CE-1 Exjade ® (deferasirox; ICL670) Efficacy and Safety Peter Marks, MD, PhD Senior Director, Clinical Development Novartis Pharmaceuticals Corporation

CE-1

ExjadeExjade®® (deferasirox; ICL670) (deferasirox; ICL670) Efficacy and SafetyEfficacy and Safety

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

CE-2

Presentation OutlinePresentation Outline

Description of compoundClinical development program

– Dose-finding studies

– Efficacy trials

– Supportive studiesProposed indication and dosingConclusions

CE-3

ICL670 (ExjadeICL670 (Exjade, deferasirox), deferasirox)

Formulated as dispersible tabletHighly specific for iron70% oral bioavailability, increased with foodHalf-life of 8 to 16 hours supports once-daily

dosingBiliary excretion (fecal elimination)

CE-4

Chelation of Iron With ICL670Chelation of Iron With ICL670

ICL670ICL670

ICL670ICL670

IronIron

Chelatediron

Chelatediron ExcretionExcretion

CE-5

Dose-Finding StudiesDose-Finding Studies

CE-6

Short-term Iron BalanceShort-term Iron BalanceStudy 0104Study 0104

ObjectivesObjectives Measure iron intake and excretion Short-term safety and tolerability

PopulationPopulation β-thalassemia major

DesignDesign Dose escalation, 12 daily doses (n = 23)

– Placebo or ICL670 at 10, 20, or 40 mg/kg Iron intake and excretion measured chemically

CE-7

Short-term Iron Excretion Short-term Iron Excretion Study 0104—Dose-ResponseStudy 0104—Dose-Response

ICL670, mg/kg/day

Ne

t ir

on

exc

reti

on

,m

g/k

g/d

ay

Placebo 10 20 40

1.2

1.0

0.8

0.6

0.4

0.2

0

Patients

Mean

n = 5 5 6 7Nisbet-Brown E, et al. Lancet. 2003;361:1597-1602.

CE-8

Randomized Phase II Dose-Finding TrialRandomized Phase II Dose-Finding TrialStudy 0105—Study 0105—ββ-thalassemia-thalassemia

ICL670 20 mg/kg/day (n = 24)

DFO 40 mg/kg given 5 days/week (n = 23)

SQUID assessments (month)

Baseline 12

Regular blood transfusions continueRANDOMIZE

6

Screening Days –28 to –6

WashoutDays –5 to –1

Run-in period

3 9

ICL670 10 mg/kg/day (n = 24)

Extension(0105E2)

DFO = Deferoxamine.

CE-9

Change in Liver Iron ConcentrationChange in Liver Iron ConcentrationStudy 0105—Study 0105—ββ-thalassemia-thalassemia

Mean ± standard deviation.LIC = Liver iron concentration.

Ch

ang

e in

LIC

, m

g/g

dry

wei

gh

t

3 6 9 12

Time on study, months–5

–4

–3

–2

–1

0

1

2

3

4

5

DFO 40 mg/kg (n = 23)

ICL670 10 mg/kg (n = 24)

ICL670 20 mg/kg (n = 24)

CE-10

Conclusions From Dose-Finding TrialsConclusions From Dose-Finding TrialsStudies 0104 and 0105Studies 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 2:1 dose ratio between deferoxamine and ICL670

– Ratio supported by data from preclinical studies in marmoset monkeys

CE-11

Clinical Development Registration ProgramClinical Development Registration Program

β-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

CE-12

Liver Iron Concentration (LIC) Measurement Liver Iron Concentration (LIC) Measurement Techniques Used in Clinical TrialsTechniques 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 ~ 1:2 in validation study

– SQUID useful as relative measure of change in LIC over time

CE-13

ICL670 Studies 0107, 0108, 0109ICL670 Studies 0107, 0108, 0109

Trial code Abbreviated title Objective

0107N = 591

Randomized comparison of ICL670 with DFO inβ-thalassemia

1˚ Efficacy (noninferiority)2˚ Safety and tolerability

0108N = 184

Noncomparative trial of ICL670 in β-thalassemia and rare anemia

1˚ Efficacy2˚ Safety and tolerability

0109N = 203

Randomized comparison of ICL670 with DFO in sickle cell

1˚ Safety2˚ 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.

CE-14

Dosing AlgorithmDosing AlgorithmStudies 0107, 0108, 0109Studies 0107, 0108, 0109

Baseline LIC,mg Fe/g dw

ICL670,mg/kg/day

Deferoxamine, mg/kg/day

2 - 3 5 20 - 30a

> 3 - 7 10 25 - 35a

> 7 - 14 20 35 - 50

> 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.

CE-15

Study 0107Study 0107

CE-16

Phase 3 Comparative Study 0107Phase 3 Comparative Study 0107β-thalassemiaβ-thalassemia

ICL670 5 to 30 mg/kg/day

Deferoxamine 20 to 60 mg/kg/day

1-year treatmentLiver biopsy a

Liver biopsy aSerum ferritin monitored monthly

Regular blood transfusions continue

RANDOMIZE

a SQUID used to measure LIC in 16% of patients.



Run-in period

CE-17

Primary endpoint: treatment success rateat 1 year

Primary EndpointPrimary EndpointStudy 0107Study 0107

Treatment success criteriaLIC at baseline,mg Fe/g dw

Success, if LIC after 1 year,mg Fe/g dw

2 to < 7 Maintenance within 1 to < 7≥ 7 to < 10 Decrease to within 1 to < 7≥ 10 Decrease of ≥ 3

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

CE-18

Primary AnalysisPrimary AnalysisStudy 0107Study 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

CE-19Secondary Endpoints and Secondary Endpoints and Subgroup AnalysisSubgroup AnalysisStudy 0107Study 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

CE-20

Analysis PopulationsAnalysis PopulationsStudy 0107 Study 0107

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.

Patients, n (%)

Analysis population

ICL670n = 297

DFOn = 294

All patientsN = 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)

CE-21

Baseline CharacteristicsBaseline CharacteristicsStudy 0107—Safety PopulationStudy 0107—Safety Population

ICL670n = 296

DFOn = 290

Sex MaleFemale

140 (47.3%)156 (52.7%)

142 (49.0%)148 (51.0%)

Race CaucasianOther

263 (88.9%)33 (10.1%)

251 (86.6%)39 (13.4%)

Age, years MedianRange

152 - 49

15.52 - 53

LIC, mg Fe/g dw MedianRange

11.32.1 - 48.1

11.02.1 - 55.1

Serum ferritin, µg/L MedianRange

2212321 - 12,646

2091453 - 15,283

CE-22

Average Iron Intake During StudyAverage Iron Intake During StudyStudy 0107—Safety PopulationStudy 0107—Safety Population

ICL670 n = 296

DFO n = 290

Iron intake, mg Fe/kg/day, mean ± SD

0.38 ± 0.11 0.41 ± 0.11

CE-23

Average Daily DoseAverage Daily DoseStudy 0107—Safety PopulationStudy 0107—Safety Population

Baseline LIC, mg Fe/g dw

Dose, mg/kg/day ≤ 3 3 to < 7 7 to < 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

LIC < 7 LIC ≥ 7

36.4 mg : 9.6 mg 47.3 mg : 24.6 mg

4 : 1 2 : 1

CE-24

Primary Efficacy ResultsPrimary Efficacy ResultsStudy 0107—Biopsy and SQUIDStudy 0107—Biopsy and SQUID

PP-1 populationICL670n = 276

DFOn = 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)

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 DFO:ICL670 > 2:1

CE-25

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0107—Change in LIC by Biopsy and SQUIDStudy 0107—Change in LIC by Biopsy and SQUID

* Student t test, change from baseline.

PP-2 PopulationICL670

All patientsDFO

All patients

All LIC groups n = 268 n = 273

Mean change ± SD –2.4 ± 8.2 –2.9 ± 5.4

LIC < 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 < .001* P < .001*

CE-26

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0107—Change in LIC by Dose GroupStudy 0107—Change in LIC by Dose Group

–15

–10

–5

0

5

10

DFO, mg/kg/day

ICL670, mg/kg/day

Ch

ang

e in

LIC

, m

g F

e/g

dw

DFO < 25 25 - 35 35 - 50 ≥ 50ICL670 5 10 20 30n = 13 15 75 68 87 77 98 108

–20

PP-2 population; LIC by biopsy and SQUID.

CE-27

DFO < 25 25 - 35 35 - 50 ≥ 50ICL670 5 10 20 30n = 6 15 40 73 117 80 117 115

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0107—Change in Ferritin by Dose GroupStudy 0107—Change in Ferritin by Dose Group

Ch

ang

e in

ser

um

fer

riti

n,

μg

/L

–3000

–2000

–1000

0

1000

2000

3000

4000DFO, mg/kg/day

ICL670, mg/kg/day

Safety population.

CE-28

Post-hoc Subgroup AnalysisPost-hoc Subgroup Analysis of 1˚ Endpoint of 1˚ Endpoint Study 0107—Biopsy and SQUIDStudy 0107—Biopsy 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)

In group with LIC ≥ 7 mg Fe/g dw (65% of patients): Noninferiority boundary prospectively defined for

the overall population was achieved

CE-29


CE-30

Study endTreatmentinitiated

ICL670 5 to 30 mg/kg/day (n = 184)

Phase 2 Noncomparative Study 0108Phase 2 Noncomparative Study 0108β-thalassemia and Rare Anemiasβ-thalassemia and Rare Anemias

1-year treatmentLiver biopsy a

Liver biopsy aSerum ferritin monitored monthlyScreening

Days –28 to –6Washout

Days –5 to –1

Run-in period

a SQUID used to measure LIC in 35% of patients.

CE-31

Study Design and AnalysisStudy Design and AnalysisStudy 0108Study 0108

Primary endpoint: Success rate asdefined for Study 0107

Hypothesis: Success rate for patients treated with ICL670 is > 50% (i.e., lower limit of the 95% CI > 50%)

Primary analysis performed on the intent-to-treat population (ITT)

CE-32Secondary Endpoints and Secondary Endpoints and Subgroup AnalysisSubgroup AnalysisStudy 0108Study 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

CE-33


Rare anemia group includes myelodysplastic syndromes (n = 47),Diamond-Blackfan anemia (n = 20), and other anemias (n = 20).

β-thalassemian = 85

Rare anemiasn = 99

All patientsn = 184

Sex MaleFemale

42 (49.4%)43 (50.6%)

51 (51.5%)48 (48.5%)

93 (50.5%)91 (49.5%)

Race CaucasianOther

56 (65.9%)29 (34.1%)

89 (89.9%)10 (10.1%)

145 (78.8%)24 (13.0%)


234 - 59

49 27

3 - 81 3 - 81


18.13.0 - 54.4

15.02.3 - 51.3

16.72.3 - 54.4


3636440 - 13,943

2674537 - 11,854

3075440 - 11,854

CE-34


β-thalassemia

n = 85

Rare anemias

n = 99

All patients

n = 184


0.35 ± 0.12 0.32 ± 0.15 0.34 ± 0.14

CE-35

Average Daily Dose of ICL670Average Daily Dose of ICL670Study 0108—ITT PopulationStudy 0108—ITT Population

Baseline LIC,mg Fe/g dw ≤ 3 3 to < 7 7 to < 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

CE-36

Primary Efficacy ResultsPrimary Efficacy ResultsStudy 0108—Biopsy and SQUIDStudy 0108—Biopsy and SQUID

β-thalassemiaRare

anemiasAll

patients P valueITT 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).

CE-37

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0108—Change in LIC by Biopsy and SQUIDStudy 0108—Change in LIC by Biopsy and SQUID

PP-2 population β-thalassemiaRare

anemiasAll

patients

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 < 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 < .001*

* Student t test change from baseline.

CE-38

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0108—Change in LIC by Dose GroupStudy 0108—Change in LIC by Dose Group

Ch

ang

e in

LIC

, m

g F

e/g

dw

–20

–15

–10

–5

0

5

10

15

5 10 20 30

β-thalassemia

Rare anemias

ICL670 dose, mg/kg/day

PP-2 population; LIC by biopsy and SQUID.n = 1 4 8 8 17 22 50 37

CE-39

Secondary Efficacy ResultsSecondary Efficacy ResultsStudy 0108—Change in Ferritin by Dose GroupStudy 0108—Change in Ferritin by Dose Group

Safety population.n 2 4 8 10 21 24 52 42

-4000

-3000

-2000

-1000

0

1000

2000

3000

4000

5000

5 10 20 30

ICL670 dose, mg/kg/day

Ch

ang

e in

ser

um

fer

riti

n,

µg

/L ?-thalassemia

Rare anemias

CE-40

Post-hoc Subgroup AnalysisPost-hoc Subgroup Analysis of 1˚ Endpoint of 1˚ Endpoint Study 0108—Biopsy and SQUIDStudy 0108—Biopsy and SQUID

β-thalassemiaRare

anemiasAll

patients P valueITT population n = 75 n = 84 n = 159Success 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 = 142Success 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).

CE-41


CE-42Phase 2 Comparative TrialPhase 2 Comparative TrialAdult and Pediatric Sickle Cell DiseaseAdult and Pediatric Sickle Cell DiseaseStudy 0109Study 0109

ICL670 5 to 30 mg/kg/daya (n = 132)

Deferoxamine 20 to 60 mg/kg/day (n = 63)

1-year treatment

SQUID SQUID

Serum ferritin monitored monthly

Regular blood transfusions continue

RANDOMIZE

Primary objective: safety

Prior therapy with deferoxamine (65%).a Modified halfway through to 20 or 30 mg/kg for most patients.

SQUID



Run-in period

CE-43

Study DesignStudy DesignStudy 0109Study 0109

Primary objective: safety and tolerabilitySecondary efficacy endpoints

– Change in liver iron concentration

– Change in serum ferritin

(Interim 24-week data provided in NDA)

CE-44


ICL670n = 132

DFOn = 63

Sex MaleFemale

52 (39.4%)80 (60.6%)

28 (44.4%)35 (55.6%)

Race CaucasianBlackOther

8 (6.1%)118 (89.4%)

6 (4.5%)

3 (4.8%)59 (93.7%)

1 (1.6%)


153 - 54

163 - 51


8.62.2 - 31.0

6.82.1 - 22.3


35311082 - 12,901

28351015 - 15,578

CE-45


ICL670 n = 132

DFO n = 63


0.21 ± 0.13 0.23 ± 0.12

CE-46

Average Daily DoseAverage Daily DoseStudy 0109—24-Week DataStudy 0109—24-Week Data

Baseline SQUID LIC,mg Fe/g dw ≤ 3 3 to < 7 7 to < 14 ≥ 14

Assigned doseICL670

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 dosedeferoxamine

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

CE-47Change in LIC and Serum Ferritin by Change in LIC and Serum Ferritin by Dose Group at 24 WeeksDose Group at 24 WeeksStudy 0109Study 0109

DFOICL670

DFOICL670

n = 5 4 21 59 15 45 17 13 n = 4 3 18 54 14 43 13 12

LIC by SQUID in PP-2 population Ferritin in safety population

-6

-5

-4

-3

-2

-1

0

1

2

3

< 255

25 - 3510

35 - 5020

? 5030

All doses in mg/kg

Ch

ang

e in

LIC

, mg

Fe/

g d

w

DFOICL670

-3000

-2000

-1000

0

1000

2000

3000

< 255

25 - 3510

35 - 5020

? 5030

All doses in mg/kg

Ch

ang

e in

ser

um

fer

riti

n, µ

g/L

DFO

ICL670

CE-48

Efficacy Conclusions for ICL670Efficacy Conclusions for ICL670Study 0107Study 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

CE-49

Efficacy Conclusions For ICL670Efficacy Conclusions For ICL670Study 0108Study 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

CE-50

SafetySafety

CE-51

Summary of Exposure to ICL670Summary of Exposure to ICL670Safety or Efficacy Studies in PatientsSafety or Efficacy Studies in Patients

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.

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

CE-52Patients Treated With Patients Treated With ICL670 in 1-Year Clinical StudiesICL670 in 1-Year Clinical StudiesStudies 0106, 0107, 0108, 0109Studies 0106, 0107, 0108, 0109

Pediatric patients receiving ICL670 by age group

• 2 to < 6 years, n = 52

• 6 to < 12 years, n = 121

• 12 to < 16 years, n = 119

Patients, n

Disease Total Adults Pediatrics

β-thalassemia 421 216 205

Sickle cell disease 132 65 67

Other rare anemias 99 79 20

Total 652 360 292

CE-53Mean Exposure, Discontinuations, and Mean Exposure, Discontinuations, and Serious Adverse EventsSerious Adverse EventsRandomized Studies 0107 and 0109Randomized Studies 0107 and 0109

0107 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).

CE-54Mean Exposure, Discontinuations, and Mean Exposure, Discontinuations, and Serious Adverse EventsSerious Adverse EventsStudies 0106 and 0108Studies 0106 and 0108

Study0106

n = 400108

n = 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)

CE-55

DeathsDeathsStudies 0106, 0107, 0108, 0109Studies 0106, 0107, 0108, 0109

Relationship to study drug

ICL670 DFO

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 death0107 unrelated: convulsions, intraventricular thrombus, sepsis0108 unrelated: cardiorespiratory arrest, pulmonary embolism, sepsis (3).

CE-56Adverse Events Irrespective of Relationship Adverse Events Irrespective of Relationship to Study Drug—Study 0107to Study Drug—Study 0107Symptoms More Commonly Observed on ICL670 Symptoms More Commonly Observed on ICL670

Pyrexia, headache, cough, nasopharyngitis, pharyngolaryngeal pain, pharyngitis, and influenza were observed with similar frequency in patients receiving ICL670 and DFO.

a Grouped term.

ICL670n = 296

DFOn = 290

Patients with AE(s), % 85.8 84.8AE preferred term, %

Abdominal paina 21.7 14.1Diarrheaa 11.8 7.6Nausea 10.5 4.8Vomiting 10.1 9.7Rasha 8.4 3.2

CE-57

ICL670n = 132

DFOn = 63

Patients with AE(s), % 96.2 98.4AE preferred term, %

Abdominal paina 28.0 14.3Nausea 22.7 11.1Vomiting 21.2 15.9Diarrheaa 19.7 4.8Rasha 13.6 4.8

Adverse Events Irrespective of Relationship Adverse Events Irrespective of Relationship to Study Drug—Study 0109to Study Drug—Study 0109Symptoms More Commonly Observed on ICL670Symptoms More Commonly Observed on ICL670

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.

CE-58Adverse Events Irrespective of Adverse Events Irrespective of Relationship to Study DrugRelationship to Study DrugPooled Analysis by DiseasePooled Analysis by Disease

a Grouped term.

ICL670Pooled β-thal

n = 421

Sickle cell

n = 132

Rareanemias

n = 99Patients with AE(s), % 89.8 96.2 98.0AE preferred term, %

Abdominal paina 23.8 28.0 28.3Diarrheaa 16.6 19.7 42.4Vomiting 13.8 21.2 29.3Rasha 12.4 13.6 12.1Nausea 11.9 22.7 27.3

CE-59Adverse Events Irrespective of Relationship Adverse Events Irrespective of Relationship to Study Drug—ICL670to Study Drug—ICL670Pooled Pooled ββ-thalassemia Population by Age-thalassemia Population by Age

Patients, %< 6

yearsn = 39

6 to < 12 yearsn = 85

12 to < 16 yearsn = 81

≥ 16years

n = 216Total

N = 421Abdominal paina 20.5 15.3 23.5 27.8 23.8Diarrheaa 30.8 8.2 16.0 17.6 16.6Vomiting 10.3 22.4 11.1 12.0 13.8Rasha 5.1 12.9 12.3 13.4 12.4Nausea 5.1 10.6 6.2 15.7 11.9

a Grouped term.

CE-60Patients With Increases inPatients With Increases inSerum CreatinineSerum CreatinineStudies 0106, 0107, 0108, 0109Studies 0106, 0107, 0108, 0109

Creatinine increase at ≥ 2 consecutivepost-baseline visits

Patients, n (%)ICL670 DFO

Pooledβ-thal

n = 421

Sicklecell

n = 132

Rareanemias

n = 99β-thal

n = 290

Sicklecell

n = 63> 33% and < ULN 137 (32.5) 48 (36.4) 23 (23.2) 40 (13.8) 14 (22.2)> 33% and > 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.

CE-61Dose Reductions for Increases inDose Reductions for Increases inSerum CreatinineSerum CreatinineStudies 0106, 0107, 0108, 0109Studies 0106, 0107, 0108, 0109

a Serum creatinine dose reduction criteria:For ≥ 15 years: 2 consecutive increases greater than 33%For < 15 years: 2 consecutive increases greater than 33% and > upper limit of normal.

13% (85/652) were dose reduced for sustained increases13% (85/652) were dose reduced for sustained increases

25% returned to 25% returned to baselinebaseline 60% stabilized60% stabilized 15% fluctuated 15% fluctuated

between baseline between baseline and maximum and maximum

increaseincrease

36% (237/652) with 2 consecutive increases in creatinine36% (237/652) with 2 consecutive increases in creatinine

CE-62

Patients With Abnormal Liver Function TestsPatients With Abnormal Liver Function TestsStudies 0106, 0107, 0108, 0109Studies 0106, 0107, 0108, 0109

ALT > 5× ULN at ≥ 2 consecutivepost-baseline visits

Patients, n (%)ICL670 DFO

Pooledβ-thal

n = 421

Sicklecell

n = 132

Rareanemias

n = 99β-thal

n = 290

Sicklecell

n = 63Patients 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.

CE-63

Additional Safety ParametersAdditional Safety ParametersComparison of ICL670 and DFOComparison 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)

CE-64

Safety Conclusions for ICL670Safety 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

CE-65

Proposed Dosing and MonitoringProposed Dosing and Monitoring

CE-66

Initial Dosing and Monitoring of Therapy Initial Dosing and Monitoring of Therapy With ICL670With 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 > 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 > 2500 µg/L)

CE-67

Monitoring of TherapyMonitoring 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

CE-68

Initial Dosing and Monitoring of TherapyInitial 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

CE-69

Ongoing Extension Studies With ICL670Ongoing Extension Studies With ICL670

Study Objective n

0105E2 Long-term safety, thalassemia 70



0108E1 Long-term safety, thalassemia/rare anemias 141

0109E1 Long-term safety, sickle cell disease 154

CE-70

Additional Studies With ICL670Additional Studies With ICL670Ongoing or PlannedOngoing 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

CE-71

Overall Summary of Efficacy and SafetyOverall 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

CE-72

Overall Summary of Safety and EfficacyOverall 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

Documents

CE-1 Exjade ® (deferasirox; ICL670) Efficacy and Safety Peter Marks, MD, PhD Senior Director, Clinical Development Novartis Pharmaceuticals Corporation