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FDA panel backs approval of oral iron chelator.

ROCKVILLE, MD. -- A long-awaited alternative to highly effective--but cumbersome and often painful--subcutaneous infusions of the iron chelator deferoxamine may soon be available for patients with chronic iron overload caused by repeated blood transfusions.

Deferasirox, an orally administered iron chelating agent taken once a day, was unanimously backed for approval by the Food and Drug Administration's Blood Products Advisory Panel for treating transfusional hemosiderosis. At a meeting, all 14 panel members supported approval for adults and children ages 6 and older.

Although the drug was studied predominantly in patients with [beta]-thalassemia, the panel supported the broader indication proposed by Novartis Pharmaceuticals--transfusional hemosiderosis--which also affects people with sickle cell anemia, myelodysplastic syndromes (MDS), and other chronic anemias. These patients develop chronic iron overload because they are dependent on transfusions.

The panel members agreed that the safety data provided enough information about the drug's safety profile to allow for an adequate risk-benefit assessment, and concluded that remaining safety concerns should be addressed in postmarketing trials.

If approved, deferasirox would be the second iron-chelating agent and the first oral iron chelator available in the United States. Currently, the only option is deferoxamine (DFO), approved in 1965, which is administered via a subcutaneous infusion. The infusion is typically given into the abdomen for 8-12 hours overnight, 5-7 times a week.

Based on 40 years of clinical use, DFO is considered safe and highly effective for reducing body iron stores in people with transfusional iron overload, thereby reducing morbidity and mortality. But poor compliance with DFO is a significant issue, particularly when children who need the treatments reach adolescence or go away to college.

Sophie Lanzkron, M.D., of Johns Hopkins in Baltimore, said that she has 25 adult sickle cell patients who receive chronic transfusions, and only 3 of them are truly compliant with DFO.

Deferasirox, which will be marketed as Exjade if approved, binds to iron atoms and is excreted in the bile. It has been granted priority review and could be approved by the end of the year. The FDA usually follows the recommendations of its advisory panels.

The panelists unanimously agreed that the studies presented by the company demonstrated the ability of the drug to lower liver iron concentration (LIC), a reflection of total body iron stores, in patients over a 1-year period, providing evidence of clinical efficacy.

Gary Brittenham, M.D., professor of pediatrics and medicine, Columbia University, New York, said that the data provided "very convincing evidence of clinical efficacy," compared with the efficacy of DFO in the general community (as opposed to the setting of a clinical trial), and that the new drug would "absolutely" be of benefit to patients.

Novartis officials presented the results of studies of adult and pediatric patients ages 2 and older who continued receiving transfusions during the studies, comparing LIC reductions over 1 year. Dosing regimens were determined according to baseline LIC values, which were obtained by liver biopsy in most patients. (In practice, serum ferritin will be monitored monthly.)

The largest study was a randomized, open-label phase III study comparing different weight-based doses of deferasirox to DFO in 586 patients ages 2 through 53 years with [beta]-thalassemia. Treatment was considered successful in 53% of patients on deferasirox, compared with 66% of those on DFO; these findings did not meet prespecified statistical criteria indicating that deferasirox was not inferior to DFO.

In an open-label study of 184 pediatric and adult patients with [beta]-thalassemia and rare anemias who were noncompliant with or intolerant to DFO and were treated with deferasirox, the success rate at 1 year was about 51%. Like the first study, this study did not meet a prespecified end point. But in both, there were significant reductions in LIC among those patients with baseline LIC levels at or above 7 mg/g (the highest levels), who received the higher doses of deferasirox (20-30 mg/kg), which were comparable to results seen with DFO.

Both studies also showed that the drug produced dose-dependent reductions in LIC and serum ferritin, and that a daily dose of 20 mg/kg maintains neutral iron balance whereas a dose of 30 mg/kg reduces existing body iron stores in people who continue to receive regular blood transfusions, according to Novartis.

Transient gastrointestinal symptoms--such as abdominal pain, diarrhea, nausea, and vomiting--and rash were the most common adverse events that occurred more often among those treated with deferasirox; these were manageable and rarely led to discontinuation of the drug, according to company presentations.

There was some evidence of kidney and hepatic adverse events. The most common lab abnormalities were mild increases in serum creatinine and increases in the transaminases; there were also at least two patients who developed drugrelated hepatitis. The increase in serum creatinine in the [beta]-thalassemia study appeared to be dose-dependent, and almost 19% of patients taking deferasirox had proteinuria, versus 7% of those on DFO, but there were no reports of renal failure, according to the FDA.

Additional safety studies are underway or are being planned by Novartis. The company markets a DFO formulation as Desferal; a generic formulation is also available.

BY ELIZABETH MECHCATIE

Senior Writer
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Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2005
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