Bursting the banks

An excess of iron is treatable with chelators, but poor compliance must be overcome.

Iron overload is the result of an excessive accumulation of iron in the body, which can lead to organ failure and even death. Extremely high levels of iron can occur as a result of hereditary haemochromatosis (a common inherited iron metabolism condition), or from multiple blood transfusions used to manage disorders such as beta-thalassaemia and sickle cell disease.

Iron is an integral component of haemoglobin and each unit of transfused red cells contains 200-250mg of iron. This means that with repeated transfusions there is inevitably a build-up of iron in the body. Symptoms of iron overload vary but can include tiredness, heart palpitations, joint pain, stomach pain, and bronze/grey skin pigmentation.

Patients with iron overload have a shortened life expectancy and the most common cause of death is heart failure.

Deferoxamine (Desferal)
For more than 30 years, deferoxamine (Desferal) has been used to treat iron overload associated with transfusiondependent anaemias. Deferoxamine is an iron chelator that binds excess body iron and promotes its excretion via the kidneys and bile.

The drug is relatively safe and effective but has to be administered via slow infusion (8-12 hours) for at least five days a week. Consequently, patient compliance is a problem and the pharmaceutical industry realised some time ago that there was room for improvement.

An obvious way to improve the convenience of a therapy is to make it orally available and, in the field of iron overload, this has resulted in deferiprone and more recently, deferasirox.

Deferiprone (Ferriprox)
Deferiprone is an orally active iron chelator that was approved in Europe in August 1999 for the treatment of iron overload in patients with thalassaemia major, when deferoxamine therapy is contraindicated or inadequate. It was originally developed at the Royal Free Hospital School of Medicine in London, and then later by Apotex.  Studies have shown that deferiprone reduces mean serum ferritin (a protein that reflects the amount of iron stored in body tissues) levels by similar amounts to deferoxamine.

To determine whether deferiprone and deferoxamine could be used successfully as a combination therapy, a study was carried out in Greece in 36 patients with beta-thalassaemia. Results were published in 2004 and showed that 25 patients maintained a satisfactory compliance, according to the authors, and there was no significant toxicity. After a mean of four months, 11 patients discontinued deferoxamine.

Deferasirox (Exjade)
Since the 2000 European launch of deferiprone, there have been further developments in iron overload R&D. Deferasirox (Exjade, ICL670) has been developed by Novartis, the company that also markets deferoxamine. Deferasirox is an iron chelator that is orally active via once-daily administration, in contrast to deferiprone which is given three times a day in general.

Novartis filed for US and EU registration of deferasirox in 2005 for the treatment of patients with chronic iron overload due to blood transfusions. According to the company, submissions in more countries will follow. The clinical trials programme that led to the registration filing for deferoxamine enrolled more than 1,000 patients, including a phase III trial in 586 patients with beta-thalassaemia and transfusion-related iron overload.

The trial compared deferasirox (5-30mg/ kg/day) with deferoxamine, and showed that at 20mg/kg/day and 30mg/kg/day doses, deferasirox had significant efficacy in maintaining, or reducing, absolute liver iron concentration. It was also generally well tolerated and most adverse events were only mild-to-moderate in severity.

Deferasirox is currently in two phase II clinical trials in the US. One trial, which began in March 2005, will examine its long-term safety and efficacy in patients with sickle cell disease who have iron overload from repeat blood transfusions.

It is expected to enrol 210 patients, will compare deferasirox with deferoxamine and aims to finish by February 2008. The second phase II trial is enrolling patients with myelodysplastic syndrome who also have chronic iron overload from blood transfusions. This began in May 2005, is expected to enrol 150 patients and may complete in April 2007.

Other companies developing drugs for iron overload include Genzyme, which is working on an orally active iron chelator known as deferitrin (GT56-252). It is in an open-label phase II clinical trial in the US, which aims to compare the safety and iron excretion properties of deferitrin with deferoxamine in 25 patients who have beta-thalassaemia and iron overload from blood transfusions.

Xenon Pharmaceuticals is developing a class of small molecules that target the Fe1 gene, a key intestinal regulator of iron absorption. Preclinical studies in animal models have shown that inhibition of Fe1 reduces iron absorption and depletes iron stores. Development is at the lead optimisation stage.

The Author
Pipeline is written by Helen Commander, Adis International, using information derived from Adis Clincial Trials Insight and R&D Insight. For more information on Adis services contact Camille Scot-Smith on 020 7981 0733