Brian W Behm1, Stephen J Bickston. 1. UVA Digestive Health Center of Excellence, University of Virginia Health Systems, 800708 UVAHS, Charlottesville, VA 22908, USA.
Abstract
BACKGROUND: Cellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. MLN-02, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that MLN-02 may be a useful therapy for ulcerative colitis. This systematic review summarizes the current evidence on the use of MLN-02 for induction of remission in ulcerative colitis. OBJECTIVES: To determine the efficacy and safety of MLN-02 for induction of remission in ulcerative colitis. SEARCH STRATEGY: A computer-assisted search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed to identify relevant publications. References from recent reviews and published articles were searched to identify additional citations. Manual searches to identify key conference abstracts were performed. Unpublished data from on-going trials were identified by correspondence with authors and experts in the field and from the manufacturer of MLN-02. SELECTION CRITERIA: Randomized controlled trials comparing MLN-02 to placebo or a control therapy for the induction of remission in ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers performed data extraction and assessment of the methodological quality of each trial. Data were analyzed using Review Manager (RevMan 4.2). MAIN RESULTS: One study satisfied the inclusion criteria for this review. In this study, MLN-02 was found to be effective for induction of clinical response (RR = 1.78, 95% CI 1.22 to 2.60) and remission (RR = 2.25, 95% CI 1.17 to 4.36) in patients with moderately severe ulcerative colitis. Patients receiving MLN-02 had higher IBDQ scores than patients receiving placebo. There was a trend toward increased endoscopic remission with MLN-02 relative to placebo, although this difference was not statistically significant (total MLN-02 20% versus placebo 8%; P = 0.05; RR = 2.46, 95% CI 0.98 to 6.15). Adverse events occurred in a similar proportion of patients treated with MLN-02 compared to placebo (RR = 1.60, 95% CI 0.67 to 3.83). Neutralizing antibodies were found in a significant proportion of patients receiving MLN-02, and in the group of patients with high antibody titers clinical remission rates were no different than placebo. No opportunistic infections were reported. AUTHORS' CONCLUSIONS: Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.
BACKGROUND: Cellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. MLN-02, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that MLN-02 may be a useful therapy for ulcerative colitis. This systematic review summarizes the current evidence on the use of MLN-02 for induction of remission in ulcerative colitis. OBJECTIVES: To determine the efficacy and safety of MLN-02 for induction of remission in ulcerative colitis. SEARCH STRATEGY: A computer-assisted search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed to identify relevant publications. References from recent reviews and published articles were searched to identify additional citations. Manual searches to identify key conference abstracts were performed. Unpublished data from on-going trials were identified by correspondence with authors and experts in the field and from the manufacturer of MLN-02. SELECTION CRITERIA: Randomized controlled trials comparing MLN-02 to placebo or a control therapy for the induction of remission in ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two independent reviewers performed data extraction and assessment of the methodological quality of each trial. Data were analyzed using Review Manager (RevMan 4.2). MAIN RESULTS: One study satisfied the inclusion criteria for this review. In this study, MLN-02 was found to be effective for induction of clinical response (RR = 1.78, 95% CI 1.22 to 2.60) and remission (RR = 2.25, 95% CI 1.17 to 4.36) in patients with moderately severe ulcerative colitis. Patients receiving MLN-02 had higher IBDQ scores than patients receiving placebo. There was a trend toward increased endoscopic remission with MLN-02 relative to placebo, although this difference was not statistically significant (total MLN-02 20% versus placebo 8%; P = 0.05; RR = 2.46, 95% CI 0.98 to 6.15). Adverse events occurred in a similar proportion of patients treated with MLN-02 compared to placebo (RR = 1.60, 95% CI 0.67 to 3.83). Neutralizing antibodies were found in a significant proportion of patients receiving MLN-02, and in the group of patients with high antibody titers clinical remission rates were no different than placebo. No opportunistic infections were reported. AUTHORS' CONCLUSIONS: Data from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.