Results from thalassa-trial, the first pivotal placebo-controlled study examining the benefit of iron chelation with deferasirox (Exjade?, Novartis), an iron chelator, in patients with non-transfusion-dependent thalassemia (NTDT), show that deferasirox can significantly reduce iron overload. The researchers concluded that the drug is significantly better than placebo at reducing liver iron concentration in patients with NTDT

These data were presented today at the 53rd Annual Meeting of the American Society of Hematology(ASH) in San Diego, CA.

Deferasirox is indicated for the treatment of chronic iron overload due to transfusional hemosiderosis in adult and pediatric patients aged 2 years and over. The study however, investigated whether patients with NTDT and iron overload can benefit from iron chelation therapy as determined by liver iron concentration (LIC).

Trial protocol
The thalassa-trial, a one-year, randomized, double-blind, placebo-controlled study, including 166 patients with beta-thalassemia intermedia (n=95), alpha-thalassemia (n=22) or Hemoglobin E/beta-thalassemia (n=49). Patients ?10 years of age with LIC ?5 mg Fe/g dw and serum ferritin >300 ng/mL were randomized to starting deferasirox doses of 5 mg/kg/day (n=55) or matching placebo (n=28) and 10 mg/kg/day (n=55) or matching placebo (n=28), assessed the efficacy of deferasirox versus placebo in NTDT patients ?10 years of age with iron overload [1].

The trial met its primary endpoint, showing that deferasirox at a 10mg/kg/day starting dose significantly reduced LIC from baseline by 3.8 mg of iron per gram of liver dry weight (Fe/g dw) compared to an increase of 0.38 mg Fe/g dw in patients on placebo (p<0.001). The study also determined that a 10 mg/kg/day dose was superior to a 5 mg/kg/day dose (p=0.009).

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In the 10 mg/kg arm, 49% of patients had a LIC decrease of at least 30% from baseline versus only 2% in the placebo arm. In addition, 56% of patients in the 10 mg/kg arm had a LIC decrease of ?3 mg at one year compared to 11% in the placebo arm. The most common adverse events reported were nausea, rash, diarrhea, headache and upper abdominal pain.[1]Adverse events were similar in all patient groups, including the placebo arm.[1]

A genetic disorder
Thalassemia refers to a diverse group of genetic disorders that affect red blood cell production, causing anemia. Unlike some types of thalassemia in which patients generally receive regular blood transfusions, NTDT patients can live without frequent transfusions. However, patients with Non-transfusion-dependent thalassemia (NTDT) are still at risk of accumulating excess iron.[2]

“Results from the thalassa study show that Exjade is effective in reducing liver iron levels in patients with NTDT,” said Ali Taher, the lead study investigator and Professor of Medicine, Division of Hematology and Oncology, American University of Beirut Medical Center, Lebanon. “Iron chelation therapy is the only option for decreasing these patients’ iron burden. These are significant findings for patients with a major unmet need.”[1]

Iron overload
NTDT refers to a group of clinically milder forms of thalassemias, including beta-thalassemia intermedia[3], Hemoglobin H disease (Hb H-alpha-thalassemia)[4] and Hemoglobin E/beta-thalassemia.[5] Despite a slower rate of iron accumulation, the burden of iron overload in NTDT patients is similar to that observed in thalassemia patients who receive regular blood transfusions. NTDT patients are not symptomatic at birth, when most thalassemias are diagnosed. Therefore they are often underdiagnosed and untreated even when symptoms appear at age 10 or later. NTDT is most commonly found in Southeast Asian, South Asian, Middle Eastern and Mediterranean populations.

“Over the past six years, Exjade has provided thalassemia patients an effective option for the treatment of chronic iron overload due to blood transfusions,” said Herv? Hoppenot, President, Novartis Oncology. “These new clinical trial data show that Exjade may also benefit NTDT patients who often are at risk for serious health complications.”
Regulatory submissions for deferasirox based on the THALASSA results are planned by the end of 2011.

[1] Taher AT, Porter JB, Viprakasit V, Kattamis A, Chuncharunee S, Sutcharitchan P, Siritanaratkul N, Galanello R, Karakas Z, Lawniczek T, Ros J, Zhang Y, Habr D and Cappellini MD. Deferasirox Significantly Reduces Liver Iron Concentration In Non-Transfusion-Dependent Thalassemia Patients with Iron Overload: Results From the 1-Year Randomized, Double-Blind, Placebo-Controlled Phase II THALASSA Study. Presented at 53rd American Society of Hematology Annual Meeting, 10-13 December, San Diego, USA
[2] Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamim H and Taher AT. Elevated liver iron concentration is a marker of increased morbidity in patients with ?-thalassemia intermedia. Haematologica 2011; 96(11):1605-1612
[3] Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2011 Sep 9.
[4] Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program. 2009:26-34
[5] Rees DC, Styles L, Vichinsky EP, Clegg JB, Weatherall DJ. The hemoglobin E syndromes. Ann N Y Acad Sci. 1998 Jun 30;850:334-43

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