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  • 1
  • 12/06/10 09:55

Transcript

  • 1. Exjade ® (deferasirox; ICL670) Conclusions on Benefit and Risk Elliott Vichinsky, MD Director, Hematology/Oncology Children’s Hospital and Research Center Oakland, California
  • 2. Iron Overload Causes Morbidity and Mortality in Patients Receiving Blood Transfusions
    • β -thalassemia major
    • Sickle cell disease
    • Other congenital and acquired disorders
  • 3. Indications and Prevalence of Chronic Transfusions in Sickle Cell Patients
    • Reasons for transfusion
    • 10% Classic CVA
    • 10% TCD > 200
    • 3% TCD > 175
    • 5% MRI/neuropsych +
    • 2% Chronic pain
    • 4% Lung
    • Reasons for transfusion
    • 8% CNS
    • 5% Lung
    • 4% Renal
    • 3% Cardiac
    • 3% Pain
    • 1% Anemia
    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. Effects of Chronic Transfusion
    • Prevention of organ damage
    • Brain injury
    • Acute chest syndrome
    • Pulmonary hypertension
    • Growth and puberty
    • Skin ulcers
    • Surgical complications
    • Hyposthenuria (bedwetting)
    • Spleen function/sequestration
    • Quality of life
    • School attendance
    • IQ
    • Energy level
    • Well-being
    • Exercise tolerance
    • Mood
  • 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. 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. 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. Deferoxamine Standard of Care in the Treatment of Iron Overload
    • Efficient chelator that is clearly efficacious in inducing negative iron balance and reducing morbidity and mortality from iron overload
    • Difficult treatment because it requires daily prolonged subcutaneous infusions
      • Effective use of deferoxamine requires a multidisciplinary team
    • Even with support from providers, compliance with deferoxamine is far from optimal
  • 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. Reasons for Noncompliance
    • Provider
    • Infusion equipment, home care
    • Monitoring DFO toxicity
    • Patient
    • Painful, invasive
    • Time consuming
    • Poor quality of life
    • High unmet need for an easy-to-use, safe, and effective oral therapy for the treatment of transfusional iron overload
  • 11. Adherence and Satisfaction With Chelation Therapy in Sickle Cell Disease
    • Prospective study of DFO adherence (SCD) a
    • 41 transfused SCD
    • Mean adherence by pharmacy refills 60%
    • Days since DFO last used 8.7 days
    • Mean number of hours of infusion 4.6 hours
    • Satisfaction—ICL670 compared to DFO b
    • Pre-randomization—21% satisfied with DFO
    • Post-randomization—84% preferred to continue ICL670
    a Treadwell 2005. b Vichinsky 2005.
  • 12. ICL670 Preclinical Data and Pharmacology
    • Extensive data on animal efficacy and toxicology
      • High selectivity for iron
      • No effects on growth or development
      • No carcinogenicity, teratogenicity
    • Pharmacokinetics
      • Long half-life facilitating once-daily administration
  • 13. ICL670 Clinical Experience
    • Clinical trial program involved 700 patients treated with ICL670 for at least 1 year
      • Thalassemia, sickle cell disease, other transfused patients with iron overload
  • 14. ICL670 Efficacy
    • ICL670 removed iron from the body in proportion to the amount of drug administered
    • ICL670 was efficacious at 20 and 30 mg/kg in maintaining or reducing liver iron concentration and serum ferritin
      • Similar effect of 20 and 30 mg/kg as comparable doses of deferoxamine
  • 15. ICL670 Safety
    • ICL670 generally well tolerated
      • Most common adverse experiences were mild to moderate gastrointestinal side effects and rash
      • Mild creatinine elevations that appear to potentially be related to excessively rapid chelation
      • No agranulocytosis, growth failure, or bone abnormalities
  • 16. ICL670 (deferasirox, Exjade ® ) Conclusions
    • 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
    • Likely to increase compliance and therefore decrease the excess iron burden in patients