluation will be carried out in collaboration with the Evidence Synthesis and Test Evaluation Research Group in Birmingham.

Lay abstract: The lack of effective treatments for liver disease is particularly frustrating at a time when deaths from cirrhosis are increasing rapidly in the UK and other developed countries. Although these diseases can be treated successfully by liver transplantation this is a costly operation with serious morbidity and mortality and patients are required to take life-long immunosuppressive drugs, which can have debilitating consequences in some patients. Furthermore there is a shortage in donors, meaning that only a fraction of patients with liver disease can be treated by transplantation. There is thus a pressing need for new approaches to treating and preventing cirrhosis. Cirrhosis is a type of scarring (fibrosis) which distorts the liver and prevents it functioning. It is caused by many different factors but a common feature is the development of liver inflammation (hepatitis) which drives the scarring process. This inflammation involves white cells from the blood that are recruited into the liver where they produce factors that drive scar formation. Our studies reporting a critical role for a protein called VAP-1 in liver scarring in animals suggest a completely new approach to treating fibrosis and preventing progression to cirrhosis. Through our long-standing collaboration with Biotie Therapies we have access to a state of the art antibody drug targeting VAP-1 which specifically binds and neutralises VAP-1 when injected into the blood. This drug, called BTT1023, has completed three early phase clinical studies, two of which have been studies in patients with the inflammatory diseases rheumatoid arthritis and psoriasis and has shown promising signs that it is effective. BTT1023 has been through extensive safety testing and has proved to be safe and well tolerated in patients providing us with a unique opportunity to test the potential of targeting VAP-1 in clinical liver disease. We are proposing to carry out a clinical trial of BTT1023 in patients with the scarring liver disease primary sclerosing cholangitis at two centres, the Universities of Birmingham and Oxford where there is internationally acclaimed expertise in looking after these patients with additional recruitment through the University of Nottingham and Leicester University hospitals. The disease currently has no effective treatment. We will also take the opportunity of the clinical trial to study how BTT1023 and VAP-1 function in liver disease. Part of the trial will involve the use of a new imaging (magnetic resonance) technique to provide images of the liver that allow us, for the first time, to measure scarring through the liver and see if this changes on treatment. Finally, because soluble VAP-1 is released into the blood in liver disease we will carry out an additional study on stored blood samples to see if soluble VAP-1 analysis can help us predict the subsequent course of PSC in large cohorts of patients in Oxford and Birmingham with additional recruitment from Nottingham and Leicester. If successful this study will open up a completely new avenue for the treatment of PSC, other chronic liver diseases and by extension, other fibrotic disorders affecting the lung, kidney and other organs.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL