HBI-002 to Prevent Vaso-Occlusive Crises in Sickle Cell Disease

PROJECT SUMMARY/ABSTRACT The goal of the proposed project is to evaluate the clinical potential of HBI-002, a novel oral low dose carbon monoxide (CO) drug product, that enables the use of low dose CO to prevent Vaso-Occlusive Crises (VOCs) in Sickle Cell Disease (SCD). Numerous studies, both preclinical and clinical, demonstrate that CO has dual mechanisms of action including anti-sickling and anti-inflammatory processes. We have produced preclinical efficacy data in two transgenic SCD mouse models with HBI-002 similar to those reported in three studies using four different transgenic SCD mouse models and other modes of low dose CO administration, all of which demonstrate that low doses of CO are a promising approach to limiting vascular stasis, reducing hemolysis, and down-regulating inflammatory processes. In addition, proof of concept clinical efficacy studies in SCD demonstrated improvements in SCD efficacy biomarkers, and epidemiological evidence also supports the therapeutic potential of low dose CO in SCD. These studies provide compelling support for a potential beneficial role for HBI-002 in limiting SCD morbidity. The safety and tolerability of low dose CO has been demonstrated by others in 21 successfully completed Phase 1 and Phase 2 clinical studies in various indications, including two Phase 1b studies in SCD patients, using a variety of forms of CO administration. Moreover, there are ongoing clinical studies with low dose CO, using various forms of CO administration, including a Phase 1 study with HBI-002. The absence of toxicity of CO at low levels of carboxy-hemoglobin (COHb) has been well defined in the literature, indicating the potential for a wide safety margin and appropriate benefit:risk ratio at the COHb levels in the studies described above, which are the target COHb levels being considered for SCD patients with HBI-002. However, barriers to chronic dosing of CO with prior therapeutic administrative approaches have prevented the development of a low dose CO therapeutic used chronically for the prevention of VOCs. To date, inhaled CO gas (iCO) and CO bound to carrier molecules such as hemoglobin (CORMs, also termed CO prodrugs) have been the modalities of choice 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 low dose CO drug product, enables the chronic use of low dose CO in SCD and is being developed for the prevention of VOCs in SCD. The administration of a low, defined dose of CO delivered by oral HBI-002 enables the further development of low dose CO as a therapeutic while obviating the problems associated with iCO or CORMs. Preclinical studies with orally administered HBI-002 have demonstrated proof- of-concept efficacy, safety, and bioavailability. These preclinical data strongly point to efficacy in preventing vaso- occlusion in SCD. In this application, we combine the expertise of Hillhurst with its innovative technology and propose to build on compelling data to study the proof of concept efficacy, safety, and pharmacokinetics of HBI-002 in SCD subjects.