Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study

Sandborn WJ1, Lee SD2, Tarabar D3, Louis E4, Klopocka M5, Klaus J6, Reinisch W7,8, Hébuterne X9, Park DI10, Schreiber S11, Nayak S12, Ahmad A12, Banerjee A12, Brown LS12, Cataldi F12, Gorelick KJ12, Cheng JB12, Hassan-Zahraee M12, Clare R12, D'Haens GR13. Gut. 2017 Oct 5. pii: gutjnl-2016-313457. doi: 10.1136/gutjnl-2016-313457. [Epub ahead of print]
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1 Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. 2 Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA. 3 Clinic of Gastroenterology and Hepatology, Military Medical Academy, Belgrade, Serbia. 4 Department of Gastroenterology, University Hospital CHU of Liege, Liège, Belgium. 5 Department of Vascular Diseases and Internal Medicine, Nicolaus Copernicus University, Toruń, Collegium Medicum in Bydgoszcz, Poland. 6 Department of Medicine, Universitatsklinikum Ulm, Ulm, Germany. 7 Department of Medicine, Division of Gastroenterology, Medical University of Vienna, Vienna, Austria. 8 Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Canada. 9 Department of Medicine, Université de Nice Sophia Antipolis, Hôpital de l'Archet, Nice, France. 10 Department of Internal Medicine, Division of Gastroenterology, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, South Korea. 11 Department of Medicine, University of Kiel, Kiel, Germany. 12 Department of Gastroenterology, Pfizer, Cambridge, Massachusetts, USA. 13 IBD Unit, Academic Medical Center, Amsterdam, The Netherlands.


OBJECTIVE: This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD).

DESIGN: Eligible adults were aged 18-75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220-450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.

RESULTS: In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.

CONCLUSIONS: Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.


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