The TOSCA Study of Immune Surveillance in Cerebrospinal Fluid (CSF) in Crohnʼs Disease (CD) Patients Treated with Anti-MAdCAM Monoclonal Antibody (MAb) PF-00547659: Cohort 1 Clinical Results (2013)

Purpose: Studies with natalizumab (N) showed that inhibition of the α4β7 integrin-MAdCAM interaction resulted in relevant and durable improvement in Crohn's disease (CD) activity. However, N is a non-selective agent that also inhibits the α4β1-VCAM interaction in the central nervous system (CNS), which may be the plausible cause of progressive multifocal leukoencephalopathy (PML): a debilitating, often fatal viral infection that results from impaired CNS immune surveillance. PF-00547659 is a fully human monoclonal antibody that binds to gut-specific MAdCAM with no affinity for VCAM. As MAdCAM is not found in the CNS, this strategy should be gut-selective and eliminate the risk of PML. Methods: TOSCA is an open-label, clinical trial to study the effects of PF-00547659 (PF) on CNS immune surveillance. There are two sequential cohorts: Cohort 1, to establish the baseline cellular composition of CSF prior to treatment with PF, and Cohort 2, to investigate the effects of an induction course of high-dose PF on those cell groups. We present the clinical results of induction therapy with PF on CD activity in Cohort 1. Adults with active CD (hsCRP >5 mg/mL and HBI ≧8, or active lesions on endoscopy, or evidence of active CD on imaging), who had either failure or intolerance to both an immunosuppressive drug (azathioprine, 6-mercaptopurine or methotrexate) and an anti-TNF agent, were enrolled. Subjects underwent two lumbar punctures, and then began treatment with PF, 225 mg SQ every 4 weeks. The final visit was at week 12, when responders were permitted into an open-label extension study. Non-responders continued for 6 months' follow-up. Results: Ten subjects entered -- seven without stoma, so HBI was measured. Baseline characteristics: mean (SD) of age (y) 43.4 (16.9), median (min, max) of CD duration (y) 13.5 (3.5, 23.9), and mean (SD) of HBI 8.4 (2.8). At week 8, mean (SD) HBI had declined to 2.1 (2.0), and 6/7 (85.7%) subjects met criteria for clinical remission (HBI<5), while at week 12, mean (SD) of HBI was 2.0 (1.4) and 6/7(85.7%) subjects were in remission. One subject had treatment emergent serious adverse events of parastomal enterocutaneous abscess and fatigue. Both events resolved in 9 days. No pattern of AEs or laboratory abnormalities was seen. Conclusion: No definitive efficacy or safety conclusion can be drawn from this small, open-label study. However, we observed in CD subjects with significant symptoms and failure or intolerance to all other approved agents, clinically relevant improvement of disease activity without significant safety concerns. Disclosure - Fabio Cataldi Employee, of Pfizer inc. Kenneth Gorelick Employee of Pfizer inc Sunday Rivers Employee of Pfizer inc Mina Hassan-Zahraee Employee of Pfizer inc John Cheng Employee of Pfizer inc Bo Jin Employee of Pfizer inc Jenny Yanhua.Zhang Employee of Pfizer inc William Sandborn Consultant Pfizer Walter Reinisch Consultant Pfizer Geert D'Haens Consultant Pfizer Andre Van Gossum None Richard Ransohoff None Olaf Stuve None. This research was supported by an industry grant from Pfizer Inc.