Iron chelator - deferasirox
Chronic iron overload is a serious risk for patients with chronic anaemias such as sickle cell anaemia or thalassaemia.
Chronic iron overload is a serious risk for patients with chronic anaemias such as sickle cell anaemia or thalassaemia.
They often need repeated, regular transfusions of red blood cells, but this leads to a potentially fatal toxic build up of iron, in the form of ferritin, in several different body tissues. It occurs because of the body's inability to eliminate the iron. Treatment is with iron chelators which scavenge and solubilise the iron deposits, turning them into forms that can be excreted naturally from the body.
The first choice chelator is deferoxamine, but this must be administered intravenously or by slow subcutaneous infusion over eight to 12 hours, five to seven times a week. There is also an orally available product, deferiprone, but this can have serious side-effects.
As a result, Novartis has developed a new class of drugs, bishydroxyphenyltriazoles, and ICL-670A, now known as deferasirox, is undergoing clinical trials.
A randomised double blind placebo-controlled study has been carried out on 24 patients with transfusion-dependent b-thalassaemia who had already been treated with deferoxamine.1 The patients were split into three study groups, and given placebo or two single ascending oral doses of deferasirox, with the doses of between 2.5 and 80mg/kg administered at least seven weeks apart. Iron chelation was observed in all but three patients given the lowest dose of the drug. Its plasma half-life of 11-19 hours suggests that once daily dosing would be successful.
A further randomised double blind placebo-controlled dose escalation study was carried out on 24 patients with b-thalassaemia and transfusional iron overload.2 They were first given a defined amount of iron, then given 10, 20 or 40mg/kg of deferasirox once a day for 12 days. The study showed the drug was an effective oral iron chelator, and the 20mg/kg regimen would be sufficient to prevent iron accumulation in most patients with b-thalassaemia.
A Phase II open label randomised trial was carried out in 71 patients with b-thalassaemia and transfusional iron overload.3 They were given 10 or 20mg/kg deferasirox a day or 40mg/kg subcutaneous deferoxamine five times a week. After 18 months of treatment, decreases in iron accumulation were similar between the two drugs, and no drug accumulation was seen. Deferasirox has been granted orphan drug status by EMEA, and Phase III trials are ongoing.