HBI-002 to Treat Ulcerative Colitis

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PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from Ulcerative Colitis (UC), which is estimated to impact approximately one million adults in the United States, leading to morbidity, heightened risk of cancer, and mortality. In multiple preclinical studies, we and others have defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in UC, including in simultaneously reducing inflammation, promoting tissue repair, and limiting pathogenic bacterial infection. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable chronic therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. The objective of the proposed project is to investigate HBI-002, a novel oral or rectally administered CO drug product that was developed to enable the chronic use of CO in UC. The safety and tolerability of CO has been demonstrated in five successful Phase 1 clinical studies supported by well-defined preclinical data sets that led to approval by the FDA for human testing. HBI-002 comprises an oral formulation containing precise amounts of CO that are not bound to a carrier molecule (i.e. not a CORM) and efficiently absorbed from the gastrointestinal tract. Preclinical in vivo pharmacokinetic and pharmacodynamic studies demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of UC as has been shown with other forms of CO and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in IBD, our central hypothesis that will be tested in this project is: HBI-002 will modulate the immune response to regulate inflammation, improve survival, and promote healing in UC mouse models.