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 47 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 47 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 47 and CCR9 in activated T cells is almost completely blocked at very low
doses, <0.4 mg/kg; thus, antagonism of RAR by OR-812 potently blocks the induction of two key gut homing
factors simultaneously. Third, OR-812 was well tolerated in a 14-day toxicity study in mice at 30 mg/kg following
significant systemic exposure, indicating a strong safety margin for this new drug class.
Our major objectives are to qualify OR-812 as a candidate for preclinical development, confirming efficacy in a
murine model of colitis, scaling up sufficient compound for safety studies, and executing an exploratory safety
study in a non-rodent species. In Aim 1, we evaluate the efficacy and potency of OR-812 in a mouse naïve T
cell transfer colitis model. In Aim 2, we develop improved methods for synthesis of OR-812 and ultimately
prepare a 500g batch for the non-rodent exploratory safety studies. In Aim 3, we identify a non-rodent species
for in vivo toxicology studies based on in vitro metabolism of OR-812 in comparison to human and confirm
adequate pharmacokinetics and bioavailability in the selected non-rodent species. In Aim 4, we conduct a 7-day
maximum tolerated dose (MTD) safety study in the non-rodent species and, based on this, conduct a 14-day
dose-range finding safety study in non-rodents with extensive assessment of target organ histopathology to
determine the No Observed Adverse Effect Level (NOAEL). The overall goal of these non-GLP safety studies is
to identify potential toxicities and confirm a preliminary safety margin for OR-812 based on the efficacious dose
in a mouse colitis model. These investigations, if satisfactory, would prepare OR-812 for its next stage: regulated
animal safety and chemical manufacturing studies appropriate for submission of an Investigational New Drug
(IND) application to the Food and Drug Administration (FDA) for a novel drug class for treatment of IBD.
