Monoclonal antibody BTT1023 targeting vascular adhesion protein 1 for treating primary sclerosing cholangitis: BUTEO single-arm Phase II trial
Authors: Arndtz Katherine , Chen Yung-Yi , Rowe Anna , Homer Victoria , Kirkham Amanda , Douglas-Pugh Jessica , Slade Daniel , Thorburn Douglas , Barnes Eleanor , Aithal Guruprasad , Newsome Philip , Smith David , Adams David , Weston Christopher , Hirschfield Gideon 
Published: March 2022

Background
Primary sclerosing cholangitis is a progressive and fibrotic liver disease. Treatments remain inadequate, and patients with persistent elevations in activity of alkaline phosphatase are at greatest risk of disease progression. Studies in patient cohorts have implicated the serum amine oxidase vascular adhesion protein 1 in the pathophysiology of disease, including liver fibrogenesis. We hypothesised that blockade of serum amine oxidase by a monoclonal antibody would result in a reduction in liver fibrosis/injury, as evaluated by serum liver tests and other non-invasive markers of liver injury.

Objectives
To evaluate the open-label effect on liver injury markers of treatment with the anti-vascular adhesion protein 1 monoclonal antibody BTT1023 in patients with primary sclerosing cholangitis over a 78-day treatment period.

Design
A single-arm, two-stage, open-label, multicentre, Phase II clinical trial.

Setting
Ambulatory liver disease practices in tertiary care hospitals.

Participants
Patients with primary sclerosing cholangitis at risk of disease progression, based on elevated activity of serum alkaline phosphatase, and without evidence of infection, liver failure or advanced disease.

Intervention
Seven intravenous infusions of BTT1023 (8 mg/kg of timolumab) over a 78-day treatment period. The intervention was split into a dose-confirmatory stage (to confirm pharmacokinetics), followed by a confirmed expansion cohort stage.

Main outcome measures
Our primary outcome measure was patient response to treatment at day 99, measured by a reduction in activity of serum alkaline phosphatase of ≥ 25% from baseline to day 99. Secondary markers of efficacy were assessed based on evaluation of changes in markers of liver injury and liver fibrosis. Safety assessments were performed throughout.

Results
Thirty-five patients were consented and screened for eligibility. Twenty-three patients were treated across the two stages of the trial. Interim assessment demonstrated a failure to meet the primary end point, leading to trial discontinuation on the grounds of futility. Multiple exploratory markers were evaluated in a final cohort of 22 patients (modified intention-to-treat analysis). No treatment-related effects were evident. No new safety concerns were seen.

Conclusions
No preliminary evidence for disease modification was demonstrated.

Limitations
It is clear that this study is limited in its design. Even if there were a better biomarker of fibrosis turnover that could be considered the ‘gold standard’, the design and duration would have had real-world resource limitations. With limited opportunity to test a new agent in large numbers of patients over a prolonged period, it was necessary to aim to see efficacy in a small cohort over a short period. Given the absence of any proven biochemical surrogate of disease activity in primary sclerosing cholangitis, alkaline phosphatase was chosen as an end point. This remains a difficult end point (yet one that does capture biliary injury) and, therefore, despite limitations, this study did demonstrate short-term safety.

Future work
Future research will require attention to an ongoing debate regarding the optimal end points for assessing efficacy, as well as consideration of duration of treatment, even in early-phase studies. This raises the challenge of how to fund early experimental trials with ‘high risk of failure’ adequately to ensure that clearer results (negative or positive) arise by the end of the study.

Trial registration
Current Controlled Trials ISRCTN11233255, EudraCT 2014-002393-37 and NCT02239211.

Funding
This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.