Twice-Weekly Subcutaneous Liposome Chelator to Treat Transfusional Iron Overload

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 efficient at removing iron on a molar basis which is over 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 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 we develop a process scale up pilot manufacturing and technology transfer of LDFO to a qualified cGMP manufacturer In specific aim we will prepare preclinical and CMC documentation for a pre IND meeting with the FDA In specific aim 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 clinical trial design for LDFO PUBLIC HEALTH RELEVANCE We will generate preclinical efficacy pharmacology and toxicology data on a novel formulation of the FDA approved chelator desferoxamine encapsulated in nanosized liposomes LDFO LDFO targets desferoxamine to the liver and spleen greatly increasing iron removal from these organs LDFO will reduce the total amount of desferoxamine administered to patients suffering from transfusional dependent iron overload diseases such as thalassemia and sickle cell anemia LDFO will also decrease the frequency of infusions and their duration in these patients Successful completion of this work will lead to a Phase I IND to test if LDFO improves iron removal and patient compliance in the iron overload diseases