# Presentation: 877396

## Exjade® (deferasirox; ICL670) Efficacy and Safety

**Peter Marks, MD, PhD****Senior Director, Clinical Development****Novartis Pharmaceuticals Corporation**

## Presentation Outline

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

## 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)**

## Chelation of Iron With ICL670

**ICL670**

**ICL670**

**Iron**

**Chelated**
**iron**

**Excretion**

## Dose-Finding Studies

## Short-term Iron BalanceStudy 0104

**Objectives**
**Measure iron intake and excretion**
**Short-term safety and tolerability**
**Population**
**β****-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**

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

**ICL670, mg/kg/day**

**Net iron excretion,****mg/kg/day**

**Placebo**

**10**

**20**

**40**

**1.2**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0**

**Patients**

**Mean**

**Nisbet-Brown E, et al. *****Lancet*****. 2003;361:1597-1602.**

## 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)**

**Baseline**

**12**

**Regular blood transfusions continue**

**RANDOMIZE**

**6**

**Screening  **
**Days –28 to –6**

**Washout**
**Days –5 to –1**

**Run-in period**

**3**

**9**

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

**Extension**
**(0105E2)**

**DFO = Deferoxamine.**

## 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)**

## 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**

## Clinical Development Registration Program

**β-t****halassemia 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**

## 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**

## ICL670 Studies 0107, 0108, 0109

| Trial code | Abbreviated title | Objective |
| --- | --- | --- |
| 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.**

## Dosing AlgorithmStudies 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.**

## Study 0107

## 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**

**Liver ****biopsy ****a**

**Serum ferritin monitored monthly**

**Regular blood transfusions continue**

**RANDOMI****ZE**

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

**Screening  **
**Days –28 to –6**

**Washout**
**Days –5 to –1**

**Run-in period**

## 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 < 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**

## 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**

## 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 **

## 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 |
| 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) |

## Baseline CharacteristicsStudy 0107—Safety 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  |

## 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 ± 0.11 | 0.41 ± 0.11
 |

## Average Daily DoseStudy 0107—Safety Population

**Average Daily Dose****Study 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 |  |

## Primary Efficacy ResultsStudy 0107—Biopsy 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) |  |

**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**

## 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 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* |

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

**–****20**

**PP-2 population; LIC by biopsy and SQUID.**

## Secondary Efficacy ResultsStudy 0107—Change in Ferritin by Dose Group

**ICL670****	****5****	****10****	****20****	****30**
**n =****	****6     15****	****40     73****	****117     80****	****117     115**

**Secondary Efficacy Results****Study 0107—Change in Ferritin by Dose Group**

**Change in serum ferritin, ****μ****g/L**

**–****3000**

**–****2000**

**–****1000**

**0**

**1000**

**2000**

**3000**

**4000**

**DFO, mg/kg/day **

**ICL670, mg/kg/day**

**Safety population.**

## Post-hoc Subgroup Analysis of 1 ̊ Endpoint Study 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**

## Study 0108

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

**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**

**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.**

## 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)**

## 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**

## 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 |
| --- | --- | --- | --- | --- |
| 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 |
|  |  |  | 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 |

## 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 ± 0.12 | 0.32 ± 0.15
 | 0.34 ± 0.14
 |

## Average Daily Dose of ICL670Study 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 doseICL670, mg/kg/day | 5 | 10 | 20 | 30 |
| Actual doseICL670, mg/kg/day, mean ± SD | 5.7 ± 1.0 | 9.7 ± 1.1 | 18.4 ± 2.5 | 27.9 ± 3.4 |

## Primary Efficacy ResultsStudy 0108—Biopsy and SQUID

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | β-thalassemia | Rareanemias | Allpatients | 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).**

## 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 = 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.**

## Secondary Efficacy ResultsStudy 0108—Change in LIC by Dose Group

**PP-2 population; LIC by biopsy and SQUID.**

**n =           1       4                    8      8****	****        17      22****	****      50       37**

## Secondary Efficacy ResultsStudy 0108—Change in Ferritin by Dose Group

**Safety population.**

**n           2      4                    8      10****	****        21      24****	****      52       42**

## Post-hoc Subgroup Analysis of 1 ̊ Endpoint Study 0108—Biopsy and SQUID

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | β-thalassemia | Rareanemias | Allpatients | 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).**

## Study 0109

## 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**

**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**

**Screening  **
**Days –28 to –6**

**Washout**
**Days –5 to –1**

**Run-in period**

## 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)**

## Baseline CharacteristicsStudy 0109—Safety 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 |

## 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 ± 0.13 | 0.23 ± 0.12
 |

## Average Daily DoseStudy 0109—24-Week Data

**Average Daily Dose****Study 0109—24-Week Data**

| Baseline SQUID LIC,mg Fe/g dw | ≤  3 | 3 to < 7 | 7 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 ± 0.29 | 11.0 ± 3.15 | 19.4 ± 1.97 | 28.9 ± 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 ± 3.82 | 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 |

## 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    13**

**n =       4   3         18    54      14   43       13    12**

**LIC by SQUID in PP-2 population**

**Ferritin in safety population**

## 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**

## 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**

## Safety

## Summary of Exposure to ICL670Safety or Efficacy Studies in Patients

**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 |
| --- | --- | --- |
| 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 |

## 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 |  |  |
| --- | --- | --- | --- |
| 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 |

## Mean Exposure, Discontinuations, and Serious Adverse EventsRandomized 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 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).**

## Mean Exposure, Discontinuations, and Serious Adverse EventsStudies 0106 and 0108

| Study | 0106n = 40 | 0108n = 184 |
| --- | --- | --- |
| Exposure, weeks, mean ± SD | 49 ± 8.4 | 48 ± 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) |

## DeathsStudies 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 death**
**0107 unrelated: convulsions, intraventricular thrombus, sepsis**
**0108 unrelated: cardiorespiratory arrest, pulmonary embolism, sepsis (3). **

## 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), % | 85.8 | 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 |

## Adverse Events Irrespective of Relationship to Study Drug—Study 0109Symptoms 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 |

**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.**

## 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), % | 89.8 | 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 |

## 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 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.**

## Patients With Increases inSerum CreatinineStudies 0106, 0107, 0108, 0109

| 

Creatinine increase at ≥ 2 consecutivepost-baseline visits | Patients, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | ICL670 |  |  | DFO |  |
|  | Pooled
β-thal
n = 421 | Sickle
cell
n = 132 | Rare
anemias
n = 99 | β-thal
n = 290 | Sickle
cell
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.**

## 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 < 15 years: 2 consecutive increases greater than 33% and > upper limit of normal.**

** ****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**

## Patients With Abnormal Liver Function TestsStudies 0106, 0107, 0108, 0109

| 

ALT > 5× ULN at     ≥ 2 consecutivepost-baseline visits | Patients, n (%) |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | ICL670 |  |  | DFO |  |
|  | 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) | 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.**

## 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)**

## 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**

## Proposed Dosing and Monitoring

## 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)**

## 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**

## 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**

## 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 |

## Additional Studies With ICL670Ongoing 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 |  |

## 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**

## 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**