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OP021 TURANDOT: a randomized, multicenter double-blind, placebo-controlled study of the safety and efficacy of Anti-MAdCAM Antibody PF-00547659 (PF) in patients with moderate to severe Ulcerative Colitis (UC)

S. Vermeire*1, W. Sandborn2, S. Danese3, X. Hebuterne4, B. Salzberg5, M. Klopocka6, D. Tarabar7, T. Vanasek8, M. Gregus9, P. Hellstern10, J.-S. Kim11, M. Sparrow12, K.J. Gorelick13, A. Ahmad14, M. Hassan-Zahraee14, V. Pradhan14, F. Cataldi14, W. Reinisch15

1Leuven University Hospital, Leuven, Belgium, 2University of California San Diego, CA, United States, 3IBD-Division Gastroenterologia, Istituto Clinico Humanitas, Rozzano, Italy, 4Hospitall→Archet, Nice Cedex, France, 5Atlanta Gastroenterology Specialist, Suwanee, United States, 6University Hospital, Nicolaus Copernicus University, Torun Bydgoszcz, Poland, 7Military Medical Academy, Belgrade, Serbia, 8Hepato-gastroenterologie, Hradec Kralove, Czech Republic, 9Gastroenterologicke a hepatologicke, Nitra, Slovakia, 10Nature Coast Clinical Research, Inverness, Florida, United States, 11Seoul National University Hospital, Seoul, South Korea, 12Alfred Hospital of Melbourne, Melbourne, Australia, 13Pfizer Inc., Collegeville, United States, 14Pfizer Inc., Cambridge, United Kingdom, 15McMaster University Health Centre, Ontario, Canada

Background

Inhibiting WBC trafficking from capillary into gut mucosa is a new approach to treating UC. Until now, all agents have acted on integrins found on circulating WBC. PF, a fully human monoclonal antibody, acts directly on MAdCAM, a cell adhesion molecule expressed mainly by intestinal venules. The TURANDOT study was designed to identify the preferred dose of PF to induce remission in subjects with moderate to severe UC.

Methods

Adults 18-65y with ≥3m history of documented UC that extended >15cm beyond the rectum, a total Mayo Score ***6 and endoscopic subscor ≥ 2, who had failed at least 1 approved therapy were eligible. Anti-TNF therapy was stopped ≥ 6 weeks before treatment and other drugs had to be stable. Prednisone doses >20mg/d (or equivalent) were prohibited. Immunosuppressant agents were stopped by week 12. Randomized treatment groups were placebo, 7.5mg, 22.5mg, 75mg or 225mg PF every 4 weeks for 3 doses. The primary end point was week 12 remission, defined as total Mayo score ≤2 with no subscore >1. Secondary end points were week 12 response (Mayo score decrease ≥3 and ≥30% decrease from baseline) and mucosal healing (Mayo endoscopy subscore ≤1).

Results

357 subjects were enrolled and 7 patients remain in safety follow-up. Treatment arms were generally comparable in age (mean 40.2 years) and gender distribution (58% male). 43% of subjects were anti-TNF naïve and the baseline Mayo score ranged from 8.1 (1.6) to 8.7 (1.7).

Remission and mucosal healing were significantly greater in the 22.5mg and 75mg dose groups vs placebo, while response was significantly greater for 22.5mg and 225mg groups vs placebo.

Conclusion

The primary endpoint of the study was met, with the strongest signal derived from every 4-weeks doses of 22.5-75 mg. PF appears to be well-tolerated and not associated with increased rate of infection.