Results from a phase I clinical trial of HBED

In summary, it has been shown that orally administered HBED causes enhanced excretion of iron in all of the thalassemia major patients studied and that both urinary and stool iron are increased in the process. Increasing the dose from 40 to 80 mg/kg divided t.i.d. caused iron balance to increase from 38% to 50%. While this is significantly less than that expected based on our preclinical studies in animals, the potential usefulness of this chelator has been demonstrated. Efforts to increase its oral bioavailability are now in progress. Lending further support to the effort is the fact that no evidence of toxicity has been observed in the studies performed to date and that negative iron balance was achieved in the one thalassemia intermedia patient studied. The results also reinforce the conclusion that DFO causes the excretion of substantially more iron than would be predicted by an assessment of serum ferritin levels or past compliance with chelation therapy. In patients with thalassemia major, serum ferritin levels relate more to tissue damage than to body iron load. Effective chelation therapy can diminish the former much faster than it can remove storage iron. Hence, in cases of iron overload, aggressive chelation therapy should not be tapered off until a significant reduction in iron excretion can be demonstrated. Routine measurements of urinary iron excretion should now be considered essential in the management of beta-thalassemia. Finally, two more patients with thalassemia intermedia will be studied in an effort to substantiate that net negative iron balance can be achieved in this subgroup of patients. We also plan to study several transfused patients in whom the dose of HBED will be increased to 120 mg/kg divided t.i.d. While the chances of achieving net negative iron balance in these patients seems remote, we hope to further demonstrate the safety of this drug with an eye toward the development of an effective prodrug.