Exjade

1
Exjade (deferasirox ICL670) Conclusions on
Benefit and Risk

• Elliott Vichinsky, MDDirector,
  Hematology/OncologyChildrens Hospital and
  Research CenterOakland, California

2
Iron Overload Causes Morbidity and Mortality in
Patients Receiving Blood Transfusions

• ß-thalassemia major
• Sickle cell disease
• Other congenital and acquired disorders

3
Indications and Prevalence of Chronic
Transfusions in Sickle Cell Patients
50,000 affected children ( 20 years
of age)
32,000 affected adults(gt 20 years of age)

• Reasons for transfusion
• 8 CNS
• 5 Lung
• 4 Renal
• 3 Cardiac
• 3 Pain
• 1 Anemia

• Reasons for transfusion
• 10 Classic CVA
• 10 TCD gt 200
• 3 TCD gt 175
• 5 MRI/neuropsych
• 2 Chronic pain
• 4 Lung

7,680 adults receivingchronic transfusions
17,000 children receiving chronic transfusions
TCD Transcranial Doppler.
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
Variable SCD Thal Control
n 250 143 44
Age, years 25 25 22
LIC, mg Fe/g dw 20.4 19.7 3.5
Abnormal ECHO, a Iron cardiomyopathy 9 19 0
Heart medications, 17 16
a Iron cardiomyopathy confirmed by 2
cardiologists. Fung et al. Blood. 20041041683a.
6
Iron Cardiomyopathy in SCD/ThalassemiaSummary of
Deaths
SCD Thal P valuea
Total deaths, n 13 3 .024
Sex, F/M 11/2 0/3
Age, years 41 10 25 0.6
Mean LIC, mg Fe/g dw 30 21
Mean ferritin, µg/L 4900 2550
LVEF, 50 53
a Chi-square, adult patients only (gt 18 years of
age). Fung et al. Blood. 20041041683a.
7
Iron Cardiomyopathy in SCD/Thalassemia Variables
Related to Any Death
Death (n 13) No death (n 280) P valuea
Age 37.3 14.0 24.1 10.8 .001a
Abnormal ECHO, 33 7 .01b
Congestive heart failure, 33 5 .004b
Heart medication use, 58 15 .001b
a Logistic regression. b Chi-square, adult
patients only (gt 18 years of age). Fung et al.
Blood. 20041041683a.
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
80-100
100
60-80
75
40-60
Cumulative survival
50
20-40
25
0-20
0
20
10
0
30
40
Time, years
Gabutti V, et al. Acta Haematologica.
19969526-36.
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
• SatisfactionICL670 compared to DFOb
• Pre-randomization21 satisfied with DFO
• Post-randomization84 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