Deferasirox: An effective once-daily orally active iron chelator

Deferasirox (ICL670) in an orally absorbed tridentate chelator of iron (III), intended as a once-daily monotherapy for transfusional iron overload. Deferasirox was identified by Novartis from over 700 molecular entities in preclinical screening, comparing favorably with parenteral desferrioxamine or oral deferiprone. Clinical phase I and II studies demonstrated an exclusively fecal route of iron excretion, with a long plasma half-life, suitable for once-daily dosing and 24-hour protection from labile iron. Systematic large-scale prospective clinical trials have been completed in thalassemia major, sickle cell disease, and other transfusionally dependent anemias, such as myelodysplastic syndrome. These show dose-dependent reduction in body iron and have identified doses necessary either to stabilize or to decrease iron loading according to transfusion requirements. Tolerability after more than two years in phase III studies is good, with a low trial dropout rate and no drug-related arthropathy or agranulocytosis. An early, nonprogressive serum creatinine increase, remaining within normal ranges, was seen in about one-third of patients. Preliminary clinical findings using T2* as well as preclinical models suggest good drug access to myocardial iron. Deferasirox is currently registered as monotherapy for transfusional iron overload in more than 65 countries worldwide, including the United States and in the European Union.