Background and aims Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis.
Methods In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03–10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α4β7+ lymphocytes was measured to demonstrate drug activity.
Results No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α4β7+ lymphocytes in patients receiving PF-00547,659.
Conclusions The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment.
Trial Register No: NCT00928681.
- ulcerative colitis
- mucosal vascular addressin cell adhesion molecule 1 protein
- human monoclonal antibody
- inflammatory bowel disease
- adhesion molecules
- IBD clinical
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Writing assistance: Editorial support with the drafting of this manuscript was provided by Samantha Stanbury PhD and Louise Norbury MSc (FireKite, UK), and funded by Pfizer Inc.
Data analysis was led by Jacqueline Spanton, Steven W. Martin and Wojciech Niezychowski at Pfizer Ltd.
Funding This study was sponsored by Pfizer Inc.
Competing interests SV has received consulting fees (<$10,000/year) from Schering-Plough, speaker fees (<$10,000/year) from Schering-Plough, UCB and Ferring, and grant support (€65,000) from UCB. JFD has received speaker fees (<$10,000/year) from Ferring and Roche. AL has received consulting fees (<$10,000/year) from UCB, speaker fees (<$10,000/year) from Abbott, Essex and the Falk Foundation, and grant support from Wolff Pharma ($80,000 in 2008), IZKF (institutional research grant of $200,000 covering the period 2006–2008) and the German Research Foundation (DFG; $70,000 over 2008/9). JP has received consulting fees (<$10,000/year) from Schering-Plough, Abbott and Ferring, speaker fees (<$10,000/year) from Schering-Plough and Abbott, and grant support from the Spanish Ministry of Science and Innovation ($175,000 over 2007/9) and Schering-Plough ($125,000 over 2008/9). SG has received speaker fees (<$10,000/year) from Schering-Plough, Centocor, UCB and Abbott, speaker fees (<$10,000/year) from Schering-Plough, Procter and Gamble and (>$10,000/year) Abbott, and grant support ($90,000 over 2006–2007) from Schering-Plough. WN has equity/stock ownership (>$10,000) in Pfizer Ltd and Johnson & Johnson, and is an employee of Pfizer Ltd. GB and J Spanton have equity/stock ownership (>$10,000) in Pfizer Ltd and are employees of Pfizer Ltd. SWM has equity/stock ownership (>$10,000) in Pfizer Ltd and Amgen, and is an employee of Pfizer Ltd. US has no financial disclosures to declare. J Sirotiakova has no competing interests.
Patient consent Obtained.
Ethics approval The research protocol was approved by the appropriate institutional review board or independent ethics committee for each study site. All participants gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.