OR-812: Pioneering Treatment for Inflammatory Bowel Disease (IBD)

Inflammatory Bowel Disease (IBD), including Crohn’s disease and ulcerative colitis, presents a significant treatment challenge for patients and their healthcare professionals, with long-term remission rates approaching 50% for existing drugs. This underscores a critical need for novel therapeutic approaches.

At the heart of IBD’s complex pathology is regulation of gut inflammation by retinoic acid receptor-α (RARα). Orphagen’s OR-812, a potent and selective antagonist of RARα, prevents the induction of key gut-homing receptors, CCR9 and α4β7, during T cell activation or inflammation.

OR-812 suppresses inflammatory T cell migration and intestinal damage in mouse models of colitis and has a potential safety margin of 30-fold based on a two-week non-GLP mouse safety study.

Current therapies and those in late-stage development for IBD hit a relatively small number of targets. Current targets include: TNFa, the cytokines IL-12 and IL-23, the integrin α4β7, the JAK1 kinase, and the sphingosine-1-phsophate (S1P) receptors. Major new targets in the pipeline are the cytokine TL1A and the JAK-related kinase Tyk2.

It is well known that gut-associated dendritic cells activate Vitamin A to retinoic acid, and the retinoic acid marks T cells for migration to the intestinal lining by inducing the expression of the gut homing markers CCR9 and α4β7. The target of retinoic acid in T cells is RARa, and OR-812, a highly selective antagonist of this nuclear receptor, blocks induction of the homing markers both in mouse studies and in human T cells.

Therefore, OR-812 is a candidate for a novel class of oral drug for treatment of IBD. OR-812 has potential as both a single agent and as a new component of combination therapy.