Twice-Weekly Subcutaneous Liposome Chelator to Treat Transfusional Iron Overload

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 DESCRIPTION (provided by applicant): We have devised a novel, stable nanoliposome encapsulated desferoxamine (DFO) formulation (LDFO) for the treatment of iron overload. Data from a pre-clinical model of iron-overload indicates that LDFO is over 50% efficient at removing iron on a molar basis, which is over 4 fold higher than the most efficient approved iron chelator. Our nanoliposomal iron chelator formulation has the potential to be a significant therapeutic improvement because heart failure remains one of the more common causes of death in children and adults with red blood cell (RBC) transfusion dependent thalassemia or sickle-cell disorders. Long-term transfusions result in the potentially lethal accumulation of iron in the body due to its release from the transfused RBC. Humans are unable to eliminate such large amounts of iron, and consequently the additional iron accumulates to toxic levels in the liver, spleen endocrine organs, and ultimately the heart. Chelation therapy is prescribed to reverse iron accumulation in these patients. Unfortunately, marketed chelators are inefficient and have severe drawbacks which include long painful infusions of desferoxamine, the necessity to take large tablets with potential life-threating adverse effects (Exjade, Novartis) or twice (Ferriprox, ApoPharma) daily. Thus, iron overload patients have poor compliance and poor outcomes. A more efficient iron removing medication could dramatically improve treatment outcomes. Patience compliance is a major factor limiting the therapeutic benefit of existing iron chelators. LDFO has the potential to revolutionize treatment for iron overload diseases; higher iron removal efficiency will lead to fewer doses, given over a shorter time period. Completion of this research could lead to a dramatically improved treatment that increases compliance rates and provides substantially better management of iron overload than current treatments in pediatric and adult thalassemia and sickle cell anemia patients. To move the LDFO formulation towards clinical development, we will pursue four specific aims. In specific aim 1, we will conduct non-GLP iron removal efficacy, pharmacology and toxicology studies in rodents of the lead LDFO followed by a pilot toxicology study in non-human primates (NHP) to assess the efficacy and safety of the LDFO formulation. In specific aim 2, we develop a process scale up, pilot manufacturing and technology transfer of LDFO to a qualified cGMP manufacturer. In specific aim 3, we will prepare preclinical and CMC documentation for a pre-IND meeting with the FDA. In specific aim 4, we undertake GLP-toxicity and toxicokinetic studies of a GMP LDFO formulation in NHP, as required by the FDA. The data generated in this research will form a large part of an IND package and will also inform the Phase 1 clinical trial design for LDFO.