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

2. CE-2 Presentation Outline  Description of compound  Clinical development program –Dose-finding studies –Efficacy trials –Supportive studies  Proposed indication and dosing  Conclusions

3. CE-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. CE-4 Chelation of Iron With ICL670 ICL670 Iron Chelated iron Chelated iron Excretion

5. CE-5 Dose-Finding Studies

6. CE-6 Short-term Iron Balance Study 0104 Objectives  Measure iron intake and excretion  Short-term safety and tolerabilityPopulation  β-thalassemia majorDesign  Dose escalation, 12 daily doses (n = 23) –Placebo or ICL670 at 10, 20, or 40 mg/kg  Iron intake and excretion measured chemically

7. CE-7 Short-term Iron Excretion Study 0104—Dose-Response ICL670, mg/kg/day Net iron excretion, mg/kg/day Placebo102040 1.2 1.0 0.8 0.6 0.4 0.2 0 Patients Mean n =5567 Nisbet-Brown E, et al. Lancet. 2003;361:1597-1602.

8. CE-8 Randomized Phase II Dose-Finding Trial Study 0105—β-thalassemia ICL670 20 mg/kg/day (n = 24) DFO 40 mg/kg given 5 days/week (n = 23) SQUID assessments (month) Baseline12 Regular blood transfusions continue RANDOMIZERANDOMIZE 6 Screening Days –28 to –6 Washout Days –5 to –1 Run-in period 39 ICL670 10 mg/kg/day (n = 24) Extension (0105E2) DFO = Deferoxamine.

9. CE-9 Change in Liver Iron Concentration Study 0105—β-thalassemia Mean ± standard deviation. LIC = Liver iron concentration. Change in LIC, mg/g dry weight 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)

10. CE-10 Conclusions From Dose-Finding Trials Studies 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

11. CE-11 Clinical 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

12. CE-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 ~ 1:2 in validation study –SQUID useful as relative measure of change in LIC over time

13. CE-13 ICL670 Studies 0107, 0108, 0109 Trial codeAbbreviated titleObjective 0107 N = 591 Randomized comparison of ICL670 with DFO in β-thalassemia 1˚ Efficacy (noninferiority) 2˚ Safety and tolerability 0108 N = 184 Noncomparative trial of ICL670 in β-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. CE-14 Dosing Algorithm Studies 0107, 0108, 0109 Baseline LIC, mg Fe/g dw ICL670, mg/kg/day Deferoxamine, mg/kg/day 2 - 3520 - 30 a > 3 - 71025 - 35 a > 7 - 142035 - 50 > 1430≥ 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. CE-15 Study 0107

16. CE-16 Phase 3 Comparative Study 0107 β-thalassemia ICL670 5 to 30 mg/kg/day Deferoxamine 20 to 60 mg/kg/day 1-year treatment Liver biopsy a Serum ferritin monitored monthly Regular blood transfusions continue RANDOMIZERANDOMIZE a SQUID used to measure LIC in 16% of patients. Screening Days –28 to –6 Washout Days –5 to –1 Run-in period

17. CE-17  Primary endpoint: treatment success rate at 1 year Primary Endpoint Study 0107 Treatment success criteria LIC at baseline, mg Fe/g dw Success, if LIC after 1 year, mg Fe/g dw 2 to < 7Maintenance within 1 to < 7 ≥ 7 to < 10Decrease to within 1 to < 7 ≥ 10Decrease of ≥ 3  Hypothesis: success rate in patients receiving ICL670 is noninferior to deferoxamine

18. CE-18 Primary Analysis Study 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. CE-19 Secondary Endpoints and Subgroup Analysis Study 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. CE-20 Analysis Populations 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 ICL670 n = 297 DFO n = 294 All patients N = 591 ITT297 (100.0)294 (100.0)591 (100.0) Safety296 (99.7)290 (98.6)586 (99.2) PP-1276 (92.9)277 (94.2)553 (93.6) PP-2268 (90.2)273 (92.9)541 (91.5)

21. CE-21 Baseline Characteristics Study 0107—Safety Population ICL670 n = 296 DFO n = 290 SexMale Female 140 (47.3%) 156 (52.7%) 142 (49.0%) 148 (51.0%) RaceCaucasian Other 263 (88.9%) 33 (10.1%) 251 (86.6%) 39 (13.4%) Age, yearsMedian Range 15 2 - 49 15.5 2 - 53 LIC, mg Fe/g dwMedian Range 11.3 2.1 - 48.1 11.0 2.1 - 55.1 Serum ferritin, µg/LMedian Range 2212 321 - 12,646 2091 453 - 15,283

22. CE-22 Average Iron Intake During Study Study 0107—Safety Population ICL670 n = 296 DFO n = 290 Iron intake, mg Fe/kg/day, mean ± SD 0.38 ± 0.110.41 ± 0.11

23. CE-23 Average Daily Dose Study 0107—Safety Population Baseline LIC, mg Fe/g dw Dose, mg/kg/day≤ 33 to < 77 to < 14≥ 14 ICL670n = 15n = 78n = 84n = 119 Assigned51020 30 Actual, mean ± SD6.2 ± 1.610.2 ± 1.219.4 ± 1.728.2 ± 3.5 DFOn = 14n = 79n = 91n = 106 Assigned20 - 3025 - 3535 - 50≥ 50 Actual, mean ± SD33.9 ± 9.936.7 ± 9.242.4 ± 6.651.6 ± 5.8 Ratio of DFO to ICL670 5.5 : 13.6 : 12.2 : 11.9 : 1 LIC < 7LIC ≥ 7 36.4 mg : 9.6 mg47.3 mg : 24.6 mg 4 : 1 2 : 1

24. CE-24 Primary Efficacy Results Study 0107—Biopsy and SQUID PP-1 population ICL670 n = 276 DFO n = 277 Success rate, %52.966.4 (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

25. CE-25 Secondary Efficacy Results Study 0107—Change in LIC by Biopsy and SQUID * Student t test, change from baseline. PP-2 Population ICL670 All patients DFO All patients All LIC groupsn = 268n = 273 Mean change ± SD–2.4 ± 8.2–2.9 ± 5.4 LIC < 7 mg Fe/g dwn = 83n = 87 Mean change ± SD4.0 ± 3.80.13 ± 2.2 LIC ≥ 7 mg Fe/g dwn = 185n = 186 Mean change ± SD–5.3 ± 8.0–4.3 ± 5.8 P <.001*

26. CE-26 Secondary Efficacy Results Study 0107—Change in LIC by Dose Group –15 –10 –5 0 5 10 DFO, mg/kg/day ICL670, mg/kg/day Change in LIC, mg Fe/g dw DFO< 2525 - 3535 - 50 ≥ 50 ICL6705102030 n =13 1575 6887 7798 108 –20 PP-2 population; LIC by biopsy and SQUID.

27. CE-27 DFO< 2525 - 3535 - 50 ≥ 50 ICL6705102030 n =6 1540 73117 80117 115 Secondary Efficacy Results Study 0107—Change in Ferritin by Dose Group Change in serum ferritin, μg/L –3000 –2000 – 1000 0 1000 2000 3000 4000 DFO, mg/kg/day ICL670, mg/kg/day Safety population.

28. CE-28 Post-hoc Subgroup Analysis of 1˚ Endpoint Study 0107—Biopsy and SQUID PP-1 populationICL670DFO LIC ≥ 7 mg Fe/g dwn = 191n = 190 Success rate, %58.658.9 (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

29. CE-29 Study 0108

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

31. CE-31 Study Design and Analysis Study 0108  Primary endpoint: Success rate as defined 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)

32. CE-32 Secondary Endpoints and Subgroup Analysis Study 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. CE-33 Baseline Characteristics Study 0108—Safety Population Rare anemia group includes myelodysplastic syndromes (n = 47), Diamond-Blackfan anemia (n = 20), and other anemias (n = 20). β-thalassemia n = 85 Rare anemias n = 99 All patients n = 184 SexMale Female 42 (49.4%) 43 (50.6%) 51 (51.5%) 48 (48.5%) 93 (50.5%) 91 (49.5%) RaceCaucasian Other 56 (65.9%) 29 (34.1%) 89 (89.9%) 10 (10.1%) 145 (78.8%) 24 (13.0%) Age, yearsMedian Range 23 4 - 59 4927 3 - 81 LIC, mg Fe/g dwMedian Range 18.1 3.0 - 54.4 15.0 2.3 - 51.3 16.7 2.3 - 54.4 Serum ferritin, µg/LMedian Range 3636 440 - 13,943 2674 537 - 11,854 3075 440 - 11,854

34. CE-34 Average Iron Intake During Study Study 0108—Safety Population β-thalassemia n = 85 Rare anemias n = 99 All patients n = 184 Iron intake, mg Fe/kg/day, mean ± SD 0.35 ± 0.120.32 ± 0.150.34 ± 0.14

35. CE-35 Average Daily Dose of ICL670 Study 0108—ITT Population Baseline LIC, mg Fe/g dw≤ 33 to < 77 to < 14≥ 14 Patientsn = 7n = 18n = 52n = 107 Assigned dose ICL670, mg/kg/day 5102030 Actual dose ICL670, mg/kg/day, mean ± SD 5.7 ± 1.09.7 ± 1.118.4 ± 2.527.9 ± 3.4

36. CE-36 Primary Efficacy Results Study 0108—Biopsy and SQUID β-thalassemia Rare anemias All patientsP value ITT population n = 85n = 99n = 184 Success rate, %52.948.550.5.441 (95% CI)(42.3, 63.6)(38.6, 58.3)(43.3, 57.8) PP-1 populationn = 80n = 85n = 165 Success rate, % 56.356.556.4.051 (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. CE-37 Secondary Efficacy Results Study 0108—Change in LIC by Biopsy and SQUID PP-2 population β-thalassemia Rare anemias All patients All LIC groups n = 76n = 71n = 147 Mean change ± SD–4.7 ± 8.6–3.7 ± 6.5–4.2 ± 7.7 LIC < 7 mg Fe/g dw n = 9n = 12n = 21 Mean change ± SD6.0 ± 4.01.6 ± 3.13.5 ± 4.1 LIC ≥ 7 mg Fe/g dw n = 67n = 59n = 126 Mean change ± SD–6.1 ± 8.0–4.8 ± 6.5–5.5 ± 7.4 P <.001* * Student t test change from baseline.

38. CE-38 Secondary Efficacy Results Study 0108—Change in LIC by Dose Group Change in LIC, mg Fe/g dw –20 –15 –10 –5 0 5 10 15 5102030 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

39. CE-39 Secondary Efficacy Results Study 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 5102030 ICL670 dose, mg/kg/day Change in serum ferritin, µg/L ?-thalassemia Rare anemias

40. CE-40 Post-hoc Subgroup Analysis of 1˚ Endpoint Study 0108—Biopsy and SQUID β-thalassemia Rare anemias All patientsP value ITT populationn = 75n = 84 n = 159 Success rate, %57.347.652.2.289 (95% CI)(46.2, 68.5)(36.9, 58.3)(44.4, 60.0) PP-1 population n = 70n = 72n = 142 Success rate, %61.455.658.5.022 (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. CE-41 Study 0109

42. CE-42 Phase 2 Comparative Trial Adult and Pediatric Sickle Cell Disease Study 0109 ICL670 5 to 30 mg/kg/day a (n = 132) Deferoxamine 20 to 60 mg/kg/day (n = 63) 1-year treatment SQUID Serum ferritin monitored monthly Regular blood transfusions continue RANDOMIZERANDOMIZE Primary objective: safety Prior therapy with deferoxamine (65%). a Modified halfway through to 20 or 30 mg/kg for most patients. SQUID Screening Days –28 to –6 Washout Days –5 to –1 Run-in period

43. CE-43 Study Design Study 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. CE-44 Baseline Characteristics Study 0109—Safety Population ICL670 n = 132 DFO n = 63 SexMale Female 52 (39.4%) 80 (60.6%) 28 (44.4%) 35 (55.6%) RaceCaucasian Black Other 8 (6.1%) 118 (89.4%) 6 (4.5%) 3 (4.8%) 59 (93.7%) 1 (1.6%) Age, yearsMedian Range 15 3 - 54 16 3 - 51 LIC, mg Fe/g dwMedian Range 8.6 2.2 - 31.0 6.8 2.1 - 22.3 Serum ferritin, µg/LMedian Range 3531 1082 - 12,901 2835 1015 - 15,578

45. CE-45 Average Iron Intake During Study Study 0109—Safety Population ICL670 n = 132 DFO n = 63 Iron intake, mg Fe/kg/day, mean ± SD 0.21 ± 0.130.23 ± 0.12

46. CE-46 Average Daily Dose Study 0109—24-Week Data Baseline SQUID LIC, mg Fe/g dw≤ 33 to < 77 to < 14≥ 14 Assigned dose ICL670 5 mg/kg n = 4 10 mg/kg n = 64 20 mg/kg n = 46 30 mg/kg n = 18 Actual average dose, mg/kg/day 4.9 ± 0.2911.0 ± 3.1519.4 ± 1.9728.9 ± 2.15 Assigned dose deferoxamine 20 - 30 mg/kg n = 6 25 - 35 mg/kg n = 21 35 - 50 mg/kg n = 19 ≥ 50 mg/kg n = 17 Actual average dose, mg/kg/day, mean ± SD 22.5 ± 3.8228.8 ± 2.9836.4 ± 9.6451.0 ± 5.67 Ratio of deferoxamine dose to ICL670 dose 4.6 : 12.6 : 11.9 : 11.8 : 1

47. CE-47 Change in LIC and Serum Ferritin by Dose Group at 24 Weeks Study 0109 DFO ICL670 DFO ICL670 n = 5 4 21 59 15 45 17 13n = 4 3 18 54 14 43 13 12 LIC by SQUID in PP-2 population Ferritin in safety population -6 -5 -4 -3 -2 0 1 2 3 < 25 5 25 - 35 10 35 - 50 20 ? 50 30 All doses in mg/kg Change in LIC, mg Fe/g dw DFO ICL670 -3000 -2000 -1000 0 1000 2000 3000 < 25 5 25 - 35 10 35 - 50 20 ? 50 30 All doses in mg/kg Change in serum ferritin, µg/L DFO ICL670

48. CE-48 Efficacy Conclusions for ICL670 Study 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 with LIC ≥ 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. CE-49 Efficacy Conclusions For ICL670 Study 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. CE-50Safety

51. CE-51 Summary of Exposure to ICL670 Safety 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 010610 mg/kg/day (49.2 weeks) 40 01075, 10, 20, 30 mg/kg/day (52.1 weeks) 296 01085, 10, 20, 30 mg/kg/day (47.2 weeks) 184 01095, 10, 20, 30 mg/kg/day (47.9 weeks) 132 Total = 652

52. CE-52 Patients Treated With ICL670 in 1-Year Clinical Studies Studies 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 DiseaseTotalAdultsPediatrics β-thalassemia421216205 Sickle cell disease1326567 Other rare anemias997920 Total652360292

53. CE-53 Mean Exposure, Discontinuations, and Serious Adverse Events Randomized Studies 0107 and 0109 01070109 Study ICL670 n = 296 DFO n = 290 ICL670 n = 132 DFO n = 63 Exposure, weeks, mean ± SD 52 ± 8.153 ± 6.748 ± 10.847 ± 12.0 All withdrawals, n (%)17 (5.7)12 (4.1)15 (11.3)9 (14.3) Withdrawals for safety, n (%) 8 (2.7)4 (1.4)7 (5.3)2 (3.2) Serious adverse events (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. CE-54 Mean Exposure, Discontinuations, and Serious Adverse Events Studies 0106 and 0108 Study 0106 n = 40 0108 n = 184 Exposure, weeks, mean ± SD 49 ± 8.448 ± 14.1 All withdrawals, n (%)1 (2.6)32 (17.4) Withdrawals for safety, n (%) 1 (2.6)18 (9.8) Serious adverse events (SAEs), n (%) 4 (10.0)32 (17.4)

55. CE-55 Deaths Studies 0106, 0107, 0108, 0109 Relationship to study drug ICL670DFO UnrelatedRelatedUnrelatedRelated 010600N/A 01070130 010850N/A 01090000 Causes of death: 0107 related: sudden death 0107 unrelated: convulsions, intraventricular thrombus, sepsis 0108 unrelated: cardiorespiratory arrest, pulmonary embolism, sepsis (3).

56. CE-56 Adverse Events Irrespective of Relationship to Study Drug—Study 0107 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. ICL670 n = 296 DFO n = 290 Patients with AE(s), %85.884.8 AE preferred term, % Abdominal pain a 21.7 14.1 Diarrhea a 11.8 7.6 Nausea10.5 4.8 Vomiting10.1 9.7 Rash a 8.4 3.2

57. CE-57 ICL670 n = 132 DFO n = 63 Patients with AE(s), %96.298.4 AE preferred term, % Abdominal pain a 28.014.3 Nausea 22.711.1 Vomiting 21.215.9 Diarrhea a 19.74.8 Rash a 13.64.8 Adverse Events Irrespective of Relationship to Study Drug—Study 0109 Symptoms 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.

58. CE-58 Adverse Events Irrespective of Relationship to Study Drug Pooled Analysis by Disease a Grouped term. ICL670 Pooled β-thal n = 421 Sickle cell n = 132 Rare anemias n = 99 Patients with AE(s), %89.896.298.0 AE preferred term, % Abdominal pain a 23.8 28.028.3 Diarrhea a 16.6 19.742.4 Vomiting13.8 21.229.3 Rash a 12.4 13.612.1 Nausea11.9 22.727.3

59. CE-59 Adverse Events Irrespective of Relationship to Study Drug—ICL670 Pooled β-thalassemia Population by Age Patients, % < 6 years n = 39 6 to < 12 years n = 85 12 to < 16 years n = 81 ≥ 16 years n = 216 Total N = 421 Abdominal pain a 20.515.323.527.823.8 Diarrhea a 30.88.216.017.616.6 Vomiting10.322.411.112.013.8 Rash a 5.112.912.313.412.4 Nausea5.110.66.215.711.9 a Grouped term.

60. CE-60 Patients With Increases in Serum Creatinine Studies 0106, 0107, 0108, 0109 Creatinine increase at ≥ 2 consecutive post-baseline visits Patients, n (%) ICL670DFO Pooled β-thal n = 421 Sickle cell n = 132 Rare anemias n = 99 β-thal n = 290 Sickle cell n = 63 > 33% and < ULN137 (32.5)48 (36.4)23 (23.2)40 (13.8)14 (22.2) > 33% and > ULN10 (2.4)3 (2.3)16 (16.2)1 (0.3)2 (3.2) Total147 (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. CE-61 Dose Reductions for Increases in Serum Creatinine Studies 0106, 0107, 0108, 0109 a Serum creatinine dose reduction criteria: For ≥ 15 years: 2 consecutive increases greater than 33% For upper limit of normal. 13% (85/652) were dose reduced for sustained increases 13% (85/652) were dose reduced for sustained increases 25% returned to baseline 60% stabilized 15% fluctuated between baseline and maximum increase 36% (237/652) with 2 consecutive increases in creatinine 36% (237/652) with 2 consecutive increases in creatinine

62. CE-62 Patients With Abnormal Liver Function Tests Studies 0106, 0107, 0108, 0109 ALT > 5× ULN at ≥ 2 consecutive post-baseline visits Patients, n (%) ICL670DFO Pooled β-thal n = 421 Sickle cell n = 132 Rare anemias n = 99 β-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) Patients with ALT elevated at baseline 24 (5.7)5 (3.8)5 (5.1)5 (1.7)0 (0.0) Total29 (6.9)5 (3.8)6 (6.1)5 (1.7)0 (0.0) ALT = Alanine aminotransferase; ULN = Upper limit of normal.

63. CE-63 Additional Safety Parameters Comparison 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. CE-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. CE-65 Proposed Dosing and Monitoring

66. CE-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 > 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)

67. CE-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. CE-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. CE-69 Ongoing Extension Studies With ICL670 StudyObjectiven 0105E2Long-term safety, thalassemia70 0106E1Long-term safety, thalassemia39 0107E1Long-term safety, thalassemia507 0108E1Long-term safety, thalassemia/rare anemias141 0109E1Long-term safety, sickle cell disease154

70. CE-70 Additional Studies With ICL670 Ongoing or Planned StudyObjectiven 2201Safety in sickle cell disease +/– hydroxyurea210 2203Expanded access, congenital anemias3000 2402Efficacy and safety, thalassemia250 2409Efficacy and safety in transfusional iron overload1541 US02/US03Safety in myelodysplastic syndromes180 PlannedFerritin-based dosing PlannedCardiac iron reduction trial examining function PlannedRenal mechanistic study PlannedHepatic impairment study

71. CE-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. CE-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