Localised Delivery of Macromolecules to the Large Intestine: Translation to Clinical Trials

Oral administration of macromolecules aimed at systemic delivery has been at the forefront of pharmaceutical research for over 50 years. Yet, in terms of clinical translation for systemic delivery, output is limited to five US Food and Drug Administration (FDA)-approved oral peptide products to date, such are the hurdles. Somewhat neglected by comparison but with potentially lower delivery demands, the goal of local delivery of macromolecules directed mostly to the terminal ileum and colon to treat inflammatory bowel conditions has led to a range of macromolecules including gut-restricted peptides, fusion proteins, enzymes, antibodies, and antisense oligonucleotides that have reached clinical trials. While some of these trials reached primary endpoints, others are at early clinical stages, but it is likely that at least a few approvable products will emerge to supplement the current cohort of parenterally administered macromolecules and oral small molecules. The outstanding successes to date are the FDA approvals of two gut-restricted guanylate cyclase C-activating peptides to treat irritable bowel syndrome (constipated). Over-expressed targets for macromolecules in the gut wall of inflammatory bowel disease patients include α₄β₇ integrin, TNF-α, CD-3, ICAM-1, and SMAD-7, while reduced responses to IL-10 and melanocortin offer opportunities for macromolecular agonists. In this Leading Article, a landscape of locally delivered macromolecules to access the gut that have recently reached clinical trials is provided.