Selective OXER1 Antagonist

We are developing a selective OXER1 antagonist aimed at treating eosinophilic driven diseases. OXER1 is a G protein-coupled receptor (GPCR) that is highly selective for 5-Oxo-eicosatetraenoic acid (5-oxo-ETE), a potent human eosinophil chemo-attractant. Migration of eosinophils to body sites including the skin, lungs and intestines is mediated by eosinophil chemo-attractants such as 5-oxo-ETE. Eosinophils are involved in acute and chronic inflammation and play an important role in a large number of allergic, inflammatory and proliferative diseases, such as skin, respiratory diseases and gastro-intestinal diseases, such as asthma, allergic rhinitis, chronic obstructive pulmonary disorder, atopic dermatitis, psoriasis and acne.

Eosinophils are major effector cells in the immune system. They are part of the innate immune system; traditionally recognized as the first line of defense against parasitic infections. Eosinophils themselves are key in mounting an appropriate immune response against pathogens. When activated, they release a cocktail of toxic proteins (to damage the parasite), along with cytokines to attract other immune cells. However, when eosinophils are chronically activated, these toxic proteins can also damage normal tissue and promote inflammation. Eosinophils are also recruited from the blood into the tissues at the sites of inflammation. They also play a role in tissue repair and resolution of inflammation.

Several biologics have been approved for the treatment of eosinophil-related diseases. Several of the approved monoclonal antibody treatments for severe eosinophilic asthma are currently in clinical trials aimed at expanding their indications to a broader range of eosinophilic disorders. Compared to approved biologics, small molecule OXE receptor antagonists may offer a promising and potentially more cost-effective option for treatment of eosinophilic-driven disorders.

The OXER1 antagonist program is based on the research of Dr. William Powell, Professor Emeritus in the Department of Medicine at McGill University, working in collaboration with Dr. Joshua Rokach of the Florida Institute of Technology which was in-licensed by the Company. Indole-based antagonists developed by Dr. Powell and Dr. Rokach, such as the lead molecule S-048, showed good in vitro potency, but drug-like properties were not optimal. 

Our objective is to develop a novel highly potent and selective first-in-class small molecule antagonist of OXER1, showing improved ADME/DMPK properties compared to existing preclinical indole-based antagonists, for the treatment of eosinophil-driven diseases.

There are currently no small molecule antagonists of OXER1 in clinical development.

Our OXER1 antagonist discovery program is currently at the preclinical stage. Our proprietary product candidates, CBI-6326 and CBI-7261, novel potent and selective OXER1 antagonists, were recently identified as a lead candidates for further development.

CBI-6326 has successfully completed non-GLP toxicology studies in rats and monkeys and the next stages of development will be focused on advancing process chemistry for the purpose of optimizing the synthesis of our lead compound and provide drug supply for possible clinical trial authorization-enabling studies and material for potential first-in-humans studies. The program is currently on hold pending financing and is expected to be 12-14 months from clinical trials once development activities fully resume.