Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: the OPERA study.
Crohn disease
Japanese
Korean
MAdCAM
PF-00547659
Journal
Intestinal research
ISSN: 1598-9100
Titre abrégé: Intest Res
Pays: Korea (South)
ID NLM: 101572802
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
29
04
2019
accepted:
15
11
2019
entrez:
5
2
2020
pubmed:
6
2
2020
medline:
6
2
2020
Statut:
ppublish
Résumé
PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD). OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509).
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD).
METHODS
METHODS
OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients.
RESULTS
RESULTS
In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment.
CONCLUSIONS
CONCLUSIONS
In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509).
Identifiants
pubmed: 32013314
pii: ir.2019.00039
doi: 10.5217/ir.2019.00039
pmc: PMC7000638
doi:
Banques de données
ClinicalTrials.gov
['NCT01276509']
Types de publication
Journal Article
Langues
eng
Pagination
45-55Subventions
Organisme : Pfizer
Références
N Engl J Med. 2010 Apr 15;362(15):1383-95
pubmed: 20393175
N Engl J Med. 2013 Aug 22;369(8):711-21
pubmed: 23964933
Br J Pharmacol. 2009 May;157(2):281-93
pubmed: 19366349
Nature. 1989 Jan 12;337(6203):179-81
pubmed: 2911352
Clin Gastroenterol Hepatol. 2011 Aug;9(8):670-678.e3
pubmed: 21642014
Am J Pathol. 1997 Jul;151(1):97-110
pubmed: 9212736
Cells. 2019 May 01;8(5):
pubmed: 31052430
Gut. 2018 Oct;67(10):1824-1835
pubmed: 28982740
Gut. 2013 Sep;62(9):1288-94
pubmed: 22760005
Nature. 1988 Jan 7;331(6151):41-6
pubmed: 3340147
J Clin Pharmacol. 2009 Sep;49(9):1012-24
pubmed: 19620385
Gastroenterology. 2005 Sep;129(3):807-18
pubmed: 16143120
J Gastroenterol Hepatol. 2015 Mar;30 Suppl 1:12-8
pubmed: 25827798
Gastroenterology. 2007 May;132(5):1672-83
pubmed: 17484865
Biochem Pharmacol. 2006 Jun 28;72(1):1-10
pubmed: 16469301
Best Pract Res Clin Gastroenterol. 2014 Jun;28(3):363-72
pubmed: 24913377