HBI-002 to Treat Diabetic Retinopathy

PROJECT SUMMARY Diabetic retinopathy (DR) is a neurovascular complication of diabetes mellitus and the leading cause of blindness in working age adults and elderly, affecting approximately 4.2 million diabetes patients in the US, of which 655,000 have vision-threatening DR. There is an urgent need for the development of additional approaches to prevent and treat diabetic retinopathy, as the current therapeutic interventions have limited efficacy and substantial drawbacks. In multiple preclinical studies, we and others have demonstrated the cytoprotective properties of low dose carbon monoxide (CO) in various disease states, including in ischemia- associated diseases such as DR 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 carried out to study the potential benefit of low dose CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable 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 CO drug product, to prevent and treat DR. The safety and tolerability of CO has been demonstrated in 25 successful Phase 1 and 2 clinical studies by others in other indications 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). Preclinical in vivo pharmacokinetic 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 DR and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in protecting against ischemia-associated and ophthalmologic disease, our central hypothesis that will be tested in this project is: HBI-002 will prevent DR by reducing oxidative stress and inflammation.