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

Abstract

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.

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

“…The main limitation is the lack of direct clinical translatability of the particles and antibodies that were used in the present study. However, biodegradable MPIOs are now available( 27 ) and anti-human MAdCAM-1 antibodies are currently under clinical investigation( 28 ), opening the way for clinical translation of our imaging method by coupling the two constructs.…”

Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule‐1 (MAdCAM‐1), in Patients With Ulcerative Colitis or Crohn's Disease

“…A phase 2, parallel, dose‐ranging, randomized, double‐blind, placebo‐controlled clinical trial in patients with moderate to severe CD who had a history of treatment failure, or intolerance to immunosuppressants and/or anti–tumor necrosis factor (TNF) agents was performed (A7281006, ClinicalTrials.gov identifier: NCT01276509; OPERA) 5 . Patients eligible for this study must have met the entry criteria (details of which have been published previously 5 ), which specified a high‐sensitivity C‐reactive protein (CRP) concentration greater than the upper limit of normal (3.0 mg/L). In this study, 3 subcutaneous (SC) dose levels (22.5, 75, and 225 mg) of ontamalimab were compared with placebo (in a 1:1:1:1 ratio).…”

“…Patients were randomly assigned to 1 of 4 treatment arms for the 12‐week induction period and stratified by the status of anti‐TNF experience or immunosuppressant intolerance/failure and concomitant immunosuppressant therapy. The primary efficacy end point was the proportion of patients with a decrease in Crohn's Disease Activity Index score of at least 70 points from baseline to week 8 or week 12 5 . A minimum of 240 randomized patients (60 per treatment group) were required to evaluate the primary end point.…”

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

“…134 However, the phase 2 OPERA study in patients with active refractory CD failed to meet its primary end point, despite evidence of target engagement. 135 In the phase 1 safety study, TOSCA, in patients with active CD, 12 weeks of SHP647/ontamalimab induction therapy did not result in a reduction in CSF lymphocytes or T-cell subsets or CD4:CD8 ratio. 136 The data from extension studies for UC (TURNADOT II) and CD (OPERA and TOSCA) demonstrated that efficacy achieved with SHP647/ontamalimab induction were maintained for up to 144 weeks and 72 weeks, respectively.…”

“…In the phase 2 TURANDOT trial in patients with moderate to severe UC, 12 weeks of SHP647/ontamalimab treatment resulted in significantly greater remission rates at 7.5 mg, 22.5 mg, and 75 mg doses every 4 weeks compared with placebo . However, the phase 2 OPERA study in patients with active refractory CD failed to meet its primary end point, despite evidence of target engagement . In the phase 1 safety study, TOSCA, in patients with active CD, 12 weeks of SHP647/ontamalimab induction therapy did not result in a reduction in CSF lymphocytes or T‐cell subsets or CD4:CD8 ratio .…”