BTT1023 is a fully human monoclonal antibody targeting VAP-1 (vascular adhesion protein-1). VAP-1 is a completely new therapeutic target. The safety and efficacy of BTT1023 has earlier been investigated in small clinical trials in rheumatoid arthritis and psoriasis patients. In March 2015, BTT1023 transitioned into Phase 2 development in fibrotic conditions and received Orphan Drug Designation in the EU for the treatment of primary sclerosing cholangitis.
Vascular adhesion protein-1 (VAP-1) as a therapeutic target
A key factor in establishing and maintaining chronic inflammation is the excessive accumulation of white blood cells, or leukocytes, in the tissue (e.g. surrounding joints, or in skin). Leukocytes exit the blood stream and move towards the site of inflammation through a series of processes, including attachment to specific adhesion proteins. These proteins are often expressed in response to initial inflammatory signals. VAP-1 is an adhesion molecule expressed on the endothelial lining of blood vessels. An exciting feature of VAP-1 is that its expression is thought to be upregulated only at the site of inflammation, limiting potential side effects of a product targeting this pathway.
BTT1023 product profile
BTT1023 is a fully human monoclonal antibody that specifically binds to VAP-1. Biotie has previously demonstrated encouraging efficacy and safety for BTT1023 in early clinical studies in rheumatoid arthritis and psoriasis patients and in a range of preclinical models of inflammatory diseases, including COPD and certain neurological conditions. More recently, Biotie has generated new data indicating that VAP-1, in addition to its clinically demonstrated role in inflammatory diseases, has an important role in fibrotic diseases. These data, generated in part in collaboration with National Institute for Health Research Liver Biomedical Research Unit at the University of Birmingham, UK, reveal significant potential for BTT1023 in certain niche liver inflammatory fibrotic diseases. The first data were published in December 2014 in the Journal of Clinical Investigation (Weston CJ, Shepherd EL, Claridge LC, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest 2014; published online Dec 22. doi: 10.1172/JCI73722. and represent potentially new and exciting development opportunities for BTT-1023 in a range of conditions.
For a scientific discussion of the role of VAP-1 in fibrosis, click here
Earlier clinical trials with BTT1023
Biotie has completed three clinical studies with BTT1023 including a single dose, placebo-controlled study in healthy volunteers and two Phase 1b trials in patients with rheumatoid arthritis and psoriasis, respectively. These trials have shown that BTT1023 is safe and generally well tolerated when administered intravenously (IV) at repeated doses of up to 8mg/kg.
Although the Phase 1b trials were not designed to enable formal statistical evaluation of efficacy, in several assessments of treatment effect in the RA trial, including Disease Activity Score based on 28 joint assessment (DAS28) criteria and American College of Rheumatology criteria (ACR), the responses observed in patients taking higher doses of BTT1023 were greater than in the placebo group, including several patients reaching an ACR50 response (a 50% reduction in their ACR score) during treatment.
In the third quarter 2010, data from the Phase 1b trial in patients with psoriasis was reported. While the efficacy signals were not as robust as in the RA trial, there were several patients on active drug that experienced an improvement in their condition. Two patients reported a transient exacerbation in their psoriasis symptoms after treatment had been completed; apart from these two cases, no serious or severe adverse events were reported.
In March 2015, Biotie announced (Stock Exchange Release) the start of patient enrolment into a Phase 2a clinical study evaluating BTT1023 in primary sclerosing cholangitis (PSC). PSC is a progressive immune mediated biliary disease characterised by bile duct inflammation and fibrosis, and accompanying hepatic fibrosis, that frequently results in the need for liver transplantation. The study is being funded through the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership in the UK. The grant holder and Co-Investigator for the study is Professor David Adams, Director of the NIHR Biomedical Research Unit in Liver Disease and Centre for Liver Research at the University of Birmingham, UK.
The BUTEO study (BTT1023, a human monoclonal antibody targeting vascular adhesion protein (VAP-1), in the treatment of patients with primary sclerosing cholangitis) is being conducted in the UK and is an investigator-sponsored open label, single arm, multi-centre study that will evaluate efficacy, safety and pharmacokinetic properties of BTT1023 in 41 patients with PSC. Patients will receive BTT1023 via intravenous infusion every two weeks over an 11 week treatment period. The primary efficacy endpoint is a reduction of elevated levels of alkaline phosphatase, a blood biomarker of bile duct inflammation; secondary endpoints include various measures of liver injury and fibrosis. The two-stage study design includes a pre-planned interim analysis. Based on current estimates, it is expected that the requisite number of patients will have been treated to enable a pre-planned interim analysis in this two-stage study in the first half of 2017.
In March 2015, the European Commission granted BTT1023 Orphan Drug Designation in the European Union for the treatment of PSC. In August 2016, the corresponding designation was granted by the FDA for BTT1023 in the United States.
Scientific literature related to the project
Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, Tomlinson JW, Hubscher SG, Reynolds GM, Aalto K, Anstee QM, Jalkanen S, Salmi M, Smith DJ, Day CP, Adams DH.
Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest. 2015 Feb;125(2):501-20. doi: 10.1172/JCI73722. Epub 2014 Dec 22. Available here