Iron Chelation Trial Shows Once-daily Exjade Significantly Removes Toxic Iron From The Heart In Patients With Thalassaemia

Main Category: Blood / Hematology
Article Date: 09 Dec 2008 - 7:00 PDT

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New data from the largest prospective trial in iron chelation demonstrate the efficacy and safety of Exjade® (deferasirox) in treating chronic transfusional iron overload, a potentially life-threatening condition for patients who have had multiple blood transfusions to treat underlying anaemias such as beta-thalassaemia.^1,2

Data from this landmark trial, known as EPIC, were presented today at the 50th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco, California.

The EPIC cardiac substudy showed that Exjade removed iron from the heart in beta-thalassaemia patients, based on a statistically significant improvement (P<0.0001) in T2* magnetic resonance imaging (a validated technique to assess cardiac iron content). The one-year substudy included 114 beta-thalassaemia patients with cardiac iron overload, the leading cause of death in these patients. ¹

These data reinforce the results from another study, also presented at ASH, which demonstrated that approximately 67% of patients treated with Exjade had decreases in cardiac iron (measured by any change in T2), and 72% of patients had decreases in liver iron after 12 months of treatment (measured by decreases in liver iron concentration levels). ³

"These data clearly demonstrate that deferasirox significantly reduces cardiac iron in beta-thalassemia patients with iron overload, which is a critical goal of treatment for these patients," said Dudley Pennell, MD, Professor of Cardiology, Royal Brompton and Harefield NHS Trust and Imperial College, London. "Cardiac complications caused by the buildup of toxic iron in the heart can be life-threatening for people living with thalassemia."

Regular blood transfusion therapy is essential for patients with chronic anaemias such as beta-thalassaemia, and may be necessary in diseases such as sickle cell disease (SCD) and myelodysplastic syndromes (MDS), in order to improve quality of life and survival. However the consequence of these blood transfusions may be iron overload as the body has no physiological means to remove iron. This iron overload is life-threatening and if left untreated causes significant tissue damage to the heart, other organs such as the liver and endocrine glands, and can ultimately lead to death. ⁴

Prior to the approval of Exjade®, the most common way of performing iron chelation was with a treatment called desferrioxamine (DFO) and involved a painful nightly infusion by needle and pump that can last from eight to 12 hours every night for five to seven nights a week. ^5,6 This treatment is demanding and inconvenient and can be particularly distressing for children and for their parents or carers who must administer the infusion.

As a result of the pain and inconvenience, many patients stopped or avoided iron chelation therapy, thus risking the toxic effects of iron overload. ⁷ Indeed, it is estimated that as recently as 2000, around 50% of UK patients with beta-thalassaemia died before the age of 35, mainly because conventional iron chelation therapy is too burdensome for full adherence. ⁷

Exjade® (deferasirox) has been awarded a prestigious UK Prix Galien award for innovative research and development in orphan drugs. Exjade, administered as a dissolvable tablet in a drink is the only once-daily oral drug that provides effective 24-hour iron chelation. The development of Exjade® was the result of more than 20 years of research, driven by the search for an effective oral iron chelator with a good tolerability profile that could transform the lives of patients by removing the need for lengthy, cumbersome and painful infusions.

References

1) Pennell, D. Efficacy and safety of deferasirox (Exjade®) in reducing cardiac iron in patients with β-thalassemia major: Results from the cardiac substudy of the EPIC trial. Poster presented at the 50th American Society of Hematology (ASH) Meeting, 6-9 December, San Francisco, CA, USA.

2) Cappellini, M. Efficacy and safety of deferasirox (Exjade®) in patients with transfusion-dependent anemias: 1-year results from the large, prospective, multicenter EPIC study. Poster presented at the 50th American Society of Hematology (ASH) Meeting, 6-9 December, San Francisco, CA, USA.

3) Wood J, et al. Deferasirox (Exjade®) monotherapy significantly reduces cardiac iron burden in chronically transfused ß-thalassemia patients: an MRI T2* study. Poster presented at the 50th American Society of Hematology (ASH) Meeting, 6-9 December, San Francisco, CA, USA.

4) Piga A, Galanello R, Forni GL et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006;91:873-880.

5) Desferal: Summary of Product Characteristics. Novartis.

6) Nisbet-Brown E, Olivieri NF, Giardina PJ et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361:1597-1602.

7) Modell, B et al. Survival in ß-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355:2051-2052.

8) Exjade: Summary of Product Characteristics. September 2008, Novartis Pharmaceuticals UK Ltd.

9) Cappellini et al. A Phase III study of deferasirox (ICL670), a once-daily oral iron chelator in patients with beta thalassaemia. Blood, 1 May 2006.Volume 107, Number 9.

About the studies

About the EPIC trial

The EPIC trial was a one-year, open-label, prospective, multicentre trial. EPIC studied the efficacy and safety of a fixed starting dose of Exjade based on transfusional iron intake, with subsequent dose titration at 3-monthly intervals based on serum ferritin (SF) trends. With 1,744 patients, this trial is the largest ever conducted for an iron chelator and included the largest cohorts of underlying anaemias in a single trial, including patients with beta-thalassaemia, MDS and aplastic anaemia. Twelve abstracts from EPIC are being presented at ASH.

Study details

[Abstract: 3873] [D Pennell, et al.]¹
This EPIC cardiac substudy evaluated the cardiac efficacy of Exjade in 114 beta-thalassaemia patients with myocardial siderosis (T2* <20 ms). Baseline myocardial T2* was <10 milliseconds (ms) in 47 (41%) patients (considered severe cardiac iron overload) and 10-20 ms in 67 (59%) patients (considered mild to moderate). Mean baseline liver iron concentration (LIC) was 28.2±10.0 mg Fe/g dry weight (dw), median SF was 5235 ng/mL, and the mean amount of transfused blood in the year prior to study entry was 185 mL/kg.¹

Patients experienced a statistically significant increase in myocardial T2* indicating a decrease in myocardial iron content. Based on a geometric mean ± coefficient of variation, change from baseline (11.2 ms ±40.5%) to 12.9 ms ±49.5% represents an increase by a factor of 1.16 from baseline (P<0.0001). Overall, 69.5% of patients taking Exjade had an improvement in T2* (>4% increase); there was no change in 14.3%; and worsening (>4% decrease) in 16.2% of patients. Left ventricular ejection fraction remained stable throughout the study. Additionally, LIC and SF levels (both indicators of total body iron) were significantly reduced from baseline by 6.6±9.9 mg Fe/g dw and 1257 ng/mL, respectively (P<0.0001). Four patients discontinued treatment due to adverse events. Most investigator-assessed drug-related adverse events were mild to moderate in severity; rash was the most common (13.2%). There is an ongoing one-year extension of this substudy. ¹

About Exjade

Exjade (deferasirox) is the first and only once-daily oral iron chelator approved for the treatment of transfusion iron overload. Developed as an alternative to desferrioxamine, it is the only chelator to demonstrate continuous 24 hour chelation of excess iron with a single oral daily dose. ⁸

Administered as a drink, Exjade is expected to transform the treatment of iron overload by making iron chelation more acceptable to patients. In a pivotal phase three study, part of the largest ever clinical trials programme for an iron chelator, it proved to be as effective as desferrioxamine in patients receiving higher doses of the drug.⁹ Exjade provides an alternative to time-consuming, frequent and often painful treatment and gives patients a well-tolerated, effective and convenient treatment option.

About Novartis

Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world. For more information, please visit www.novartis.com.

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