A novel, pleiotropic oral drug class that inhibits gut migration of activated T cells

ABSTRACT Inflammatory bowel disease (IBD) is a lifelong inflammatory condition of the gut in which modulation of the immune system is the major therapeutic strategy. However, despite development of novel therapies, including antibodies to TNF and IL-12/IL-23p40, and inhibitors of T cell gut homing such as vedolizumab and ozanimod,

only 30-50% of patients experience a sustained therapeutic benefit. Orphagen is developing first-in-class specific small molecule antagonists to the retinoic acid receptor-alpha (RAR) that regulate the induction of both the gut homing integrin 47 and a second gut homing receptor, CCR9, during T cell activation. Our preliminary data

confirm that inhibition of retinoic acid signaling through RAR is a promising therapeutic approach to IBD. First, we showed that a probe RAR antagonist significantly improved gut histology in a mouse naïve T cell transfer colitis model and inhibited 47 expression and accumulation of inflammatory T cells in the colonic lamina

propria of Citrobacter rodentium-infected mice. Second, with a more specific RAR lead antagonist, OR-812, an orally bioavailable new chemical entity designed at Orphagen, we showed in a mouse model of oral antigen stimulation that the induction of 47 and CCR9 in activated T cells is almost completely blocked at very low

doses,