Biotherapy making use of monoclonal antibodies (mAb) has demonstrated its efficacy over the past several years in treatment of numerous pathologies, and especially inflammatory bowel diseases (IBD). The only currently used strategy in treatment of Crohn’s disease (CD) and ulcerative colitis (UC) is based on neutralizing tumor necrosis factor (TNF). During the course of disease, this molecule is abundantly produced in the intestine and actively participates in development of the inflammatory reaction causing digestive tube lesions. Several types of Ab of differing conceptions, all of which neutralize TNF, are currently on the market. Infliximab (Remicade) and adalimumab (Humira) are authorized for treatment of CD, while only infliximab is authorized for UC. Although adalimumab was conceived more recently and normally would have fewer undesirable effects, its efficacy in treatment of UC had not previously been tested. This has now been done with the publication of the first clinical double-blind trial compared to a placebo, in the journal GUT, January 2011. Results of that study confirm, first of all, that adalimumab treatment is well tolerated by patients. When compared to results obtained with infliximab during the course of treatment for UC, however, it would appear that adalimumab is not as effective in inducing remission (at 8 weeks). Analysis of results by subgroups of patients nonetheless showed that adalimumab seems to work in patients with active disease which is resistant to classical treatments. On the heels of these results, various critical points have been raised pertaining to the dose used and the duration of treatment. A forthcoming publication of a similar study comprising follow-up of patients over a longer period (52 weeks) should enable evaluation of the relevance of adalimumab use in treatment of UC. Although not totally convincing, the results are nonetheless encouraging, but further in-depth studies are needed.
A second strategy, also using mAb, does not consist of neutralizing intestinal inflammatory molecules, but rather, of acting at an earlier stage by preventing the immune cells that cause synthesis of such molecules from attaining the digestive tube. At the beginning of the 2000s, this strategy proved promising in treatment of CD using a mAb called natalizumab (Tysabri). Unfortunately, that molecule was momentarily taken off the European market for treatment of IBD after severe secondary effects upon the central nervous system were noted. The basic problem with this approach lies in identifying the right targets for neutralization so as to selectively prevent immune cells from reaching the intestine of patients with IBD, while at the same time allowing these immune cells to continue to perform their role in other organs. It was with this principle in mind that an Ab was developed which bears the experimental name “PF-00547.659”. Its target is a molecule (called MadCAMP) primarily expressed in blood vessels that irrigate the intestine. This molecule is essential for enabling passage of blood immune cells toward intestinal tissues. Its neutralization would thus prevent the mechanism of immune cell translocation, thereby provoking a decrease in the intestinal inflammatory response. The first clinical trial testing the harmlessness and efficacy of this Ab in patients with UC was published in the February issue of Gut. In general, the treatment seemed to be well tolerated by patients. Despite some clinical and endoscopic improvement in treated patients compared to patients given a placebo, no statistically significant clinical benefits could be demonstrated for PF-00547.659. These initial results thus currently appear somewhat disappointing in light of what seemed to be a promising therapeutic strategy. Nonetheless, the study lays the groundwork for larger clinical investigations, necessary for determining the potential role of PF-00547.659 in treatment of UC.
By Benjamin Bertin
References
Walter Reinisch, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut Online First, January 5, 2011
Severine Vermeire, et al. The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. Gut Online First, February 11, 2011
