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. There is an urgent need for the development of additional approaches to prevent and treat DR, 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 animal models of DR. The objective of the proposed project is to advance HBI-002, a novel oral low dose CO drug product, into translationally relevant animal models of diabetic retinopathy in preparation for a future clinical trial. The clinical safety and tolerability of CO at levels up to 13.9% peak COHb has been demonstrated in 22 Phase 1 and Phase 2 clinical trials (including in subarachnoid hemorrhage and acute respiratory distress syndrome) using a variety of forms of CO administration., Dosing and follow up in a Phase 1 study in healthy adult subjects with the oral low dose CO drug product HBI-002 have been completed demonstrating safety and appropriate pharmacokinetics as measured by Cmax, though final data analysis is ongoing. The absence of toxicity of CO at low COHb levels has been well demonstrated in the literature, providing supportive safety data for the COHb levels under consideration for the prevention of diabetic retinopathy. However, barriers to chronic dosing of CO with prior therapeutic administrative approaches have prevented the development of a CO therapeutic for chronic use, as would be the case in this indication. To date, inhaled CO gas (iCO) and CO bound to carrier molecules such as hemoglobin or released by organic molecules (CORMs, also termed CO prodrugs) have been the modalities of choice for administration of CO in the majority of studies. However, these other forms of low dose CO are not expected to be viable therapeutic options for chronic dosing 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 toxicity, stability, and CO release characteristics, all of which have proven to be substantial barriers to development. HBI-002, a novel oral CO drug product that enables the chronic use of low dose CO, is being developed for the treatment of diabetic retinopathy. The administration of a defined, low dose of CO delivered by oral administration of HBI-002 enables further development of low dose CO as a therapeutic while obviating the problems associated with iCO or CORMs. A Phase 1 clinical study with HBI-002 has demonstrated appropriate safety and pharmacokinetics as measured by Cmax. Initial SBIR/STTR Phase 1 grant-supported preclinical studies with orally administered HBI-002 have demonstrated proof-of-concept efficacy and safety. These preclinical data strongly point to efficacy in treating DR. In this application, we combine the expertise of Hillhurst’s experienced team with its innovative technology and propose to build on the compelling preclinical data to study the proof of concept efficacy in translationally relevant models of DR.