Intestinal permeability as a clinical surrogate endpoint in the development of future Crohn's disease therapies

Abstract

Inflammatory bowel disease (IBD) including Ulcerative colitis (UC) and Crohn's disease (CD) is a major cause of gastrointestinal pathology in children and adolescents. Intestinal hyper-permeability plays a critical role in the etiology of pediatric CD by affecting the penetration of pathogens, toxic compounds and macromolecules; it also plays a central role in pharmaceutical product development. The mechanisms of barrier function and defects in permeability have great potential for guiding the development of novel drugs for treatment of IBD. Intestinal permeability is typically measured with the mannitol and lactulose tests in vivo; the results are expressed as the permeability index. The sensitivity and specificity of these tests are superior to other currently used surrogate markers in current CD clinical trials. However, the measurement of intestinal permeability has not been listed as a clinical endpoint. Somatropin (Growth Hormone) and Infliximab (anti-TNFalpha) have been used to treat pediatric CD. These agents significantly improve the inflammation in the GI tract and the imbalance of electrolytes in animals with colitis and CD patients by decreasing intestinal hyperpermeability. Herein, we discuss the feasibility of using intestinal permeability as an endpoint in the clinical trials of CD by current investigations and relevant patents.