OP022 Anti-MAdCAM-1 Antibody (PF-00547659) for Active Refractory Crohn's Disease: Results of the OPERA study
G. D'Haens*1, S. Lee2, D. Tarabar3, E. LOUIS4, M. Klopocka5, D.I. Park6, J. Claus7, X. Hébuterne8, W. Reinisch9, S. Schreiber10, K.J. Gorelick11, J. Cheng11, M. Hassan-Zahraee11, L. Brown12, A. Ahmad13, A. Banerjee13, F. Cataldi11, W. Sandborn14
1University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 2University of Washington, Gastroenterology, Seattle, WA, United States, 3MMA, Gastroenterology, Belgrade, Serbia, 4University Hospital CHU of Liège, Gastroenterology, Liège, Belgium, 5Nicolaus Copernicus University in Toruń, Gastroenterology, Bydgoszcz, Poland, 6Kangbuk Samsung Hospital-Sungkyunkwan University, Gastroenterology, Seoul, South Korea, 7Universitätsklinikum Ulm, Gastroenterology, Ulm, Germany, 8CHU de Nice et Université de Nice Sophia-Antipolis, Gastroenterology, Nice, France, 9Medical University of Vienna, Internal Medicine/Gastroenterology, Vienna, Austria, 10University of Kiel, Gastroenterology, Kiel, Germany, 11Pfizer Inc., Gastroenterology, Cambridge, United States, 12Pfizer Inc., Gastroenterology, Cambridge, MA, United Kingdom, 13Pfizer Inc., Gastroenterology, Cambridge, MA, United States, 14Univeristy of California San Diego, Division of Gastroenterolgy, San Diego, United States
Inhibition of white blood cell (WBC) translocation from the bloodstream to the intestine is a promising new approach to the management of Inflammatory Bowel Disease. PF-00547659 (PF) is a fully human monoclonal antibody targeting MAdCAM on endothelial cells instead of its integrin ligand. OPERA is a randomized, multicenter double-blind, placebo-controlled study of safety and efficacy of PF in subjects with Crohn's disease (CD)
Adults ages 18-75, with active moderate to severe CD (CDAI 220-450) and a history of failure or intolerance to anti-TNF and/or immunosuppressant drugs were eligible if they had hsCRP >3.0 mg/L and ulcers on colonoscopy. Subjects were randomized to placebo, 22.5 mg, 75 mg or 225 mg arms. The primary end point was CDAI-70 response at week 8 or 12. Secondary end points were remission and CDAI-100 response and safety. Disease biomarkers studied were blood β 7+ CD4+ central memory T-cell level (frequency and β 7 expression) by FACS, CRP, and soluble MAdCAM
267 subjects were enrolled, and 2 patients remain in safety follow-up. CDAI-70 response showed a nominal difference between PF-00547659 and placebo without reaching statistical significance. However, remission at week 12 appeared to be substantially higher in the subjects with above median baseline CRP levels (CRP >18). Soluble MAdCAM in treated, but not in placebo subjects decreased significantly at week 2 compared with baseline, in a dose-related manner, and remained low during the study. Circulating β 7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12, in PF treated subjects in a dose-dependent manner.
Baseline characteristics and selected outcomes are presented in Table 1 and efficacy results in Table 2.
Table 1 Patient charecteristics.
Table 2 Efficacy results at Week 12.
Effect size (active - placebo) of remission, response and mucosal healing *p<0.05
Dose 7.5mg 22.5mg 75mg 225mg Remission 8%* 13%* 12%* 3% Response 9% 25%* 16%* 21%* Mucosal Healing 8% 19%* 16%* 7%
Effect size (active - placebo) of remission, response and mucosal healing
While the primary endpoint was not met because of a high placebo response, PF was pharmacologically active as shown by a dose-related increase in circulating β 7+ T lymphocytes and a sustained dose-related decrease in MAdCAM. Higher baseline CRP levels appear to differentiate responders to PF versus placebo. No safety signal was observed in this study