Target Mediated Disposition (TMD) Model Based Dose Selection for Fixed SC Doses of Anti-MAdCAM-1 Monoclonal Antibody (PF-00547659) in Crohnʼs Disease

Abstract

Purpose: In inflammatory bowel disease (IBD), there is still a large unmet medical need despite the introduction of anti-TNFs and new mechanisms of action are needed particularly for patients who have failed other treatments. PF-00547659 is a fully human IgG2κ anti-human MAdCAM monoclonal antibody that binds to recombinant human MAdCAM to reduce lymphocyte homing to the gut and GI inflammation. Based upon the encouraging results of a phase IIa and pharmacokinetic (PK) study in ulcerative colitis (UC) (Vermiere S, Gut 2011), a large phase 2b study in Crohn's Disease (CD) was initiated. The PK properties of PF-00547659 are typical of those displayed by IgG2 monoclonal antibodies with target-mediated disposition exhibiting dose-dependent clearance and good SC bioavailability. The dose selection strategy for this CD study which desired fixed SC doses was based upon TMD Modeling in UC (Martin SW DDW 2009 W1042). Methods: The PK data from the UC study covering a wide range of IV and SC administered doses (0.01-10 mg/kg) provided sufficient information for mechanistic characterization of an antibody exhibiting nonlinear kinetics with high affinity for MAdCAM. The TMD model was used for simulation of 8 levels of fixed doses from 7.5 mg to 225 mg. The primary criteria for optimal doses was target suppression over 12 weeks. 500 monte-carlo simulations were performed including inter-subject and intra-subject variability. Results: Monthly SC doses of 75 mg provide greater than 95% target suppression over 12 weeks in 90% of subjects. Two additional doses of one half-log below (22.5 mg) and above (225 mg) were selected to provide information regarding the minimal and maximum effective suppression level necessary for efficacy in CD. The selected dose range has good separation in PK exposure, is within the range that was well tolerated and exhibited signs of clinical activity in UC (Figure).Figure: No Caption available.Conclusion: Based upon the simulation results, PF-00547659 SC monthly doses of 22.5 mg, 75 mg and 225 mg were selected for the phase 2b CD study. Doses above 22.5 mg SC inhibits > 90% of MAdCAM activity with the CI narrowing with increasing doses up to 225 mg SC which inhibits 99.8% of MAd-CAM activity. Disclosure: William Sandborn - Consultant Pfizer, Jason WIlliams - Pfizer Employee, Fabio Cataldi - Pfizer Employee, Gail Comer - Pfizer Employee. This research was supported by an industry grant from Pfizer.