861 Safety and Efficacy of Pf-00547,659, a Fully Human Anti-MAdCAM Antibody, in Ulcerative Colitis. Results of a First in Human Study

INTRODUCTION: MAdCAM is predominantly expressed on high endothelial venules of intestinal lymphoid tissue and expression is increased at sites of gastrointestinal inflammation. MAdCAM binds a4b7 integrin on lymphocytes facilitating their migration to the inflamed intestinal tract. PF-00547,659, a fully human anti-MAdCAM IgG2 antibody blocksMAdCAM/ a4b7 dependent lymphocyte recruitment to the gut and is therefore anticipated to reduce gut inflammation and mucosal damage. AIM: To evaluate efficacy, safety and pharmacokinetics of PF-00547,659 in patients with active UC (Mayo score > 6). METHODS: In this doubleblind placebo-controlled study a total of 80 patients were included, of whom 30 in 6 singledose (SD) cohorts (doses from 0.03 to 10 mg/kg IV and 3 mg/kg SC or placebo) and 50 in 5 multiple-dose (MD) cohorts (doses from 0.1 to 3.0 mg/kg IV and 0.3 to 1 mg/kg SC or placebo every 4-weeks). Efficacy was measured at week 4 in SD cohorts and at week 4 and week 12 in MD cohorts. Safety information was collected during the double-blind treatment and the follow-up period. Patients were followed-up until the drug plasma levels were below the detection level. RESULTS: Safety: PF-547,659 was well tolerated with an adverse event (AE)profile similar to placebo. There were no safety concerns from laboratory tests, BP and ECG measurement. No anti-drug antibodies were detected. Efficacy: Results from an interim analysis performed after all patients completed Week 12 in the MD cohorts are presented. CONCLUSION: PF-00547,659 was well tolerated with AE profile similar to placebo. Within the limitations of a small sample size, the compound performed better than placebo in clinical as well as endoscopic endpoints and biomarker levels. No dose-response was observed.