Retinoid antagonists for inflammatory BOWEL disease and Gut inflammation
We have identified potent and selective antagonists of retinoic acid for treatment of inflammatory bowel disease (IBD) and/or other forms of gut inflammation such as GVHD (graft versus host disease). Our lead compounds have excellent oral bioavailability in mice, and they potently inhibit the induction of expression of two key gut-homing receptors, CCR9 and ∝4β7, during inflammatory T cell activation in gut-associated lymphatic tissue. The compounds appear to be well-tolerated, and we are currently evaluating our proprietary retinoid antagonists in animal models of gut inflammation and colitis.
The cell surface molecules, CCR9 and ∝4β7, each have a critical role in the migration of activated T cells to the intestine. Blockage of ∝4β7 by the monoclonal antibody vedolizumab (Entyvio®) is an effective treatment for IBD. Our clinical hypothesis is that selective inhibition of one retinoic acid receptor (RAR) subtype will lead to exquisitely sensitive blockage of the induction of both gut-homing receptors and marked reduction of gut inflammation in IBD patients.
IBD is a major autoimmune disease market. A new oral medication, such as a retinoid antagonist, would be expected to have wide application. IBD patients are confronted by the fact that long-term remission by any single drug is less than 50%. The clinical community unambiguously recognizes the need for new therapeutic modalities.
Orphagen is a first mover for the retinoid antagonist approach to treatment of IBD.