Efficacy of the Novel Oral Iron Chelator Deferitrin in Metabolic Iron Balance Studies.

Deferiprone (L1, Ferriprox) and deferasirox (ICL670, Exjade), two orally effective iron-chelating agents, have revolutionized the management of iron overload. Nonetheless, neither drug is effective in all patients, deferoxamine (DFO) still being the only drug capable of placing all affected individuals in net negative iron balance. Deferitrin (4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, GT56-252), is a tridentate ligand with a demonstrated efficacy and an acceptable toxicity profile in preclinical evaluations in primates. In Phase 1 studies, it was well absorbed and no safety issues were identified. Thus, given the need for additional oral chelation options, we explored the efficacy of deferitrin in iron-overloaded patients with β-thalassemia major. Total iron balance studies were carried out wherein the effectiveness of single daily ascending doses of deferitrin (4.5, 6.75, 11 and 17 mg/kg/day) was compared with that of a standard DFO regimen (40 mg/kg infused subcutaneously over 8 hours). Twenty patients were admitted to our clinical research center for 28 days and placed on fixed individualized low-iron diets. On days 5 – 10 they were infused nightly with DFO and on days 15 – 24 given a dose of deferitrin with breakfast. Groups of 4 patients were studied at the three lowest doses of deferitrin, only 2 patients being given 17 mg/kg. Drug-free days allowed for washout of stool iron due to previous treatments, a stool marker being given at the beginning and end of each period of drug evaluation. Safety was assessed by hematology (CBC and coagulation parameters), chemistry (electrolytes, BUN, creatinine, liver function tests), urinalysis, and urinary β-2-microglobulin as well as by EKG, physical examination and monitoring of adverse events. Iron balance due to DFO ranged from 52% – 325% (mean 157%) with 40% – 77% (mean 61%) of total iron excretion appearing in the stool. Only 4 patients failed to achieve net negative iron balance. The response to deferitrin was highly variable at each dose studied, there being patients who responded poorly and others in whom there was a good response. Overall, iron balance ranged from 7% – 42%, nearly all of the iron excreted (0.04 – 0.14 mg/kg/day) appearing in the stool. Of note, total iron excretion appeared to reach a plateau at a deferitrin dose of 11 mg/kg/day. As animal studies suggested that more iron might be excreted upon giving the drug in divided doses, we interrupted our evaluation of 17 mg/kg/day and studied an additional 6 patients at 25 mg/kg/day, the drug being divided t.i.d. with breakfast, dinner and a bedtime snack. Iron balance in these patients ranged from 28% – 62% (mean 43%), stool iron excretion (0.14 – 0.29 mg/kg/day) accounting for 99% of the total. Their DFO-induced iron balance was similar to that of the patients previously studied, ranging from 123% – 233% (mean 173%). At all doses, no significant changes were noted in the EKGs or any hematological, biochemical or urinary parameters. There were no serious adverse events. These results suggest that deferitrin was orally effective and, while less effective than DFO, it was of sufficient efficacy to warrant further evaluation in a longer-term study as an alternative to DFO.