Orphagen Pharmaceuticals Receives $1.7 Million NIH Funding to Develop Novel Oral Therapeutic for Inflammatory Bowel Disease
Orphagen Pharmaceuticals, a biotech company specializing in the discovery and development of small molecule ligands that modulate orphan or unexplored members of the nuclear receptor family, has recently received a significant funding award. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has granted the company up to $1.7 million through the Small Business Innovation Research (SBIR) program. This funding will support the preclinical development of OR-812, a selective nuclear receptor antagonist, as a novel oral therapeutic for treating ulcerative colitis and Crohn’s disease, two forms of inflammatory bowel disease (IBD).
Inflammatory bowel disease is a lifelong, debilitating inflammatory condition of the gut, where modulation of the immune system is the major therapeutic strategy. Despite the development of novel therapies, including monoclonal antibodies to TNFα and IL-12/IL-23, and inhibitors of T cell gut homing such as vedolizumab and ozanimod, less than half of patients experience a sustained therapeutic benefit. This highlights the need for new and innovative treatments.
Orphagen’s research into unexplored members of the nuclear receptor family led to the identification of retinoic acid receptor alpha (RARα) as a promising target for inhibiting autoimmune inflammation of the intestinal mucosa. RARα plays a central role in the intestinal immune response and regulates the induction of homing markers that drive activated T cells to migrate to the intestinal mucosa. In vivo pharmacological studies at Orphagen have shown that RARα antagonists can block the induction of the gut-homing integrin α4β7, the target for vedolizumab, a major inflammatory bowel disease drug, with very high potency. Additionally, the induction of a second important gut-homing receptor, CCR9, is also blocked by OR-812 during T-cell activation.
The potential for efficacy in this drug class was supported by studies carried out in the laboratory of Professor Casey Weaver, the Leonard H. Robinson Endowed Chair in Pathology at the University of Alabama, Birmingham, a noted pioneer in mucosal immunology. His group demonstrated that an RARα antagonist can inhibit α4β7 expression and cause a significant reduction in the accumulation of inflammatory T cells in the lamina propria of the colon of Citrobacter rodentium-infected mice, a model of gut mucosal inflammation resembling IBD. Furthermore, OR-812 markedly suppressed gut mucosal inflammation and erosion in a T cell transfer model of colitis in mice, which is known to respond to most major classes of drugs for IBD.
Preliminary safety studies carried out at Orphagen are consistent with a robust safety margin for OR-812. Dr. Scott Thacher, Ph.D., CEO of Orphagen, emphasized the significance of this funding, stating, “This award recognizes the innovative preclinical work that Orphagen has done to characterize retinoic acid receptor alpha (RARα) as a target for inhibiting autoimmune inflammation of the intestinal mucosa. We’ll use this funding from the NIDDK to further evaluate the properties of our lead compound, OR-812, a potent and selective RARα antagonist with promising preclinical efficacy, safety, and pharmacokinetics for the treatment of IBD.”
Dr. Thacher also highlighted the potential of OR-812 to offer IBD patients a novel oral medicine with a differentiated mechanism of action from current therapies, noting, “Innovative therapeutics for autoimmune diseases of the intestinal mucosa have largely been dominated by injectable drugs. Our small molecule, OR-812, has the potential to offer IBD patients a novel oral medicine with a differentiated mechanism of action from current therapies.”
Professor Casey Weaver underscored the global need for new therapies, stating, “Globally, there is a pressing need for new therapies as the incidence of IBD continues to increase. Selectively blocking the action of retinoic acid through RARα is clearly one promising approach.”
This funding award marks a significant step forward in the development of OR-812, offering hope for new and effective treatments for patients suffering from inflammatory bowel disease.