Phase I Study of BB3 in Dialysis Patients

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DESCRIPTION (provided by applicant): Kidney transplantation is the most effective therapeutic modality for end-stage renal disease; it offers a better quality of life and a longer survival. Despite improvements in surgical and organ preservation techniques over the last decade, renal dysfunction and/or failure remains a significant problem following transplantation. Ischemia-reperfusion injury associated with the retrieval, storage and implantation of the kidney is a major alloantigen-independent contributor to primary non-function and delayed graft function. Moreover, marginal kidneys, i.e. kidneys from non-heart-beating donors, aged donors, or from donors with mild-to-moderate hypertension/diabetes, are highly susceptible to ischemia-reperfusion injury, and often fail transplantation. Increased use of such marginal kidneys because of demand further increases the incidence of graft dysfunction. Current pharmacotherapeutic strategies for attenuation of post-ischemic renal injury are frequently delivered in the form of additives to the organ preservation solution. Despite the deleterious and often delayed effects associated with normothermic reperfusion, few, if any, strategies target the kidney following transplantation. Hepatocyte growth factor (HGF), also know as scatter factor, is a renal trophic factor with potent organ protective and regenerative effects. However, its relative instability in solution, the difficulties associated with its administration in vivo, proteolysis of the delivered protein, and cost prohibitive production schemes lessen the feasibility and effectiveness of the use of SF/HGF in both the organ preservation solution and the renal recipient. Low molecular weight compounds that mimic the activity of SF/HGF could overcome these logistical difficulties and provide effective therapy. We have identified and developed BB3, a novel small molecule HGF mimetic. BB3 replicates the bioactivities of the native protein in every assay tested to date. In several in vivo studies, BB3 showed beneficial effects in renal transplantation. Supported by the SBIR program, a comprehensive panel of preclinical regulatory studies comprising genotoxicology, in vivo toxicology and safety pharmacology studies for BB3 has been completed. Following the filing of an IND, FDA has allowed the drug to proceed to the clinic. BB3 in a Phase I clinical trial with healthy volunteers has been completed. The current application proposed to conduct a Phase I clinical trial in hemodialysis patients to characterize the pharmacokinetic (PK) properties of BB3. The data from these two clinical studies form a solid basis for the Phase II study in renal transplantation. PUBLIC HEALTH RELEVANCE: A small molecule organ protective agent has significant clinical potential in renal transplantation.