The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Abstract

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 placebocontrolled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03e10 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 a 4 b 7 + 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 a 4 b 7 + 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.

Rôle et ciblage de l’intégrine α4β7 dans la physiopathologie des MICI et de l’infection par le VIH

“…Un essai multicentrique randomisé réalisé en double aveugle chez 80 patients atteints de rectocolite hémorragique active, modérée à sévère, montre des taux de réponse (évalués par endoscopie) après 4 et 12 semaines de 50 % et 42 % respectivement dans le groupe traité contre 26 % et 29 % dans le groupe placebo. Ces différences ne sont pas significatives [20]. L'innocuité du produit est actuellement évaluée dans deux essais 4 .…”

Novel Drug Therapies for the Treatment of Crohn's Disease

“…It inhibits the function of the β7+ memory T-cells and its affinity to mouse and human MAdCAM was proven [36]. Eighty moderately-severely active UC patients have been involved into a multicentre RCT study to evaluate the efficacy of PF00547659 [37]. Study drug was administered in an 0.03-10 mg/kg iv./sc.…”

New Drugs on the Horizon for IBD

“…These include another anti-α 4 β 7 antibody in early development (AMG 181) [17], antibody to MAdCAM-1 (PF-00547,659) [18], anti-β 7 antibody (etrolizumab) [19], and vercirnon, an antagonist for CCR9, a small bowel-specific chemokine (CCX282-B) [20]. …”

“…PF-00547,659 (anti-MAdCAM antibody) has been studied in a phase 2 randomized controlled trial in UC [18]. Patients with active UC (Mayo score ≥6 and endoscopic subscore ≥2) were assigned initially to a single dose of placebo (n = 6), PF-00547,659 0.03 mg/kg i.v., 0.1 mg/kg i.v., 0.3 mg/kg i.v., 1 mg/kg i.v., 10 mg/kg i.v., or 3 mg/kg s.c. (n = 4 per group).…”