Efficacy and Safety of a Humanized α4β7 Antibody in Active Crohn's Disease (CD)
Brian G. Feagan, Gordon Greenberg, Gary Wild, John W. D. McDonald, Richard Fedorak, Pierre Pare, Kei Kishimoto, Jose-Carlos Gutierrez-Ramos, Julie Krop
[This is the MLN02 Crohn's abstract. It appears that they might have used too low a dose].
Selective blockade of leukocyte-vascular endothelium interactions is a promising strategy for the treatment of IBD. The α4β7 integrin is an adhesion molecule that mediates selective recruitment of lymphocytes to the gut. Its ligand, MadCaM, is almost exclusively expressed in the intestinal vascular endothelium. We evaluated the efficacy, pharmacokinetics, and safety of MLN-02, a humanized monoclonal antibody directed against α4β7 in patients with mild-moderately active CD. Methods: 185 patients were enrolled in a double-blind, placebo controlled, dose-finding trial. Eligible patients (CDAI > 220, receiving a stable dose of 5-ASA or antibiotics or no medical therapy for CD) were randomized to receive placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-02 administered intravenously on Days 1 and 29. Disease activity was assessed by CDAI score on Day 57 (remission = CDAI £150, response = CDAI decrease ³70 points). Pharmacokinetic and pharmacodynamic (saturation of α4β7 on peripheral blood lymphocytes- PBLs) assessments were obtained from a 30 patient subset. Results: Remission rates were: placebo- 20.7%, 0.5 mg/kg- 29.5% (placebo vs. 0.5 mg/kg p=0.30) and 2.0 mg/kg- 36.9% (placebo vs. 2.0 mg/kg p=0.04) whereas the corresponding response rates were 41.4%, 49.2% (placebo vs. 0.5mg/kg p=0.36), and 53.1% (placebo vs. 2.0 mg/kg p=0.14) Pharmacokinetic data indicated the antibody had a half-life of approximately 12 days. Pharmacodynamic data suggested that complete saturation of α4β7 was not achieved over the duration of treatment. Subgroup analysis showed that patients who obtained consistent and sustained saturation of α4β7 on PBLs were more likely to enter remission than those who did not. No important differences in adverse events were noted among the three treatment groups. Conclusion MLN-02, administered at 2 .0 mg/kg, is a biologically active therapy for the treatment of active CD. Future trials to evaluate higher doses of mln02 and the relation of higher doses to sustained saturation are under consideration. |
