Efficacy and Safety of Deferasirox

Efficacy and Safety of Deferasirox

Cappellini Maria Domenica, Zanaboni Laura
US Hematology Volume 2
Published: January 2010
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Abstract
Deferasirox represents a new class of once-daily iron chelators. It was first licensed in 2005 for the treatment of adult and pediatric patients with chronic iron overload due to blood transfusions. These approvals were based on data from the core program of one-year clinical trials, which involved more than 1,000 patients in what is the largest and most rigorous prospective clinical evaluation of any iron-chelating agent to date. Deferasirox has been studied in adults and children with a wide range of conditions, including b-thalassemia, myelodysplastic syndromes, and sickle cell disease. Recent data have highlighted the importance of timely deferasirox dose adjustments and described the efficacy and safety of deferasirox at doses >30mg/kg/day. The pharmacokinetic profile of deferasirox across all age groups shows it to be well absorbed, with a mean elimination half-life of eight to 16 hours that supports once-daily dosing. In clinical trials, deferasirox has demonstrated consistent dose-dependent efficacy, producing sustained reductions in serum ferritin, labile plasma iron, and cardiac iron load. The safety profile of deferasirox presents mostly as mild adverse events (primarily gastrointestinal symptoms, skin rash, and increases in serum creatinine) that resolve rapidly with no reports of progressive renal, hepatic, or bone marrow effects. This adverse event profile is seen to be manageable with appropriate clinical monitoring. Data from the extension phases of these studies are beginning to accumulate, with experience of up to seven years of deferasirox therapy now available. Deferasirox represents a significant development in the treatment of iron overload and has further potential applications.

Keywords
Deferasirox, iron chelation, anemia, serum ferritin, labile plasma iron, myelodysplastic syndromes, safety, efficacy

<>Disclosure: Maria Domenica Cappellini, MD, is a member of the speaker’s bureau and board for protocol 2209 (Exjade in Thalassemia Intermedia) for Novartis and a member of the European Gaucher Registry sponsored by Genzyme. Laura Zanaboni, MD, has no conflicts of interest to declare.

Received: June 2, 2009 Accepted: October 29, 2009
Correspondence: Maria Domenica Cappellini, MD, Department of Internal Medicine, Fondazione, Policlinico, Mangiagalli, Regina Elena, Università di Milano, Via F Sforza 35, 20122 Milano, Italy. E: maria.cappellini@unimi.it

Support: Supported by Novartis Pharmaceuticals Corporation.

Blood transfusion therapy and accompanying iron chelation have dramatically improved the quality of life for many patients with severe anemias. Diseases such as b-thalassemia, once fatal in early childhood, can now be managed as chronic conditions compatible with prolonged life. Today, life expectancy varies between 25 and 55 years, depending on patient compliance with medical treatment, particularly iron chelation therapy. Deferoxamine (Desferal®, DFO; Novartis Pharma AG, Basel, Switzerland) is the current reference standard of care; however, it requires subcutaneous infusion lasting eight to 12 hours per day, five to seven days a week for as long as the patient continues to receive blood transfusions. This regimen is problematic for many patients, interfering significantly with their daily life and, therefore, often resulting in poor patient compliance.1 A three-times-daily agent, deferiprone (Ferriprox®; Apopharma, Toronto, Canada), became available in Europe in 1999 and is available outside the US and Canada for the second-line treatment of iron overload in adult patients with thalassemia major for whom DFO therapy is contraindicated, inadequate, or intolerable.2

Deferasirox (Exjade®; Novartis Pharma AG, Basel, Switzerland) was developed in response to the significant clinical need for a convenient, effective, and well-tolerated oral iron-chelating agent. Deferasirox was designed through a rational drug development program to require only once-daily dosing. In pre-clinical studies, deferasirox was seen to be more effective than DFO in mobilizing iron from the hepatocellular pool.3 It is predominantly metabolized by glucoronidation, with subsequent biliary excretion.4 Deferasirox and its metabolites are mainly excreted in the feces (84% of the dose); renal excretion is minimal (8% of the dose, 6% as hydroxylated deferasirox). Deferasirox is approved in over 90 countries worldwide for the treatment of chronic iron overload due to blood transfusions in patients from two years of age upwards.

Clinical Experience with Deferasirox
Efficacy
The deferasirox clinical development program is the largest ever conducted for any iron-chelating agent. Five pivotal clinical studies have assessed the efficacy, safety, and tolerability of deferasirox across a number of transfusion-dependent anemias.5–9 The trial program is also notable for its inclusion of patients with a wide range of ages. Pediatric patients were well represented, with approximately 40% of patients being two to 16 years of age. Older adults have also been represented in studies of patients with myelodysplastic syndromes (MDS). To date, up to 1,000 patients with a variety of different anemias have been involved in the core program of one-year studies, more than 900 of whom have continued to receive deferasirox in the extension phases that will gather data for up to an additional four years. An overview of key deferasirox clinical efficacy data is given in Table 1.

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Keywords:
Deferasirox, iron chelation, anemia, serum ferritin, labile plasma iron, myelodysplastic syndromes, safety, efficacy, Deferasirox facts, Deferasirox information, iron chelating agents, influence of iron chelation, oral iron chelator, iron chelation possible mechanism for aspirin, deferiprone iron chelation, serum ferritin concentration, raised serum ferritin, ferritin multiple sclerosis, myelodysplastic syndromes pathology, myelodysplastic syndromes genetics, myelodysplastic syndromes diagnosis, myelodysplastic syndromes therapy, oral labile plasma iron, deferasirox labile plasma iron,

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