A Randomized Controlled Trial of a Humanized á4â7 Antibody in Ulcerative Colitis
Brian Feagan, Gordon Greenberg, Gary Wild, John McDonald, Richard Fedorak, Pierre Pare, Kei Kishimoto, Jose-Carlos Guitterez-Ramos, Julia Krop, Margaret Vandervoort.
[This is supposed to be a late-breaking abstract for the Digestive Disease Week, which is about to start. The plot thickens. Results appear to be favorable.
Now we need the help from Rick. What can this tell us about MLN in Crohn's (missed the primary endpoint) and Antegren for the same condition, if anything? It looks under all circumstances as if the pairing of MLNM/DNA will have to continue the development at least in UC. The source is btw a poster on ELN's Yahoo board who thought this was Antegren].
Blockade of leukocyte–vascular endothelium interactions is a promising treatment strategy for IBD. The T cell integrin, á4â7, mediates selective recruitment of lymphocytes to the gut. Its ligand, MadCaM, is almost exclusively expressed in the intestinal vascular endothelium. We evaluated the efficacy, PK/PD, and safety of MLN-02, a humanized monoclonal antibody to á4â7, in patients with moderately active UC. Methods: 181 patients were enrolled in this multi-center, double blind, placebo controlled trial. Patients had a minimum Ulcerative Colitis Clinical Score (UCCS) of 5, and endoscopically active UC (minimum Grade II changes on Modified Baron Score [MBS], minimum extent 25 cm). Patients remained on a stable dose of 5-ASA if received prior to screening. Participants were randomized to receive either two intravenous doses of MLN-02 (0.5 or 2.0 mg/kg) or placebo at Days 1 and 29. UCCS and sigmoidoscopic ratings were evaluated at baseline and at 29 and 43 days after randomization. Clinical remission, the primary efficacy measure, was defined as a UCCS score of 0 or 1 and an MBS of 0 or 1 with no blood in the stool, on day 43. Results: The mean age of the participants was 41 and 54 % were male. 83% of patients were receiving 5-ASA, the median USSC score was 7, and the median MBS was 3. Remission rates on day 43 were 33%, 34%, and 15%, for the 0.5, 2.0 mg/kg and placebo groups respectively (p=0.03). 29% of patients receiving 0.5 mg/kg and 14% receiving 2.0 mg/kg had an MBS of 0 (normal mucosa) compared with 8% of those who received placebo (p=0.01). The corresponding proportion of patients who experienced a decrease of . 3 UCCS points from the baseline value was 66%, 57%, and 33% respectively (p= 0 .001). Serious adverse events, mostly UC related, occurred in 8% of those who received MLN-02 vs 5% for placebo. An infusion reaction occurred in one MLN-02 treated patient (0.8%) who developed mild angioedema. Conclusion: In this study, MLN-02 appears to be a generally well-tolerated and effective therapy for active UC and warrants further investigation. |
