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

PROJECT SUMMARY ABSTRACT The goal of the proposed project is to evaluate the potential of the gasotransmitter carbon monoxideCOas an agent to prevent Vaso Occlusive CrisesVOCsin Sickle Cell DiseaseSCDusing a novel oral formulation of COHBINumerous studiesboth in vitro and in vivodemonstrate that CO has cytoprotective properties through anti oxidantanti inflammatory and anti apoptotic processesOur SBIR Phasesupported research has produced efficacy data similar to that reported in four studies using four different transgenic sickle cell mouse models that the heme oxygenaseCO pathway is key in SCDdemonstrating that low doses of CO are a novel approach to limiting vascular stasis and down regulating inflammatory processesThese studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCDThe safety and tolerability of CO has been demonstrated in eight successfully completed Phaseand Phasestudiesincluding two Phaseb studies in SCD patientsusing a variety of forms of CO administrationMoreoverthere are ten ongoing clinical studies with COusing various forms of CO administrationThe absence of toxicity of CO at low levels of carboxy hemoglobinCOHbhas been well defined in the literatureproviding supportive safety data for the targeted COHb levels being considered for SCD patients with HBIHBIa liquid formulation of COis being developed for the prevention of VOCs in SCDThe administration of a defined dose of CO delivered by oral administration of HBIenables the further development of CO as a therapeutic while obviating the problems associated with previously studied inhaled or intravenously administered carrier metal COincluding environmental safetydosing and compliance with chronic administrationinhaled COand carrier molecule toxicitystabilityand bioavailabilitycarrier metal bound COPharmacokinetic and pharmacodynamic studies in rodents with orally administered HBIhave demonstrated proof of concept feasibilitytolerabilityand bioavailabilityThe next step in development is to evaluate the mechanisticpreclinical toxicologicand clinical safetytolerabilitypharmacokineticand pharmacodynamic profile of HBIfor further development in sickle cell disease PROJECT NARRATIVE This application aims to evaluate whether HBIan oral carbon monoxideCOtherapeutichas an appropriate preclinical mechanistic and toxicologic profile for further development in sickle cell diseaseSCDand also to evaluate the clinical safetytolerabilitypharmacokinetic and pharmacodynamic profile of HBIin normal healthy volunteersIf successfulthis research will provide critical safetydosingmechanisticand clinical proof of concept information for advancing HBIinto a Phaseclinical trial in SCD patientswith the ultimate objective being to provide a therapeutic to reduce the incidence of vaso occlusive crises and inflammationthus reducing the incidence of disability and premature mortality in this devastating disease