Exjade

1
Exjade (deferasirox ICL670) Efficacy and Safety

• Peter Marks, MD, PhDSenior Director, Clinical
  DevelopmentNovartis Pharmaceuticals Corporation

2
Presentation Outline

• Description of compound
• Clinical development program
• Dose-finding studies
• Efficacy trials
• Supportive studies
• Proposed indication and dosing
• Conclusions

3
ICL670 (Exjade?, deferasirox)

• Formulated as dispersible tablet
• Highly specific for iron
• 70 oral bioavailability, increased with food
• Half-life of 8 to 16 hours supports once-daily
  dosing
• Biliary excretion (fecal elimination)

4
Chelation of Iron With ICL670
ICL670
Chelated iron
Excretion
Iron
ICL670
5
Dose-Finding Studies
6
Short-term Iron BalanceStudy 0104

• Objectives
• Measure iron intake and excretion
• Short-term safety and tolerability
• Population
• ß-thalassemia major
• Design
• Dose escalation, 12 daily doses (n 23)
• Placebo or ICL670 at 10, 20, or 40 mg/kg
• Iron intake and excretion measured chemically

7
Short-term Iron Excretion Study
0104Dose-Response
1.2
Patients
1.0
Mean
0.8
Net iron excretion,mg/kg/day
0.6
0.4
0.2
0
Placebo
10
20
40
ICL670, mg/kg/day
Nisbet-Brown E, et al. Lancet. 20033611597-1602.
8
Randomized Phase II Dose-Finding TrialStudy
0105ß-thalassemia
Regular blood transfusions continue
RANDOMIZE
ICL670 10 mg/kg/day (n 24)
ICL670 20 mg/kg/day (n 24)
DFO 40 mg/kg given 5 days/week (n 23)
Run-in period
Baseline
12
6
3
9
SQUID assessments (month)
Screening Days 28 to 6
Washout Days 5 to 1
Extension (0105E2)
DFO Deferoxamine.
9
Change in Liver Iron ConcentrationStudy
0105ß-thalassemia
5
ICL670 10 mg/kg (n 24)
4
ICL670 20 mg/kg (n 24)
DFO 40 mg/kg (n 23)
3
2
1
Change in LIC, mg/g dry weight
0
1
2
3
4
9
3
12
6
5
Time on study, months
Mean standard deviation. LIC Liver iron
concentration.
10
Conclusions From Dose-Finding TrialsStudies 0104
and 0105

• ICL670 produces dose-dependent iron excretion
  over the range from 10 to 40 mg/kg
• Comparable pharmacodynamic effect is seen with a
  21 dose ratio between deferoxamine and ICL670
• Ratio supported by data from preclinical studies
  in marmoset monkeys

11
Clinical Development Registration Program

• ß-thalassemia major was used as the model disease
  for the demonstration of efficacy
• Regularly transfused population
• Well-documented pattern of complications
• Patients with other anemias, including sickle
  cell disease, myelodysplastic syndromes (MDS),
  and Diamond-Blackfan anemia (DBA), were included
  primarily to assess safety

12
Liver Iron Concentration (LIC) Measurement
Techniques Used in Clinical Trials

• Liver biopsy by a validated methodology performed
  at a single central laboratory
• Magnetic liver susceptometry using a
  superconducting quantum interference device
  (SQUID) at 3 centers using the same protocol
• Ratio of LIC (measured by SQUID) to biopsy found
  to be 12 in validation study
• SQUID useful as relative measure of change in LIC
  over time

13
ICL670 Studies 0107, 0108, 0109
Trial code Abbreviated title Objective
0107 N 591 Randomized comparison of ICL670 with DFO inß-thalassemia 1 Efficacy (noninferiority) 2 Safety and tolerability
0108 N 184 Noncomparative trial of ICL670 in ß-thalassemia and rare anemia 1 Efficacy 2 Safety and tolerability
0109 N 203 Randomized comparison of ICL670 with DFO in sickle cell 1 Safety 2 Efficacy
All 3 studies conducted in adult and pediatric
patients 2 years of age. FDA feedback received
under special protocol assessment for all 3
protocols.
14
Dosing AlgorithmStudies 0107, 0108, 0109
Baseline LIC, mg Fe/g dw ICL670, mg/kg/day Deferoxamine, mg/kg/day
2 - 3 5 20 - 30a
gt 3 - 7 10 25 - 35a
gt 7 - 14 20 35 - 50
gt 14 30 50
dw Dry weight. a Deferoxamine patients with
LIC values of 2 to 7 could be maintained on the
dose administered prior to the study, even if
higher than in the above dosing schema.
15
Study 0107
16
Phase 3 Comparative Study 0107ß-thalassemia
RANDOMIZE
ICL670 5 to 30 mg/kg/day
Regular blood transfusions continue
Deferoxamine 20 to 60 mg/kg/day
Run-in period
1-year treatment
Liver biopsy a
Liver biopsy a
Serum ferritin monitored monthly
Screening Days 28 to 6
Washout Days 5 to 1
a SQUID used to measure LIC in 16 of patients.
17
Primary EndpointStudy 0107

• Primary endpoint treatment success rateat 1 year

Treatment success criteria Treatment success criteria
LIC at baseline,mg Fe/g dw Success, if LIC after 1 year,mg Fe/g dw
2 to lt 7 Maintenance within 1 to lt 7
7 to lt 10 Decrease to within 1 to lt 7
10 Decrease of 3

• Hypothesis success rate in patients receiving
  ICL670 is noninferior to deferoxamine

18
Primary AnalysisStudy 0107

• Noninferiority is established if the lower limit
  of the 95 confidence interval (CI) for the
  difference in success rates between ICL670 and
  deferoxamine is greater than 15
• Primary efficacy analysis was performed in the
  per protocol-1 (PP-1) population of patients
• Includes patients completing the study and
  patients discontinuing for safety who were
  considered as treatment failures

19
Secondary Endpoints and Subgroup AnalysisStudy
0107

• Protocol specified
• Change in liver iron concentration in patients
  with LIC 7 mg Fe/g dw (inferential)
• Change in liver iron concentration (descriptive)
• Change in serum ferritin levels (descriptive)
• Post-hoc subgroup analysis
• Noninferiority in success rate in patients with
  LIC 7 mg Fe/g dw

20
Analysis PopulationsStudy 0107
Patients, n () Patients, n () Patients, n ()
Analysis population ICL670 n 297 DFO n 294 All patients N 591
ITT 297 (100.0) 294 (100.0) 591 (100.0)
Safety 296 (99.7) 290 (98.6) 586 (99.2)
PP-1 276 (92.9) 277 (94.2) 553 (93.6)
PP-2 268 (90.2) 273 (92.9) 541 (91.5)
Intent-to-treat (ITT) All patients
randomized. Safety All patients taking at least
one dose of study medication. Per protocol-1
(PP-1) Patients with baseline and final liver
iron concentration (LIC) values and
discontinuations due to safety. Per protocol-2
(PP-2) All patients who had baseline and final
liver iron concentration measurements.
21
Baseline CharacteristicsStudy 0107Safety
Population
ICL670 n 296 DFO n 290
Sex Male Female 140 (47.3) 156 (52.7) 142 (49.0) 148 (51.0)
Race Caucasian Other 263 (88.9) 33 (10.1) 251 (86.6) 39 (13.4)
Age, years Median Range 15 2 - 49 15.5 2 - 53
LIC, mg Fe/g dw Median Range 11.3 2.1 - 48.1 11.0 2.1 - 55.1
Serum ferritin, µg/L Median Range 2212 321 - 12,646 2091 453 - 15,283
22
Average Iron Intake During StudyStudy
0107Safety Population
ICL670 n 296 DFO n 290
Iron intake, mg Fe/kg/day, mean SD 0.38 0.11 0.41 0.11
23
Average Daily DoseStudy 0107Safety Population
Baseline LIC, mg Fe/g dw Baseline LIC, mg Fe/g dw Baseline LIC, mg Fe/g dw Baseline LIC, mg Fe/g dw
Dose, mg/kg/day 3 3 to lt 7 7 to lt 14 14
ICL670 n 15 n 78 n 84 n 119
Assigned 5 10 20 30
Actual, mean SD 6.2 1.6 10.2 1.2 19.4 1.7 28.2 3.5
DFO n 14 n 79 n 91 n 106
Assigned 20 - 30 25 - 35 35 - 50 50
Actual, mean SD 33.9 9.9 36.7 9.2 42.4 6.6 51.6 5.8
Ratio of DFO to ICL670 5.5 1 3.6 1 2.2 1 1.9 1
Ratio of DFO to ICL670 LIC lt 7 LIC lt 7 LIC 7 LIC 7
36.4 mg 9.6 mg 36.4 mg 9.6 mg 47.3 mg 24.6 mg 47.3 mg 24.6 mg
4 1 4 1 2 1 2 1
24
Primary Efficacy ResultsStudy 0107Biopsy and
SQUID
PP-1 population ICL670 n 276 DFO n 277
Success rate, 52.9 66.4
(95 CI) (47.0, 58.8) (60.9, 72.0)
Difference (95 CI) 13.5 (21.6, 5.4) 13.5 (21.6, 5.4)

• Factors that may have affected outcome
• Conservative dosing of ICL670 to minimize risk of
  overchelation in patients with lower LIC
• Maintenance of effective prestudy DFO doses in
  low-LIC group resulting in DFOICL670 gt 21

25
Secondary Efficacy ResultsStudy 0107Change in
LIC by Biopsy and SQUID
PP-2 Population ICL670 All patients DFO All patients
All LIC groups n 268 n 273
Mean change SD 2.4 8.2 2.9 5.4
LIC lt 7 mg Fe/g dw n 83 n 87
Mean change SD 4.0 3.8 0.13 2.2
LIC 7 mg Fe/g dw n 185 n 186
Mean change SD 5.3 8.0 4.3 5.8
P lt .001 P lt .001
Student t test, change from baseline.
26
Secondary Efficacy ResultsStudy 0107Change in
LIC by Dose Group
10
5
0
Change in LIC, mg Fe/g dw
5
10
DFO, mg/kg/day
ICL670, mg/kg/day
15
20
DFO lt 25 25 - 35 35 - 50 50 ICL670 5 10 20 30 n
13 15 75 68 87 77 98 108
PP-2 population LIC by biopsy and SQUID.
27
Secondary Efficacy ResultsStudy 0107Change in
Ferritin by Dose Group
4000
DFO, mg/kg/day
ICL670, mg/kg/day
3000
2000
1000
Change in serum ferritin, µg/L
0
1000
2000
3000
DFO lt 25 25 - 35 35 - 50 50 ICL670 5 10 20 30 n
6 15 40 73 117 80 117 115
Safety population.
28
Post-hoc Subgroup Analysis of 1 Endpoint Study
0107Biopsy and SQUID
PP-1 population ICL670 DFO
LIC 7 mg Fe/g dw n 191 n 190
Success rate, 58.6 58.9
(95 CI) (51.7, 65.6) (52.0, 65.9)
Difference (95 CI) 0.3 (10.2, 9.6) 0.3 (10.2, 9.6)

• In group with LIC 7 mg Fe/g dw (65 of
  patients)
• Noninferiority boundary prospectively defined for
  the overall population was achieved

29
Study 0108
30
Phase 2 Noncomparative Study 0108ß-thalassemia
and Rare Anemias
Treatment initiated
Study end
ICL670 5 to 30 mg/kg/day (n 184)
Run-in period
1-year treatment
Liver biopsy a
Liver biopsy a
Serum ferritin monitored monthly
Screening Days 28 to 6
Washout Days 5 to 1
a SQUID used to measure LIC in 35 of patients.
31
Study Design and AnalysisStudy 0108

• Primary endpoint Success rate asdefined for
  Study 0107
• Hypothesis Success rate for patients treated
  with ICL670 is gt 50 (i.e., lower limit of the
  95 CI gt 50)
• Primary analysis performed on the intent-to-treat
  population (ITT)

32
Secondary Endpoints and Subgroup AnalysisStudy
0108

• Protocol specified
• Change in liver iron concentration in patients
  with LIC 7 mg Fe/g dw (inferential)
• Change in liver iron concentration (descriptive)
• Change in serum ferritin levels (descriptive)
• Post-hoc subgroup analysis
• Success rate in patients with LIC 7 mg Fe/g dw

33
Baseline CharacteristicsStudy 0108Safety
Population
ß-thalassemian 85 Rare anemias n 99 All patients n 184
Sex Male Female 42 (49.4) 43 (50.6) 51 (51.5) 48 (48.5) 93 (50.5) 91 (49.5)
Race Caucasian Other 56 (65.9) 29 (34.1) 89 (89.9) 10 (10.1) 145 (78.8) 24 (13.0)
Age, years Median Range 23 4 - 59 49 27
Age, years Median Range 23 4 - 59 3 - 81 3 - 81
LIC, mg Fe/g dw Median Range 18.1 3.0 - 54.4 15.0 2.3 - 51.3 16.7 2.3 - 54.4
Serum ferritin, µg/L Median Range 3636 440 - 13,943 2674 537 - 11,854 3075 440 - 11,854
Rare anemia group includes myelodysplastic
syndromes (n 47),Diamond-Blackfan anemia (n
20), and other anemias (n 20).
34
Average Iron Intake During StudyStudy
0108Safety Population
ß-thalassemia n 85 Rare anemias n 99 All patients n 184
Iron intake, mg Fe/kg/day, mean SD 0.35 0.12 0.32 0.15 0.34 0.14
35
Average Daily Dose of ICL670Study 0108ITT
Population
Baseline LIC,mg Fe/g dw 3 3 to lt 7 7 to lt 14 14
Patients n 7 n 18 n 52 n 107
Assigned doseICL670, mg/kg/day 5 10 20 30
Actual doseICL670, mg/kg/day, mean SD 5.7 1.0 9.7 1.1 18.4 2.5 27.9 3.4
36
Primary Efficacy ResultsStudy 0108Biopsy and
SQUID

ß-thalassemia Rareanemias Allpatients P value
ITT population n 85 n 99 n 184
Success rate, 52.9 48.5 50.5 .441
(95 CI) (42.3, 63.6) (38.6, 58.3) (43.3, 57.8)

PP-1 population n 80 n 85 n 165
Success rate, 56.3 56.5 56.4 .051
(95 CI) (45.4, 67.1) (45.9, 67.0) (48.8, 63.9)
1-sided P values were calculated versus 50
success rate (no control arm).
37
Secondary Efficacy ResultsStudy 0108Change in
LIC by Biopsy and SQUID
PP-2 population ß-thalassemia Rareanemias Allpatients
All LIC groups n 76 n 71 n 147
Mean change SD 4.7 8.6 3.7 6.5 4.2 7.7
LIC lt 7 mg Fe/g dw n 9 n 12 n 21
Mean change SD 6.0 4.0 1.6 3.1 3.5 4.1
LIC 7 mg Fe/g dw n 67 n 59 n 126
Mean change SD 6.1 8.0 4.8 6.5 5.5 7.4
P lt .001
Student t test change from baseline.
38
Secondary Efficacy ResultsStudy 0108Change in
LIC by Dose Group
n 1 4 8
8 17 22 50 37
PP-2 population LIC by biopsy and SQUID.
39
Secondary Efficacy ResultsStudy 0108Change in
Ferritin by Dose Group
n 2 4 8
10 21 24 52 42
Safety population.
40
Post-hoc Subgroup Analysis of 1 Endpoint Study
0108Biopsy and SQUID

ß-thalassemia Rareanemias Allpatients P value
ITT population n 75 n 84 n 159
Success rate, 57.3 47.6 52.2 .289
(95 CI) (46.2, 68.5) (36.9, 58.3) (44.4, 60.0)
PP-1 population n 70 n 72 n 142
Success rate, 61.4 55.6 58.5 .022
(95 CI) (50.0, 72.8) (44.1, 67.0) (50.3, 66.6)
1-sided P values were calculated versus 50
success rate (no control arm).
41
Study 0109
42
Phase 2 Comparative TrialAdult and Pediatric
Sickle Cell DiseaseStudy 0109
RANDOMIZE
ICL670 5 to 30 mg/kg/daya (n 132)
Regular blood transfusions continue
Deferoxamine 20 to 60 mg/kg/day (n 63)
Run-in period
SQUID
SQUID
SQUID
1-year treatment
Serum ferritin monitored monthly
Screening Days 28 to 6
Washout Days 5 to 1
Primary objective safety
Prior therapy with deferoxamine (65). a Modified
halfway through to 20 or 30 mg/kg for most
patients.
43
Study DesignStudy 0109

• Primary objective safety and tolerability
• Secondary efficacy endpoints
• Change in liver iron concentration
• Change in serum ferritin
• (Interim 24-week data provided in NDA)

44
Baseline CharacteristicsStudy 0109Safety
Population
ICL670 n 132 DFO n 63
Sex Male Female 52 (39.4) 80 (60.6) 28 (44.4) 35 (55.6)
Race Caucasian Black Other 8 (6.1) 118 (89.4) 6 (4.5) 3 (4.8) 59 (93.7) 1 (1.6)
Age, years Median Range 15 3 - 54 16 3 - 51
LIC, mg Fe/g dw Median Range 8.6 2.2 - 31.0 6.8 2.1 - 22.3
Serum ferritin, µg/L Median Range 3531 1082 - 12,901 2835 1015 - 15,578
45
Average Iron Intake During StudyStudy
0109Safety Population
ICL670 n 132 DFO n 63
Iron intake, mg Fe/kg/day, mean SD 0.21 0.13 0.23 0.12
46
Average Daily DoseStudy 010924-Week Data
Baseline SQUID LIC,mg Fe/g dw 3 3 to lt 7 7 to lt 14 14
Assigned dose ICL670 5 mg/kgn 4 10 mg/kgn 64 20 mg/kgn 46 30 mg/kgn 18
Actual average dose, mg/kg/day 4.9 0.29 11.0 3.15 19.4 1.97 28.9 2.15
Assigned dose deferoxamine 20 - 30 mg/kgn 6 25 - 35 mg/kgn 21 35 - 50 mg/kgn 19 50mg/kgn 17
Actual average dose, mg/kg/day, mean SD 22.5 3.82 28.8 2.98 36.4 9.64 51.0 5.67
Ratio of deferoxamine dose to ICL670 dose 4.6 1 2.6 1 1.9 1 1.8 1
47
Change in LIC and Serum Ferritin by Dose Group
at 24 WeeksStudy 0109
Ferritin in safety population
LIC by SQUID in PP-2 population
DFO ICL670
DFO ICL670
n 5 4 21 59 15 45
17 13
n 4 3 18 54 14 43
13 12
48
Efficacy Conclusions for ICL670Study 0107

• The boundary for non-inferiority was not met for
  the population as a whole
• Prespecified noninferiority boundary was met in a
  post-hoc subgroup analysis in patients withLIC
  7 mg Fe/g dw (65) treated with 20 to 30 mg/kg
• Statistically significant reduction in LIC in
  patients with LIC 7 mg Fe/g dw treated with 20
  to 30 mg/kg
• Dose-dependent reduction in LIC and ferritin
• Optimal ratio of DFO to ICL670 is 2 to 1

49
Efficacy Conclusions For ICL670Study 0108

• Statistically significant reduction in LIC in
  patients with LIC 7 mg Fe/g dw treated with 20
  to 30 mg/kg
• Dose dependent reduction in LIC and ferritin
• Treatment effects generally consistent with Study
  0107

50
Safety
51
Summary of Exposure to ICL670Safety or Efficacy
Studies in Patients
Study number ICL670 dose (mean duration of exposure) N
0106 10 mg/kg/day (49.2 weeks) 40
0107 5, 10, 20, 30 mg/kg/day (52.1 weeks) 296
0108 5, 10, 20, 30 mg/kg/day (47.2 weeks) 184
0109 5, 10, 20, 30 mg/kg/day (47.9 weeks) 132
Total 652
Study 0105E2 (n 51) had a median duration of
127 weeks (interim report). An additional 48
patients were involved in pharmacology studies,
and 186 healthy volunteers participated in
bioavailability, drug interaction, and cardiac
safety studies.
52
Patients Treated With ICL670 in 1-Year Clinical
StudiesStudies 0106, 0107, 0108, 0109
Patients, n Patients, n Patients, n
Disease Total Adults Pediatrics
ß-thalassemia 421 216 205
Sickle cell disease 132 65 67
Other rare anemias 99 79 20
Total 652 360 292

• Pediatric patients receiving ICL670 by age group
• 2 to lt 6 years, n 52
• 6 to lt 12 years, n 121
• 12 to lt 16 years, n 119

53
Mean Exposure, Discontinuations, and Serious
Adverse EventsRandomized Studies 0107 and 0109
0107 0107 0109 0109
Study ICL670 n 296 DFO n 290 ICL670 n 132 DFO n 63
Exposure, weeks, mean SD 52 8.1 53 6.7 48 10.8 47 12.0
All withdrawals, n () 17 (5.7) 12 (4.1) 15 (11.3) 9 (14.3)
Withdrawals forsafety, n () 8 (2.7) 4 (1.4) 7 (5.3) 2 (3.2)
Serious adverseevents (SAEs), n () 26 (8.8) 22 (7.6) 61 (46.2)a 27 (42.9)a
a Majority of SAEs in Study 0109 were sickle cell
crises (23 in both arms).
54
Mean Exposure, Discontinuations, and Serious
Adverse EventsStudies 0106 and 0108
Study 0106n 40 0108n 184
Exposure, weeks, mean SD 49 8.4 48 14.1
All withdrawals, n () 1 (2.6) 32 (17.4)
Withdrawals forsafety, n () 1 (2.6) 18 (9.8)
Serious adverseevents (SAEs), n () 4 (10.0) 32 (17.4)
55
DeathsStudies 0106, 0107, 0108, 0109
Relationship to study drug ICL670 ICL670 DFO DFO
Relationship to study drug Unrelated Related Unrelated Related
0106 0 0 N/A N/A
0107 0 1 3 0
0108 5 0 N/A N/A
0109 0 0 0 0
Causes of death 0107 related sudden death 0107
unrelated convulsions, intraventricular
thrombus, sepsis 0108 unrelated
cardiorespiratory arrest, pulmonary embolism,
sepsis (3).
56
Adverse Events Irrespective of Relationship to
Study DrugStudy 0107Symptoms More Commonly
Observed on ICL670
ICL670 n 296 DFO n 290
Patients with AE(s), 85.8 84.8
AE preferred term,
Abdominal paina 21.7 14.1
Diarrheaa 11.8 7.6
Nausea 10.5 4.8
Vomiting 10.1 9.7
Rasha 8.4 3.2
Pyrexia, headache, cough, nasopharyngitis,
pharyngolaryngeal pain, pharyngitis, and
influenza were observed with similar frequency in
patients receiving ICL670 and DFO. a Grouped term.
57
Adverse Events Irrespective of Relationship to
Study DrugStudy 0109Symptoms More Commonly
Observed on ICL670
ICL670 n 132 DFO n 63
Patients with AE(s), 96.2 98.4
AE preferred term,
Abdominal paina 28.0 14.3
Nausea 22.7 11.1
Vomiting 21.2 15.9
Diarrheaa 19.7 4.8
Rasha 13.6 4.8
Pyrexia, headache, and pharyngolaryngeal pain
were observed with similar frequency in patients
receiving ICL670 and DFO. Cough and
nasopharyngitis were more common with DFO (ICL670
13.6 versus DFO 20.6). a Grouped term.
58
Adverse Events Irrespective of Relationship to
Study DrugPooled Analysis by Disease
ICL670 ICL670 ICL670
Pooled ß-thal n 421 Sickle cell n 132 Rareanemias n 99
Patients with AE(s), 89.8 96.2 98.0
AE preferred term,
Abdominal paina 23.8 28.0 28.3
Diarrheaa 16.6 19.7 42.4
Vomiting 13.8 21.2 29.3
Rasha 12.4 13.6 12.1
Nausea 11.9 22.7 27.3
a Grouped term.
59
Adverse Events Irrespective of Relationship to
Study DrugICL670Pooled ß-thalassemia Population
by Age
Patients, Patients, Patients, Patients, Patients,
lt 6yearsn 39 6 to lt 12 yearsn 85 12 to lt 16 yearsn 81 16yearsn 216 TotalN 421
Abdominal paina 20.5 15.3 23.5 27.8 23.8
Diarrheaa 30.8 8.2 16.0 17.6 16.6
Vomiting 10.3 22.4 11.1 12.0 13.8
Rasha 5.1 12.9 12.3 13.4 12.4
Nausea 5.1 10.6 6.2 15.7 11.9
a Grouped term.
60
Patients With Increases inSerum
CreatinineStudies 0106, 0107, 0108, 0109
Creatinine increase at 2 consecutivepost-baseline visits Patients, n () Patients, n () Patients, n () Patients, n () Patients, n ()
Creatinine increase at 2 consecutivepost-baseline visits ICL670 ICL670 ICL670 DFO DFO
Creatinine increase at 2 consecutivepost-baseline visits Pooled ß-thal n 421 Sickle cell n 132 Rare anemias n 99 ß-thal n 290 Sickle cell n 63
gt 33 and lt ULN 137 (32.5) 48 (36.4) 23 (23.2) 40 (13.8) 14 (22.2)
gt 33 and gt ULN 10 (2.4) 3 (2.3) 16 (16.2) 1 (0.3) 2 (3.2)

Total 147 (34.9) 51 (38.7) 39 (39.4) 41 (14.1) 16 (25.4)
Each patient with an increase in serum creatinine
is included in only one of the above categories.
61
Dose Reductions for Increases inSerum
CreatinineStudies 0106, 0107, 0108, 0109
36 (237/652) with 2 consecutive increases in
creatinine
13 (85/652) were dose reduced for sustained
increases
25 returned to baseline
60 stabilized
15 fluctuated between baseline and maximum
increase
a Serum creatinine dose reduction criteria For
15 years 2 consecutive increases greater than
33 For lt 15 years 2 consecutive increases
greater than 33 and gt upper limit of normal.
62
Patients With Abnormal Liver Function
TestsStudies 0106, 0107, 0108, 0109
ALT gt 5 ULN at 2 consecutivepost-baseline visits Patients, n () Patients, n () Patients, n () Patients, n () Patients, n ()
ALT gt 5 ULN at 2 consecutivepost-baseline visits ICL670 ICL670 ICL670 DFO DFO
ALT gt 5 ULN at 2 consecutivepost-baseline visits Pooled ß-thal n 421 Sickle cell n 132 Rare anemias n 99 ß-thal n 290 Sickle cell n 63
Patients with ALT normal at baseline 5 (1.2) 0 (0.0) 1 (1.0) 0 (0.0) 0 (0.0)
Patients with ALT elevated at baseline 24 (5.7) 5 (3.8) 5 (5.1) 5 (1.7) 0 (0.0)

Total 29 (6.9) 5 (3.8) 6 (6.1) 5 (1.7) 0 (0.0)
ALT Alanine aminotransferase ULN Upper limit
of normal.
63
Additional Safety ParametersComparison of ICL670
and DFO

• No significant differences between ICL670 and DFO
  in the following safety parameters
• Episodes of neutropenia or thrombocytopenia
• Trace metal changes (copper, zinc)
• Changes in the lens of the eye
• Hearing loss
• Growth or development (pediatrics)

64
Safety Conclusions for ICL670

• The most common adverse events with greater
  frequency in patients receiving ICL670 were
  transient gastrointestinal symptoms and rash
• Mild increases in serum creatinine mostly within
  the normal range and increased transaminases were
  the most common laboratory abnormalities
• Neutropenia, thrombocytopenia, trace metal,
  ophthalmologic, auditory changes similar to
  deferoxamine during a 1-year period
• No effects on pediatric growth or development
  during a 1-year period

65
Proposed Dosing and Monitoring
66
Initial Dosing and Monitoring of Therapy With
ICL670

• Initiate therapy after the transfusion of
  approximately 20 U (equivalent to 100 mL/kg) of
  PRBC or when there is evidence from clinical
  monitoring that iron overload is present (e.g.,
  the serum ferritin level is gt 1000 µg/L)
• The recommended initial daily dose is 20 mg/kg
• An initial daily dose of 30 mg/kg may be
  considered for patients with severe iron overload
  (e.g., serum ferritin gt 2500 µg/L)

67
Monitoring of Therapy

• It is recommended that serum ferritin be
  monitored monthly and the dose should be adjusted
  if necessary every 3 to 6 months according to the
  trend in serum ferritin level observed during
  that time

68
Initial Dosing and Monitoring of Therapy

• Serum creatinine and liver function tests should
  be monitored monthly
• The dose of ICL670 should be reduced if the serum
  creatinine is increased on 2 consecutive
  occasions by 33 compared with baseline
• Therapy with ICL670 should be discontinued in
  patients with liver function tests that are
  rising on consecutive occasions in the absence of
  an alternative etiology

69
Ongoing Extension Studies With ICL670
Study Objective n
0105E2 Long-term safety, thalassemia 70
0106E1 Long-term safety, thalassemia 39
0107E1 Long-term safety, thalassemia 507
0108E1 Long-term safety, thalassemia/rare anemias 141
0109E1 Long-term safety, sickle cell disease 154
70
Additional Studies With ICL670Ongoing or Planned
Study Objective n
2201 Safety in sickle cell disease / hydroxyurea 210
2203 Expanded access, congenital anemias 3000
2402 Efficacy and safety, thalassemia 250
2409 Efficacy and safety in transfusional iron overload 1541
US02/US03 Safety in myelodysplastic syndromes 180
Planned Ferritin-based dosing
Planned Cardiac iron reduction trial examining function
Planned Renal mechanistic study
Planned Hepatic impairment study
71
Overall Summary of Efficacy and Safety

• Treatment success rate with ICL670 is similar to
  deferoxamine when patients with liver iron
  concentration 7 mg Fe/g dw are treated with
  doses of 20 to 30 mg/kg
• ICL670 at a daily dose of 20 mg/kg maintains
  neutral iron balance and a dose of 30 mg/kg
  reduces existing body iron stores when regular
  blood transfusions are given
• ICL670 produces iron excretion in proportion to
  the dose administered

72
Overall Summary of Safety and Efficacy

• GI side effects, rash, increases in serum
  creatinine, and transaminases are manageable
• Monthly monitoring of serum creatinine and
  transaminases is recommended in the label
• Favorable overall benefit-to-risk profile to
  address the unmet medical need for a safe and
  effective oral iron chelator