# Presentation: 785144

## Exjade® Novartis NDA 21-882 

**Oncologic Drugs Advisory Committee **
**Pediatric Oncology Subcommittee Meeting**
**Gaithersburg, Maryland**
**March 14, 2006**
**George G. Shashaty, M.D. **
**Division of Medical Imaging and Hematology Products**

**Center for Drug Evaluation and Research**** **

## Iron Metabolism

**Body iron balance – input vs output**
**Iron highly conserved**
**Normal TBI - 3-5 gm**
**Normal LIC - <1.5 mg Fe/gm dw**
**TBI****mg/kg****       = 10.6 x LIC**
**“****Safe” LIC  - <7.0 mg Fe/gm dw**
**One unit of blood transfusion contains 200-250 mg Fe**
**100 ml blood/kg (15-20 units of blood) causes an increase in LIC to >7.0 mg Fe/gm dw**
**Excess iron affects the heart, liver, endocrine organs**

## Exjade

**Oral iron chelating agent**
**Orphan drug designation**
**Fast track designation**
**Priority review**
**Accelerated approval granted November 2, 2005**
**Indication:  For use in the treatment of chronic iron overload from blood transfusions (transfusional hemosiderosis) in adult and pediatric patients at least 2 years of age**** **

## Traditional Therapy for Hemosiderosis

**Deferoxamine (DFO) was the only approved treatment (1968)**
**Parenterally administered/10-12 hours/day**
**Given 5-7 days/week**
**Clinical effectiveness and safety of DFO known based on long history of clinical use**
**Comparator for controlled trials of Exjade**
**Placebo control study not appropriate for the indication**

## Studies Reviewed

**                                      **

## Study 0107

**Randomized, DFO-controlled, open-label, parallel group, multi-institutional**
**299 patients age <16 years, 154 received Exjade, 145 received DFO **
**Dose of drugs based on LIC at baseline**
**Efficacy based on the difference in “success” rate between Exjade and DFO**

## Study 107Demographics

**Variable                                    Exjade                                DFO**
_**Age (yrs)**_
**n                                                   296                                    290**
**Mean                                             17.0                                  17.3        **
**Median                                          15                                     15.5**
**Range                                         2 - 49                                 2 - 53**
_**Age group (yrs)**_
**<6                                               30 (10.1%)                       28 (9.7%)**
**6 - <12                                        67 (22.6%)                       68 (23.4%)**
**12 - <16                                      57 (19.3%)                       49 (16.9%)**
**16 - <50                                    142 (48.0%)                     144 (49.7%)**
**50 - <65                                        0 (0.0%)                           1 (0.3%**
_**Sex, n (%)**_
**Male                                          140 (47.3%)                     142 (49.0%)                                      **
**Female                                      156 (52.7%)                     148 (51.0%)**
_**Race, n (%)**_
**Caucasian                                263 (88.9%)                      251 (86.6%)**
**Black                                            2 (0.7%)                            1 (0.3%)**
**Asian                                            9 (3.0%)                           10 (3.4%)**
**Others                                        22 (7.4%)                           28 (9.7%)****                            **

## Study 107Dose Cohorts

**Exjade dose prespecified according to baseline LIC**
**DFO dose **
**prespecified according to baseline LIC **_**or**_
**Patients could continue on prior effective DFO dose**

## Study 0107Primary Efficacy Analysis (PP-1) 

**                                    ****Exjade                 DFO**
**                                                 ****N=276                N=277**
**Success rate (%)                      52.9                   66.4**
**Difference and 95% CI                -13.5  [-21.6,-5.4]**

## Study 0107Change in LIC from Baseline (PP-2)

**       **** ****                     ****Liver Iron Concentration (LIC), mg Fe/g dw**
**                                    ****Baseline           End-of-Study     Change**
**Exjade (N=268)**
**   ****Mean                            14.1                       11.7                 -2.4**
**   **
**DFO (N=273)**
**   ****Mean                            13.2                       10.4                 -2.9**
**   **

## Study 0107Change in LIC from Baseline for Patients Who Received Exjade 20 or 30 mg/kg/day (initial dose) (PP-2)

**       **** ****                      ****Liver Iron Concentration (LIC), mg Fe/g dw**
**                                    ****Baseline           End-of-Study     Change**
**Exjade (N=185)**
**   ****Mean                            18.5                       13.1                 -5.3***
**   **
*** **significant change from baseline, p<0.001

## Study 0107Mean Change in LIC (mg Fe/gm dw) from Baseline by Age Group (PP-2)

| Age Group | EXJADE (N) | DFO   (N) |
| --- | --- | --- |
|    2 - <6 | -1.1       (27) | -3.8     (28) |
|    6 - <12 | -4.0       (61) | -2.5     (66) |
|    12 - <16 | -2.8       (55) | -3.5     (49) |
|    > 16 | -1.8       (125) | -2.6     (129) |

## Study 0107 Changes in serum ferritin from baseline to end of study 

**                                   **

## Efficacy Summary

**Although pre-specified primary endpoint not met, treatment with either Exjade or DFO reduced LIC from baseline.  This reduction in iron burden occurred in the face of a continuing transfusion requirement.**
**Secondary endpoints, including change in LIC and changes in serum ferritin levels, are consistent with a treatment effect of Exjade.**

## Supportive Study 0108

**Single arm, open label, multi-institutional treatment with Exjade for 48 weeks**
**Enrollment:  85 subjects with ****β****-thalassemia, 99 subjects with rare anemias**
**15 patients with ****β****-thalassemia and 20 patients with rare anemias were <age 16**
**Exjade dosing same as in Study 0107**
**Evaluated change in LIC**

## Study 0108Change in LIC from Baseline with Exjade in Total Population (PP-2)

**       **** ****                      ****Liver Iron Concentration (LIC), mg Fe/g dw**
**                                    ****Baseline           End-of-Study     Change**
_**All Patients (N=147)**_
**   ****Mean                            18.0                     13.8                -4.2**
_**All Patients with Who Received 20 or 30 mg/kg/day (initial dose) (N=126)**_
**   ****Mean                            20.2                     14.8                 -5.5**
**   **

## Safety Populations

**                                                       ****Patients receiving **_**>**_**1 Dose of**
**                                                       **_**_________________________**_
_**Population**_**                                               **_**Exjade**_**                 **_**DFO                 **_
******-Thalassemia (12 month studies)           421                    290**
**Rare anemias (12 month study)                 99                      --**
**Sickle cell disease (12 month safety)      132                      63**
**Long-term safety (extension studies         51                      --**
**   ****up to 35 months) ****β****-thalassemia**
**Clinical pharmacology studies                237                      --****                                          **
- 	(volunteers and β-thalassemia)

## Pediatric Safety PopulationAll Exjade Treated Patients

**	****	****	****	****	****	**_**Age**_
**	****	****	****	****	**_**<6**__**	**__**6-<12**__**	**__**12-<16**_
**Β****-thalassemia****	****39****	****  85****	****	****81**
**Rare anemias****	****	****  9****	****    6****	****	****  5**
**Sickle cell ****	****	****  4****	****  30****	****	****33**
**Total****	****	****	****52****	****121****	****	****119**

## Study 0107: Notable Differences in Adverse Events for Exjade vs. DFO (All Patients)

**                                                             ****Exjade                     DFO**
**                                                                          ****N=296                    N=290**
**	****	****	****	****	****            ****n (%)                     n (%)**
**Any Adverse Event                                          254  (85.8)              246  (84.8)      **
**Gastrointestinal                                               126  (42.6)               91  (31.4)**
**   ****[Chiefly abdominal pain, diarrhea, nausea,**
**   ****vomiting, gastroenteritis, constipation] **
**Skin/Subcutaneous tissue                                65  (22.0)                45  (15.5)**
**    ****Rash                                                                               25 (8.4)                         9 (3.1)                  **
**Creatinine increased                                         113 (38.2)                41 (14.1)**
**Transaminases increased                                  17 (5.7)                     5 (1.7)**
**Urine protein/creatinine ratio >0.6mg/mg         55 (18.6)                   21 (7.2)**
**Hepatobiliary                                                     14  (4.7)                     5  (1.7)     **

## Adverse Events - Kidney

_**Study 0107**_
**Increase in serum creatinine triggered a dose reduction or interruption in 11.1% of Exjade patients.  **
**The increase in creatinine appeared to be dose-dependent:  2.6% at 10mg, 8.3% at 20 mg and 20.2% at 30 mg Exjade.**
**No reports of renal failure**
**The DFO dose was not reduced in any patient as a result of an increase in creatinine **
** **

## Adverse Events - Liver

_**Study 0107**_** **
**Increased transaminases (**_**>**_**5x ULN) in 5.7% of Exjade treated patients and in 1.7% of DFO treated patients. **
**Clinical drug-induced hepatitis:  Two cases both leading to discontinuation of Exjade**
**Increased transaminases led to discontinuation of Exjade in 2 patients **
**Increased transaminases led to dose adjustment or interruption in 3 Exjade patients.**
**Bilirubin levels were no different in  the two arms of the trial**

## Adverse Events - Special Senses

_**Study 0107**_** **
**Cataract formation  - 1 Exjade patient, age 16 ****	****	****	****	****(drug D/C)  **
**                        ****	****      ****- 2 DFO patients, ages ****	****	****	****	****18, 36. **
**Diminished hearing - 9 patients receiving ****	****	****	****	****	****Exjade (ages 5-33)**
**	****	****	****	****      ****- 7 patients receiving DFO ****	****	****	****	****(ages 7-38) ****	****	****	****           ****	****	****(drug ****	****interrupted in 2) **
**Vertigo - 1 Exjade patient (no intervention)**

## Safety Summary

**Main organs for safety concerns are the kidney and the liver**
**Gastrointestinal and dermatological AEs appear manageable**
**Frequency of uncommon, important AEs is not known because the safety population is limited**
**Frequency and types of AEs associated with long term use of drug is not known**

## Unique Pediatric Issues

**Efficacy/safety of Exjade in children and adults appear to be similar except in children < age 6**
**In Study 0107, in children <age 6 (N=30) compared to all patients age 6 years and older:**
**The clearance of Exjade was greater (by 50%) **
**The mean iron intake from transfusion was greater (0.48 vs 0.37 mg/kg/d) **
**Increases in serum creatinine on 2 consecutive occasions were more frequent (50% vs 36.8%)**
**Rash and vomiting were less common, diarrhea was more common**
**Growth and development was normal over the 48 weeks of the trials**

## Exjade Dosage

**Recommended dose of Exjade is 20 mg/kg/d because doses between 5-10 mg/kg/d were ineffective in decreasing LIC. **
**Therapy is commenced after:**
**The transfusion of 100 mL/kg packed red blood cells and**
**persistent serum ferritin of >1000 ug/L **
**Changes in Exjade dose are based on frequent determination of serum ferritin**
**In the clinical trials, dosing was based on LIC**

## Benefit/Risk Assessment

**For patients treated with Exjade at doses of 20 to 30 mg/kg/day, a decrease in LIC was seen during premarket studies even though patients continued to receive transfusions.**
**Exjade was associated with clinical adverse events and laboratory abnormalities, mostly non-serious, in clinical studies.  The safety database, however, is limited.**
**The effects of Exjade on long term morbidity/mortality due to transfusion related hemosiderosis have not been demonstrated.**

## Post-marketing Commitments under Subpart H

**Registry to assess the safety of Exjade administration in children aged 2 to <6 during 5 years of follow-up**
**Study of efficacy/safety of Exjade, 20 mg/kg/d in patients with LIC <7 mg Fe/g dw**
**Devise and conduct a study to assess iron concentration and cardiac function in patients treated with Exjade **
**Completion of the studies in patients with sickle cell syndromes and the ongoing extension studies, including pediatric patients **

## Exjade

_**Discussion and questions: **_**Considerations for PMC protocol development **
** ****Long term use in pediatric patients**
** ****Use among patients with lower LIC**
** ****Cardiac effects**