Orphagen Pharmaceuticals Gets NIH Grant for New IBD Drug

Orphagen Pharmaceuticals, a biotech firm focused on developing small molecule ligands that target lesser-known nuclear receptors, has received a grant of up to $1.7 million from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This funding, provided through the Small Business Innovation Research (SBIR) program, will aid in the preclinical development of OR-812. OR-812 is a selective nuclear receptor antagonist designed as an innovative oral treatment for ulcerative colitis and Crohn’s disease, both of which are forms of inflammatory bowel disease (IBD).

Scott Thacher, Ph.D., CEO of Orphagen, expressed that this award acknowledges the company's groundbreaking preclinical work regarding retinoic acid receptor alpha (RARα) as a target for reducing autoimmune inflammation in the gut. The NIDDK funding will allow further examination of OR-812, a potent and selective RARα antagonist that has shown promising preclinical efficacy, safety, and pharmacokinetics for treating IBD.

Thacher highlighted that current treatments for autoimmune diseases affecting the intestinal mucosa are mainly injectable drugs. He emphasized that OR-812 offers a novel oral alternative with a unique mechanism distinct from existing therapies, potentially benefiting IBD patients.

IBD affects up to two million Americans, causing chronic inflammation in the digestive tract and requiring modulation of the immune system as a key treatment strategy. Despite advancements in treatments such as monoclonal antibodies targeting TNFα and IL-12/IL-23 and inhibitors like vedolizumab and ozanimod, fewer than 50% of patients achieve long-term therapeutic success.

Orphagen's research leading to this grant stems from its exploration of under-investigated nuclear receptors, which have historically yielded significant drugs for cancer, metabolic diseases, and inflammation. RARα, one of these targets, plays a crucial role in the intestinal immune response and controls the movement of activated T cells to the gut lining. Studies at Orphagen have demonstrated that RARα antagonists can effectively block highly potent targets like the gut homing integrin α4β7, which vedolizumab targets, and the gut homing receptor CCR9 during T cell activation.

Research led by Professor Casey Weaver from the University of Alabama, Birmingham, supports the potential efficacy of this drug class. His laboratory results indicate that an RARα antagonist can inhibit α4β7 expression and significantly reduce inflammatory T cells in the colon in a mouse model of IBD. Moreover, OR-812 was shown to considerably reduce gut inflammation and erosion in another mouse model of colitis, which typically responds to most major IBD treatments. Preliminary safety evaluations at Orphagen suggest that OR-812 has a strong safety profile.

Professor Weaver remarked on the growing global need for new IBD treatments, noting that selectively inhibiting retinoic acid via RARα is a promising strategy.

Inflammatory bowel disease (IBD) encompasses conditions like Crohn’s disease (CD) and ulcerative colitis (UC), characterized by chronic inflammation of the gastrointestinal tract. UC is a chronic condition affecting the mucosa of the large intestine, leading to continuous inflammation along the colon's innermost lining. It causes debilitating flares several times a year for many patients, affecting their quality of life. Some patients recover after a single episode, while others may require frequent hospitalizations and surgeries. In contrast, CD can impact any part of the intestinal tract and affects all intestinal wall layers, with localized inflammation throughout the GI tract.

Orphagen Pharmaceuticals is dedicated to harnessing the potential of orphan nuclear receptors. Their scientists have identified small molecule ligands for these largely untapped drug targets, exploring lead molecules in autoimmune diseases and oncology. Orphagen's success includes partnering its first program for ROR-gamma antagonists in autoimmune disease with a mid-sized pharmaceutical company. Financial support from partnerships and non-dilutive sources, such as federal grants, has propelled Orphagen’s proprietary drug discovery programs, including OR-812 for IBD.