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  • 1
  • 12/06/10 09:55
  • PPT

    1. 1. Exjade ® (deferasirox; ICL670) Conclusions on Benefit and Risk Elliott Vichinsky, MD Director, Hematology/Oncology Children’s Hospital and Research Center Oakland, California
    2. 2. Iron Overload Causes Morbidity and Mortality in Patients Receiving Blood Transfusions <ul><li>β -thalassemia major </li></ul><ul><li>Sickle cell disease </li></ul><ul><li>Other congenital and acquired disorders </li></ul>
    3. 3. Indications and Prevalence of Chronic Transfusions in Sickle Cell Patients <ul><li>Reasons for transfusion </li></ul><ul><li>10% Classic CVA </li></ul><ul><li>10% TCD > 200 </li></ul><ul><li>3% TCD > 175 </li></ul><ul><li>5% MRI/neuropsych + </li></ul><ul><li>2% Chronic pain </li></ul><ul><li>4% Lung </li></ul><ul><li>Reasons for transfusion </li></ul><ul><li>8% CNS </li></ul><ul><li>5% Lung </li></ul><ul><li>4% Renal </li></ul><ul><li>3% Cardiac </li></ul><ul><li>3% Pain </li></ul><ul><li>1% Anemia </li></ul>17,000 children receiving chronic transfusions 50,000 affected children (≤ 20 years of age) TCD = Transcranial Doppler. 32,000 affected adults (> 20 years of age) 7,680 adults receiving chronic transfusions
    4. 4. Effects of Chronic Transfusion <ul><li>Prevention of organ damage </li></ul><ul><li>Brain injury </li></ul><ul><li>Acute chest syndrome </li></ul><ul><li>Pulmonary hypertension </li></ul><ul><li>Growth and puberty </li></ul><ul><li>Skin ulcers </li></ul><ul><li>Surgical complications </li></ul><ul><li>Hyposthenuria (bedwetting) </li></ul><ul><li>Spleen function/sequestration </li></ul><ul><li>Quality of life </li></ul><ul><li>School attendance </li></ul><ul><li>IQ </li></ul><ul><li>Energy level </li></ul><ul><li>Well-being </li></ul><ul><li>Exercise tolerance </li></ul><ul><li>Mood </li></ul>
    5. 5. Iron Cardiomyopathy in SCD/Thalassemia National Trial in Chronically Transfused Patients a Iron cardiomyopathy confirmed by 2 cardiologists. Fung et al. Blood . 2004;104:1683a. — 16 17 Heart medications, % 0 19 9 Abnormal ECHO, % a Iron cardiomyopathy 3.5 19.7 20.4 LIC, mg Fe/g dw 22 25 25 Age, years 44 143 250 n Control Thal SCD Variable
    6. 6. Iron Cardiomyopathy in SCD/Thalassemia Summary of Deaths a Chi-square, adult patients only (> 18 years of age). Fung et al. Blood . 2004;104:1683a. 53 50 LVEF, % 2550 4900 Mean ferritin, µg/L 21 30 Mean LIC, mg Fe/g dw 25 ± 0.6 41 ± 10 Age, years 0/3 11/2 Sex, F/M .024 3 13 Total deaths, n P value a Thal SCD
    7. 7. Iron Cardiomyopathy in SCD/Thalassemia Variables Related to Any Death a Logistic regression. b Chi-square, adult patients only (> 18 years of age). Fung et al. Blood . 2004;104:1683a. .001 b 15 58 Heart medication use, % .004 b 5 33 Congestive heart failure, % .01 b 7 33 Abnormal ECHO, % .001 a 24.1 ± 10.8 37.3 ± 14.0 Age P value a No death (n = 280) Death (n = 13)
    8. 8. Deferoxamine Standard of Care in the Treatment of Iron Overload <ul><li>Efficient chelator that is clearly efficacious in inducing negative iron balance and reducing morbidity and mortality from iron overload </li></ul><ul><li>Difficult treatment because it requires daily prolonged subcutaneous infusions </li></ul><ul><ul><li>Effective use of deferoxamine requires a multidisciplinary team </li></ul></ul><ul><li>Even with support from providers, compliance with deferoxamine is far from optimal </li></ul>
    9. 9. Survival Correlates With Compliance With Deferoxamine 50 0-20% 30 40 25 75 100 Cumulative % survival 20 10 20-40% 40-60% 60-80% 80-100% Gabutti V, et al. Acta Haematologica. 1996;95:26-36. Time, years 0 0
    10. 10. Reasons for Noncompliance <ul><li>Provider </li></ul><ul><li>Infusion equipment, home care </li></ul><ul><li>Monitoring DFO toxicity </li></ul><ul><li>Patient </li></ul><ul><li>Painful, invasive </li></ul><ul><li>Time consuming </li></ul><ul><li>Poor quality of life </li></ul><ul><li>High unmet need for an easy-to-use, safe, and effective oral therapy for the treatment of transfusional iron overload </li></ul>
    11. 11. Adherence and Satisfaction With Chelation Therapy in Sickle Cell Disease <ul><li>Prospective study of DFO adherence (SCD) a </li></ul><ul><li>41 transfused SCD </li></ul><ul><li>Mean adherence by pharmacy refills 60% </li></ul><ul><li>Days since DFO last used 8.7 days </li></ul><ul><li>Mean number of hours of infusion 4.6 hours </li></ul><ul><li>Satisfaction—ICL670 compared to DFO b </li></ul><ul><li>Pre-randomization—21% satisfied with DFO </li></ul><ul><li>Post-randomization—84% preferred to continue ICL670 </li></ul>a Treadwell 2005. b Vichinsky 2005.
    12. 12. ICL670 Preclinical Data and Pharmacology <ul><li>Extensive data on animal efficacy and toxicology </li></ul><ul><ul><li>High selectivity for iron </li></ul></ul><ul><ul><li>No effects on growth or development </li></ul></ul><ul><ul><li>No carcinogenicity, teratogenicity </li></ul></ul><ul><li>Pharmacokinetics </li></ul><ul><ul><li>Long half-life facilitating once-daily administration </li></ul></ul>
    13. 13. ICL670 Clinical Experience <ul><li>Clinical trial program involved 700 patients treated with ICL670 for at least 1 year </li></ul><ul><ul><li>Thalassemia, sickle cell disease, other transfused patients with iron overload </li></ul></ul>
    14. 14. ICL670 Efficacy <ul><li>ICL670 removed iron from the body in proportion to the amount of drug administered </li></ul><ul><li>ICL670 was efficacious at 20 and 30 mg/kg in maintaining or reducing liver iron concentration and serum ferritin </li></ul><ul><ul><li>Similar effect of 20 and 30 mg/kg as comparable doses of deferoxamine </li></ul></ul>
    15. 15. ICL670 Safety <ul><li>ICL670 generally well tolerated </li></ul><ul><ul><li>Most common adverse experiences were mild to moderate gastrointestinal side effects and rash </li></ul></ul><ul><ul><li>Mild creatinine elevations that appear to potentially be related to excessively rapid chelation </li></ul></ul><ul><ul><li>No agranulocytosis, growth failure, or bone abnormalities </li></ul></ul>
    16. 16. ICL670 (deferasirox, Exjade ® ) Conclusions <ul><li>ICL670 is a convenient, well-tolerated, and effective once-daily oral iron chelator for the treatment of chronic iron overload in adult and pediatric patients </li></ul><ul><li>Likely to increase compliance and therefore decrease the excess iron burden in patients </li></ul>

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