Use of Biomarkers

There are many ways in which biomarkers can be usefully employed during the clinical development of new treatments for IBD.34 They can be used to select patients for study or to increase the homogeneity of the cohort. Clinical indices are a crude instrument for patient selection; a patient cohort defined clinically as having mild disease may show great variability in levels of intestinal inflammation. A fecal biomarker of intestinal inflammation, such as the neutrophil marker calprotectin, may help concentrate the cohort with regard to those patients with active intestinal inflammation. Biomarkers can also be used to define an acute response to drug treatment. For example, treatment of patients with UC or CD with either the anti-TNF-a antibodies CDP-571 or infliximab, or the anti-a4 integrin antibody natalizumab, has been shown to reduce circulating C-reactive protein (CRP) levels, sometimes rapidly. Of course, the clinical significance of these acute changes needs to be carefully understood and is not a replacement for improvements in disease activity assessments.

Biomarkers can also be used to confirm the mechanistic activity of an investigational drug and even identify pharmacologically active doses for further study. For example, acute administration of natalizumab has been shown to evoke a rise in circulating levels of T lymphocytes in both CD and UC patients.36'37 These data confirm that natalizumab can inhibit the homing of these cells to the inflamed GI tract, increasing the levels in the peripheral circulation. Such mechanistic biomarkers do not need to be limited to analysis of blood. Biopsy material can provide a useful matrix in which to demonstrate the activity of an investigational drug using biomarkers of activity. For instance, treatment with infliximab has been shown to downregulate markers of mucosal inflammation from biopsies of CD patients, when studied ex vivo.38

The level of certain soluble biomarkers may also be useful in predicting therapeutic response. A number of clinical trials, with agents that target TNF-a, have demonstrated that the most significant improvements in clinical disease activity appear to be in those patients with elevations in CRP. These observations were first made in clinical trials with infliximab,39 but have since been replicated with CDP-571.35 Based on these data, threshold values for CRP have been proposed as predictors of therapeutic response.

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