Journal Article

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

Klopocka, Maria, Lee, Scott D, Sandborn, William J, Brown, Lisa S, Clare, Robert, Ahmad, Alaa, Hassan-Zahraee, Mina, Cataldi, Fabio, Cheng, John B, Tarabar, Dino, Park, Dong-Il, Louis, Edouard, Reinisch, Walter, Nayak, Satyaprakash, Klaus, Jochen, Schreiber, Stefan, Hébuterne, Xavier, Banerjee, Anindita, Gorelick, Kenneth J, D’Haens, Geert R

2018

Overview

ObjectiveThis 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).DesignEligible 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.ResultsIn 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.ConclusionsClinical 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.Trial registration numberNCT01276509; Results.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Aged / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / C-reactive protein / C-Reactive Protein - analysis / CD4 antigen / Cell adhesion & migration / Cell adhesion molecules / Clinical trials / Colon / Colonoscopy - methods / Crohn Disease - diagnosis / Crohn Disease - drug therapy / Crohn Disease - metabolism / Crohn's disease / Dose-Response Relationship, Drug / Double-Blind Method / Drug dosages / Drug Monitoring - methods / Endoscopy / Female / Gastroenterology / Gastroenterology & hepatology / Gastroentérologie & hépatologie / Gastrointestinal Agents - administration & dosage / Gastrointestinal Agents - adverse effects / Human health sciences / Humans / Immunological memory / Immunosuppressive agents / Inflammation / Inflammatory Bowel Disease / integrins / Intestine / Intolerance / Lymphocytes / Lymphocytes T / Male / Memory cells / Middle Aged / Monoclonal antibodies / Mucosa / Nervous system / Patient Acuity / Patients / pharmacotherapy / Remission / Sciences de la santé humaine / Severity of Illness Index / Treatment Outcome / Tumor necrosis factor-TNF / Ulcers