Iron-overload and the use of iron chelation to treat it are of profound clinical importance. In certain conditions including β-thalassemia, sickle cell disease, and myelodysplastic syndromes, patients are regularly transfused with red blood cells to correct anemia. The transfusions, while life-saving, result in a perilous situation wherein excess iron from hemoglobin accumulates in the patient’s tissue. Iron-overload causes severe damage to the heart, liver, pancreas and other organs, and, in time, is fatal. For this reason, patients on maintenance transfusion therapy are treated with a chelator in an effort to maintain their bodies in iron balance.
In addition, iron plays an important role in a variety of retinal and neurodegenerative diseases including age-related macular-degeneration (AMD), Parkinson’s Disease, Alzheimer’s Disease, amyotrophic lateral sclerosis (ALS), Friedrich’s Ataxia, and Traumatic Brain Injury (TBI).
Notably, SP-420 and certain chelators from Abfero’s portfolio have the ability to cross the blood brain barrier and the blood retinal barrier. This feature opens a vast field of potential therapeutic applications across a range of devastating retinal and neurodegenerative diseases.
Transfusion-related iron-overload: Iron-overload resulting from blood transfusion is a significant cause of morbidity and mortality. Excess iron accumulation in the heart, liver, pancreas and other organs results in heart failure, cirrhosis, liver cancer, diabetes mellitus, growth impairment, and lack of sexual maturation. To date SP-420, one of the few orally active iron chelators, has shown to be well-absorbed, with high tissue exposure to heart, liver, pancreas, and brain with potentially fewer adverse effects than commercially available iron chelators. Three Phase 1 clinical safety trials have been completed, together with all necessary toxicology and manufacturing work necessary to complete clinical efficacy studies. Abfero plans to initiate a Phase 2 efficacy trial in patients with transfusion-related iron-overload in Q2 2019. The study sites are in Canada and in Lebanon, Thailand, and Turkey where there are many patients with transfusion-dependent β-thalassemia. The trial will measure liver and cardiac iron using magnetic resonance imaging (MRI), the FDA-approvable endpoints and the standard for assessing clinical effectiveness in this indication.
Age-related macular degeneration (AMD): AMD in its early stage affects ~10 million people in the US and is the leading cause of blindness in older patients. Approximately 1 million patients have advanced “wet” AMD which can be treated with anti-VEGF injections and approximately 1 million others have advanced “dry” AMD with retinal geographic atrophy (GA) for which there is no effective therapy. Professor Josh Dunaief at University of Pennsylvania, an Abfero advisor, has developed extensive data on retinal accumulation of iron in AMD and the beneficial effects of iron chelation in treating retinal degeneration. Studies in a disease model have shown that SP-420 enters the retina, removes iron, and prevents retinal degeneration. Abfero has completed the necessary toxicology studies and met the FDA at a pre-IND meeting and is now positioned to initiate Phase 1 and Phase 2 trials in AMD. The Phase 1 study will assess safety and a retinal biomarker of iron-mediated retinal oxidative damage. The Phase 2 study will measure the rate of progression in GA, the FDA-approvable endpoint for this indication.
Traumatic Brain Injury (TBI): TBI occurs in over 2.5 million persons per year in the US. Injuries include contusions, hematomas, and diffuse axonal injury with microhemorrhages. Iron released from blood in the brain contributes significantly to acute and secondary injury by promoting inflammation, neuronal dysfunction, and cell death. In animal models of TBI, an increase of iron in the brain is associated with the problems commonly observed in patients following moderately severe TBI (spasticity, gait abnormalities, memory-loss, and anxiety). Abfero investigational chelators, including SP-420, have been shown to restore normal iron content in the brain and to prevent these problems. Abfero believes this approach could represent a major advance in the treatment of TBI. Abfero is seeking funds to support a Phase 2 study of SP-420 administered over 3 weeks in patients with mild to moderate TBI with brain microhemorrhages detected on MRI. Clearance of iron from the microhemorrhages will be used as a surrogate marker to guide dose-selection for a subsequent Phase 3 clinical trial necessary for FDA approval.
Composition of matter claims have issued in the US and a number of other countries around the world. Patent applications have also been filed covering medical uses of SP-420 and novel dosing regimens. An application covering novel “cellular recovery” dosing regimens shown to significantly increase the therapeutic index of chelators was filed in 2017.
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