Transcript Exjade Novartis NDA 21-882 Oncologic Drugs Advisory Committee

Exjade®
Novartis
NDA 21-882
Oncologic Drugs Advisory Committee
Pediatric Oncology Subcommittee Meeting
Gaithersburg, Maryland
March 14, 2006
George G. Shashaty, M.D.
Division of Medical Imaging and Hematology Products
Center for Drug Evaluation and Research
Iron Metabolism
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Body iron balance – input vs output
Iron highly conserved
Normal TBI - 3-5 gm
Normal LIC - <1.5 mg Fe/gm dw
TBImg/kg
= 10.6 x LIC
“Safe” LIC - <7.0 mg Fe/gm dw
One unit of blood transfusion contains 200-250 mg
Fe
• 100 ml blood/kg (15-20 units of blood) causes an
increase in LIC to >7.0 mg Fe/gm dw
• Excess iron affects the heart, liver, endocrine
organs
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Exjade
• Oral iron chelating agent
• Orphan drug designation
• Fast track designation
• Priority review
• Accelerated approval granted November 2, 2005
• Indication: For use in the treatment of chronic iron
overload from blood transfusions (transfusional
hemosiderosis) in adult and pediatric patients at
least 2 years of age
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Traditional Therapy for
Hemosiderosis
• Deferoxamine (DFO) was the only approved
treatment (1968)
• Parenterally administered/10-12 hours/day
• Given 5-7 days/week
• Clinical effectiveness and safety of DFO
known based on long history of clinical use
• Comparator for controlled trials of Exjade
• Placebo control study not appropriate for
the indication
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Studies Reviewed
Study
Type
N of
Patients
Population
Endpoint
Liver Iron
Concentration
0105
Randomized, openlabel, controlled
71
β
years
0106
Non-comparative
40
β
<17 years
0107
Randomized, openlabel, controlled
586
ß-thalassemia age 2
and greater
0108
Non-comparative, openlabel
184
β
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LIC at baseline and at 10 mg/kg
48 weeks
(Pediatric)
LIC at baseline and at 5-30 mg/kg
48 weeks
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12 (48) weeks
(Dose
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Study 0107
• Randomized, DFO-controlled, open-label,
parallel group, multi-institutional
• 299 patients age <16 years, 154 received
Exjade, 145 received DFO
• Dose of drugs based on LIC at baseline
• Efficacy based on the difference in
“success” rate between Exjade and DFO
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Study 107
Demographics
Variable
Exjade
Age (yrs)
n
Mean
Median
Range
296
17.0
15
2 - 49
DFO
290
17.3
15.5
2 - 53
Age group (yrs)
<6
6 - <12
12 - <16
16 - <50
50 - <65
30 (10.1%)
67 (22.6%)
57 (19.3%)
142 (48.0%)
0 (0.0%)
28 (9.7%)
68 (23.4%)
49 (16.9%)
144 (49.7%)
1 (0.3%
Sex, n (%)
Male
Female
140 (47.3%)
156 (52.7%)
142 (49.0%)
148 (51.0%)
Race, n (%)
Caucasian
Black
Asian
Others
263 (88.9%)
2 (0.7%)
9 (3.0%)
22 (7.4%)
251 (86.6%)
1 (0.3%)
10 (3.4%)
28 (9.7%)
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Study 107
Dose Cohorts
• Exjade dose prespecified according
to baseline LIC
• DFO dose
– prespecified according to baseline
LIC or
– Patients could continue on prior
effective DFO dose
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Study 0107
Primary Efficacy Analysis (PP-1)
Success rate (%)
Difference and 95% CI
Exjade
N=276
DFO
N=277
52.9
66.4
-13.5 [-21.6,-5.4]
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Study 0107
Change in LIC from Baseline (PP-2)
Liver Iron Concentration (LIC), mg Fe/g dw
Baseline
End-of-Study Change
Exjade (N=268)
Mean
14.1
11.7
-2.4
DFO (N=273)
Mean
13.2
10.4
-2.9
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Study 0107
Change in LIC from Baseline for Patients
Who Received Exjade 20 or 30 mg/kg/day
(initial dose) (PP-2)
Liver Iron Concentration (LIC), mg Fe/g dw
Baseline
End-of-Study Change
Exjade (N=185)
Mean
18.5
13.1
-5.3*
* significant change from baseline, p<0.001
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Study 0107
Mean Change in LIC (mg Fe/gm dw)
from Baseline by Age Group (PP-2)
Age Group
EXJADE (N)
DFO (N)
2 - <6
-1.1
(27)
-3.8
(28)
6 - <12
-4.0
(61)
-2.5
(66)
12 - <16
-2.8
(55)
-3.5
(49)
> 16
-1.8
(125)
-2.6
(129)
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Study 0107
Changes in serum ferritin from
baseline to end of study
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Efficacy Summary
•
Although pre-specified primary endpoint
not met, treatment with either Exjade or
DFO reduced LIC from baseline. This
reduction in iron burden occurred in the
face of a continuing transfusion
requirement.
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Secondary endpoints, including change in
LIC and changes in serum ferritin levels, are
consistent with a treatment effect of Exjade.
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Supportive Study 0108
• Single arm, open label, multi-institutional
treatment with Exjade for 48 weeks
• Enrollment: 85 subjects with βthalassemia, 99 subjects with rare anemias
• 15 patients with β-thalassemia and 20
patients with rare anemias were <age 16
• Exjade dosing same as in Study 0107
• Evaluated change in LIC
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Study 0108
Change in LIC from Baseline with
Exjade in Total Population (PP-2)
Liver Iron Concentration (LIC), mg Fe/g dw
Baseline
End-of-Study Change
All Patients (N=147)
Mean
18.0
13.8
-4.2
All Patients with Who Received 20 or 30 mg/kg/day (initial dose)
(N=126)
Mean
20.2
14.8
-5.5
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Safety Populations
Population
Patients receiving >1 Dose of
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Exjade
DFO
-Thalassemia (12 month studies)
Rare anemias (12 month study)
Sickle cell disease (12 month safety)
421
99
132
Long-term safety (extension studies
up to 35 months) β-thalassemia
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237
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Clinical pharmacology studies
(volunteers and β-thalassemia)
290
-63
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Pediatric Safety Population
All Exjade Treated Patients
<6
Age
6-<12
Β-thalassemia
Rare anemias
Sickle cell
39
9
4
85
6
30
81
5
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Total
52
121
119
12-<16
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Study 0107: Notable Differences in Adverse Events
for Exjade vs. DFO (All Patients)
Exjade
N=296
n (%)
DFO
N=290
n (%)
Any Adverse Event
254 (85.8)
246 (84.8)
Gastrointestinal
126 (42.6)
91 (31.4)
[Chiefly abdominal pain, diarrhea, nausea,
vomiting, gastroenteritis, constipation]
Skin/Subcutaneous tissue
Rash
Creatinine increased
65 (22.0)
25 (8.4)
45 (15.5)
9 (3.1)
113 (38.2)
41 (14.1)
Transaminases increased
17 (5.7)
5 (1.7)
Urine protein/creatinine ratio >0.6mg/mg
55 (18.6)
21 (7.2)
Hepatobiliary
14 (4.7)
5 (1.7)
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Adverse Events - Kidney
Study 0107
• Increase in serum creatinine triggered a
dose reduction or interruption in 11.1% of
Exjade patients.
• The increase in creatinine appeared to be
dose-dependent: 2.6% at 10mg, 8.3% at 20
mg and 20.2% at 30 mg Exjade.
• No reports of renal failure
• The DFO dose was not reduced in any
patient as a result of an increase in
creatinine
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Adverse Events - Liver
Study 0107
• Increased transaminases (>5x ULN) in 5.7% of
Exjade treated patients and in 1.7% of DFO treated
patients.
• Clinical drug-induced hepatitis: Two cases both
leading to discontinuation of Exjade
• Increased transaminases led to discontinuation of
Exjade in 2 patients
• Increased transaminases led to dose adjustment
or interruption in 3 Exjade patients.
• Bilirubin levels were no different in the two arms
of the trial
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Adverse Events - Special Senses
Study 0107
• Cataract formation - 1 Exjade patient, age 16
(drug D/C)
- 2 DFO patients, ages
18, 36.
• Diminished hearing - 9 patients receiving
Exjade (ages 5-33)
- 7 patients receiving DFO
(ages 7-38)
(drug interrupted in 2)
• Vertigo - 1 Exjade patient (no intervention)
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Safety Summary
• Main organs for safety concerns are the kidney
and the liver
• Gastrointestinal and dermatological AEs appear
manageable
• Frequency of uncommon, important AEs is not
known because the safety population is limited
• Frequency and types of AEs associated with long
term use of drug is not known
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Unique Pediatric Issues
• Efficacy/safety of Exjade in children and adults appear to be
similar except in children < age 6
• In Study 0107, in children <age 6 (N=30) compared to all
patients age 6 years and older:
– The clearance of Exjade was greater (by 50%)
– The mean iron intake from transfusion was greater (0.48
vs 0.37 mg/kg/d)
– Increases in serum creatinine on 2 consecutive
occasions were more frequent (50% vs 36.8%)
– Rash and vomiting were less common, diarrhea was more
common
• Growth and development was normal over the 48 weeks of
the trials
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Exjade Dosage
• Recommended dose of Exjade is 20 mg/kg/d
because doses between 5-10 mg/kg/d were
ineffective in decreasing LIC.
• Therapy is commenced after:
– The transfusion of 100 mL/kg packed red blood
cells and
– persistent serum ferritin of >1000 ug/L
• Changes in Exjade dose are based on frequent
determination of serum ferritin
• In the clinical trials, dosing was based on LIC
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Benefit/Risk Assessment
• For patients treated with Exjade at doses of 20 to
30 mg/kg/day, a decrease in LIC was seen during
premarket studies even though patients continued
to receive transfusions.
• Exjade was associated with clinical adverse
events and laboratory abnormalities, mostly nonserious, in clinical studies. The safety database,
however, is limited.
• The effects of Exjade on long term
morbidity/mortality due to transfusion related
hemosiderosis have not been demonstrated.
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Post-marketing Commitments
under Subpart H
• Registry to assess the safety of Exjade
administration in children aged 2 to <6 during 5
years of follow-up
• Study of efficacy/safety of Exjade, 20 mg/kg/d in
patients with LIC <7 mg Fe/g dw
• Devise and conduct a study to assess iron
concentration and cardiac function in patients
treated with Exjade
• Completion of the studies in patients with sickle
cell syndromes and the ongoing extension
studies, including pediatric patients
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Exjade
• Discussion and questions:
Considerations for PMC protocol
development
– Long term use in pediatric patients
– Use among patients with lower LIC
– Cardiac effects
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