# Presentation: 702772

## Exjade® Novartis NDA 21-882 

**Blood Products Advisory Committee Meeting**
**Rockville, Maryland**
**September 29, 2005**
**George G. Shashaty, M.D. **
**Division of Medical Imaging and Hematology Products**

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

## Sponsor’s Proposed 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**** **

## Current Therapy for Hemosiderosis

**Deferoxamine (DFO) is the only approved treatment (1965)**
**Parenterally administered**
**Each infusion lasts 10-12 hours/day**
**Must be 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**

## Exjade

**Oral iron chelating agent**
**Orphan drug designation**
**Fast track designation**
**Priority review**
**Treatment Protocol approved to allow Exjade access to patients prior to marketing approval.**

## Outline of Presentation

**Studies reviewed**
**Efficacy**
**Safety**
**Proposed dosing**
**Summary**
**Risk/benefit assessment**

## Studies Reviewed

**                                      **

## Study 0107

**Pivotal trial with non-inferiority design with DFO as comparator**
**Randomized, open-label, parallel group, multi-institutional**
**Enrollment:  586 patients with ****β****-thalassemia treated for 48 weeks**
**Dose of drugs based on LIC at baseline**
**Efficacy based on the difference in “success” rate between Exjade and DFO**

## Measurement of LIC

**Liver biopsy**
**“****gold standard”**
**used in 84% of patients**
**SQUID ( superconducting quantum interference device)**
**not validated for measuring LIC**
**used in 16% of patients**

## Study 0107Dosing Regimens

**   ****LIC at Baseline           Exjade Dose           DFO Dose***
**                                        ****(mg/kg/day)          (mg/kg/day)**
**2 to 3 mg Fe/g dw                    5                     20 to 30**
**>3 to 7 mg Fe/g dw                10                     25 to 35**
**>7 to 14 mg Fe/g dw               20                    35 to 50**
**>14 mg Fe/g dw                      30                      = 50**
**  **
**  *****  ****Patients previously receiving DFO could remain on their previous dose.**

## Study 0107Definition of Success

## Study 0107Non-Inferiority Analysis

**Efficacy is shown if the lower bound of the 95% confidence interval for the difference in success rates is greater than -15%.**
**The data available are insufficient to determine the effect of deferoxamine on LIC after 1 year of therapy, thus calling into question the ability to perform a non-inferiority study to establish efficacy.**

## Study 0107:  Analysis Populations

**                                                                                 ****Exjade                DFO**
**                                                                                  ****n (%)                  n (%)**
**Intent-to-Treat (ITT)                                               297 (100)           294 (100)         **
**All randomized patients**
**Safety                                                                     296  (99.7)         290 (98.6)**
**All patients who received at least**
**one dose of study medication**
**Per Protocol-1 (PP-1; primary efficacy pop)      276 (92.9)          277 (94.2)**
**All patients who received study drug who had an LIC **
**(by the same methodology) at baseline and at study’s end**
**including those who discontinued study drug prematurely **
**because of AEs, abnormal tests or an iron overload related death**
**Per Protocol -2 (PP-2)                                           268 (90.2)         273  (92.9)     **
**All patients who had an LIC (by the same methodology) at **
**baseline and at study’s end**

## 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%)**
**Oriental                                        9 (3.0%)                           10 (3.4%)**
**Others                                        22 (7.4%)                           28 (9.7%)****                            **

## Study 107Dose Cohorts

**Subgroup                                                        Exjade                                DFO**
**                                                                          ****N=296                               N=290**
_**Baseline LIC dosing category, n (%)**_
_**<**_**3 mg Fe/g/dw                                                 15 (5.1)                         14 (4.8)**
**>3 - 7 mg Fe/g dw                                         78 (26.4)                       79 (27.2)**
**>7 - 14 mg Fe/g dw                                          84 (28.4)                       91 (31.4)**
**>14 mg Fe/g dw                                              119 (40.2)                    106 (36.6)**
_**Dose cohort (based on initial dose), n (%)**_
**5 mg/kg Exjade / <25 mg/kg DFO                   15 (5.1)                              7 (2.4)**
**10 mg/kg Exjade / 25-<35 mg/kg DFO            78 (26.4)                          40 (13.8)**
**20 mg/kg Exjade / 35-<50 mg/kg DFO            84 (28.4)                        119 (41.0)**
**30 mg/kg Exjade / **_**>**_**50 mg/kg DFO               119 (40.2)                        124 (42.8)**
_**Average daily dose (mg/kg) during study (mean; median)**_
_**<**_**3 mg Fe/g/dw                                                 6.2; 5.0                         33.9; 30.0**
**>3 -  7 mg Fe/g dw                                         10.2; 10.0                       36.7; 35.0**
**>7 - 14 mg Fe/g dw                                        19.4; 20.0                       42.4; 40.8**
**>14 mg Fe/g dw                                              28.2; 30.0                       51.6; 51.0**

## Study 107 Disposition of Patients

**                                                   ****Exjade                DFO   **
**                                                   ****N=296               N=290      **
**Disposition                                  n (%)               n (%)      **
**   ****Completed                           279 (94.3)         278 (95.9) **
**   ****Discontinued                         17 ( 5.7)            12 (4.1)   **
**      ****Adverse events                    8 (2.7)               1 (0.3)     **
**      ****Death                                    1 (0.3)                3 (1.0)   **
**      ****Protocol violation                2 (0.7)                2 (0.7)   **
**      ****Withdrew consent               6 (2.0)                6 (2.1) **

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

**                                   **

## 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**
**Exjade dosing same as in Study 0107**
**Evaluated change in LIC from baseline to end of study**

## 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**
**   **

## Study 0108Change in LIC from Baseline with Exjade in -Thalassemia Subpopulation (PP-2)

**       **** ****                      ****Liver Iron Concentration (LIC), mg Fe/g dw**
**                                    ****Baseline           End-of-Study     Change**
_**All **__****__**-Thal Patients (N=76)**_
**   ****Mean                            19.3                       14.6                 -4.7**
**   **
_****__**-Thal Patients who received Exjade 20 or 30 mg/kg/day (initial dose) (N=67)**_
**   ****Mean                            21.2                       15.1                 -6.1**

## Study 0108 Mean Changes in Serum Ferritin (ug/L) from Baseline to End of Study

**Dose Cohort       ______**_****__**-Thal         **_**         _____**_**Rare Anemias__**_**  **
**                             ****n       mean change          n         mean change       **
**5 mg/kg               2             895.5                   4              2583.5**
**10 mg/kg             8           1116.3                  10               409.3**
**20 mg/kg           21             497.7                  24              -544.9**
**30 mg/kg           52          -1023.2                  42              -645.3**

## Efficacy Summary

**The single pivotal Study 0107 failed to demonstrate non-inferiority of Exjade to DFO, based on the protocol-specified statistical analysis.**
**In Study 0107, treatment with either Exjade or DFO reduced LIC from baseline.  This is consistent with a biological effect in reducing iron burden.  This reduction in iron burden occurred in the face of a continuing transfusion requirement.**
**In Study 0107, analyses of secondary endpoints, including change in LIC and changes in serum ferritin levels, are consistent with a treatment effect of Exjade.**
**Study 0108 results show a decrease in LIC from baseline suggestive of a treatment effect of Exjade.**

## Safety

**Characterization of safety database**
**Safety in comparative study in ********-thalassemia patients (Study 0107)**
**Deaths**
**Discontinuations due to adverse events**
**Serious adverse events**
**Most frequent adverse events **
**Organ-specific toxicity (0107 and other studies)**
**Deaths in all studies**
**Safety summary**

## 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 (6 month interim)      132                      63**
**Long-term safety (extension studies         51                      --**
**   ****up to 35 months) ****β****-thalassemia**
**Clinical pharmacology studies                237                      --****                                          **
- 	(volunteers and β-thalassemia)

## Study 0107  Deaths

**                               **

## Study 0107Discontinuations Due to Adverse Events

**Event                                       Exjade                     DFO**
**                                                 ****N=296                     N=290**
**Any event, n (%)                              9  (3.0)                    4  (1.4)**
**       ****Death                                      1  (0.3)                   3  (1.0)**
**       ****Hepatic AE                             4  (1.3)                   0**
**       ****Other                                      4  (1.0)                    1 (0.3)**

## Study 0107 Serious Adverse Events (N, %)

**Primary Organ System Class****	****                      Exjade                DFO**
**                                                                                       ****N=296               N=290**
- Any primary system organ class	                      27 (9.1)	      25 (8.6)
- Infections and infestations 	                                             7 (2.4)                 9 (3.1)
-     Septic shock*                                                                 --                      1 (0.3)
- Gastrointestinal disorders	                                             4 (1.4)                 5 (1.7)
-     Abdominal pain	                                             1 (0.3)	        1 (0.1)
-     Vomiting                                                                         --	        2 (0.7)
- General disorders                                                            5 (1.7)                2 (0.7)
-      Pyrexia                                                  	   3 (1.0)	        2 (0.7)
-      Sudden death*                                                            1 (0.3)                   --
- Injury etc.	                                                                   5 (1.7)	        1 (0.3)
- Cardiac disorders	                                              2 (0.7)	        3 (1.0)
-      Intracardiac thrombus*                                                   --                     1 (0.3)
- Nervous system disorders	                                              3 (1.0)	         2 (0.7)
-      Convulsion                                                                     --	         2 (0.7)
- Blood and lymphatic system disorders                             2 (0.7)	         2 (0.7)
- Musculoskeletal disorders	                                              2 (0.7)	         2 (0.7)
-      Back pain                                                                       --	         2 (0.7)
- Surgical and medical procedures	                        2 (0.7)	         2 (0.7)
-      Splenectomy	                                             2 (0.7)	         2 (0.7)
- Hepatobiliary disorders	                                             2 (0.7)	             --
-      Hepatitis	                                                                  2 (0.7)	             --
- Metabolic and nutritional disorders  	                           --	         2 (0.7)
- Renal and urinary disorders                        	      --	         2 (0.7)
- Skin disorders                                          	  2 (0.7)	             --
- Reproductive disorders   	                                                --	         2 (0.7)
**                                     ***fatal event

## Study 0107Adverse Events Occurring in >5% of Patients  (N, %)

**Preferred Term                  ****	****       Exjade                DFO**
**                                                                       ****N=296               N=290**
- Any Event                                                    254 (85.8)       246 (84.8)
- Pyrexia	                                                 56 (18.9)          69 (23.8)
- Headache	                                                 47 (15.9)	         59 (20.3)
- Abdominal pain	                            41 (13.9)	         28 (9.7)
- Cough	                                                 41 (13.9)	         55 (19.0)
- Nasopharyngitis	                            39 (13.2)         42 (14.5)
- Diarrhea	                                                 35 (11.8)          21 (7.2)
- Influenza	                                                 32 (10.8)	         29 (10.0)
- Nausea	                                                 31 (10.5)	         14 (4.8)
- Pharyngolaryngeal pain	                            31 (10.5)         43 (14.8)
- Creatinine increased	                            33 (11.1)              0
- Vomiting	                                                 30 (10.1)	         28 (9.7)
- Respiratory tract infection	                            28 (9.5)	         23 (7.9)
- Bronchitis	                                                 27 (9.1)	         32 (11.0)
- Rash	                                                 25 (8.4)	           9 (3.1)
- Abdominal pain upper	                            23 (7.8)	         15 (5.2)
- Pharyngitis	                                                 23 (7.8)	         30 (10.3)
- Arthralgia	                                                 22 (7.4)	         14 (4.8)
- Acute tonsillitis	                            19 (6.4)	         15 (5.2)
- Fatigue	                                                 18 (6.1)	         14 (4.8)
- Rhinitis	                                                 18 (6.1)	         22 (7.6)
- Back pain	                                                 17 (5.7)	         32 (11.0)
- Ear infection	                                                 16 (5.4)	           7 (2.4)
- Urticaria	                                                 11 (3.7)	         17 (5.9)

## Study 0107: Notable Differences in Adverse Events for Exjade vs. DFO

**                                                             ****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)                  **
**Investigations                                                    57 (19.3)                 16 (5.5)  **
**     ****Creatinine increased                                                     33 (11.1)                           0**
**     ****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 triggering dose reduction or interruption in 11.1% of Exjade patients and no DFO patients.  The increase appeared to be dose-dependent:  2.6% at 10mg, 8.3% at 20 mg and 20.2% at 30 mg Exjade.**
**Heavy proteinuria in 18.6% of Exjade patients compared to 7.2% of DFO patients**
**No reports of renal failure**
_**Other Studies**_
**Similar  findings in other studies, except for patients with rare anemias, in whom an increase in serum creatinine led to dose reduction or interruption in 19.2% (19/99) patients**

## 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 increased in 33% of patients in both the Exjade and the DFO arms**
_**Other Studies**_
**Similar findings were present in other studies**

## Adverse Events - Special Senses

_**Study 0107**_** **
**Cataract formation - 1 Exjade patient, age 16 (drug D/C)  **
**                        ****	****	****- 2 DFO patients, ages 18, 36. **
**Diminished hearing - 8 patients receiving Exjade**
**	****	****	****	**** ****- 7 patients receiving DFO (drug ****	****	****	****	****   interrupted in 2) **
**Vertigo - 1 Exjade patient (no intervention)**
_**Other Studies**_
**Similar findings in other studies**
**Retinal hole in 1 patient in Study 0108**
**Cataracts in 3 patients in Study 0108**
**Retinal vascular changes in Study 0109**
**4 patients receiving Exjade**
**2 patients receiving DFO**

## DeathsDuring Clinical Trials

**Study    Number of  Patients       Population               Deaths**
**                    ****Exjade /  DFO                                          Exjade / DFO**
**  **
**0105                48 / 23                   ********-thalassemia                0 / 0**
**0106                40 / --                     ********-thalassemia               0 **
**0107             296 / 290                  ********-thalassemia               1 / 3**
**0108              184 / --                    ********-thalassemia +            0 ( ********-thal)  **
**                                                       ****rare anemias               6 (rare anemias)**
**0109              132 / 63              sickle cell syndromes      0**

## Notable Adverse Events Extension Studies

**Combined population – 426 patients (****β****-thal, 360; rare anemias, 66)**
**Length of studies – mostly 72-96 weeks**
**Deaths (****β****-thal) (1) – CHF (1)**
**	****	****      ****(MDS) (4) – complications of MDS (3), post ****	****	****	****    liver biopsy bleeding (1) **
**Drug discontinuations (5) -  steatosis with increased transaminases (1), glycosuria (1), colitis (1), Henoch Schonlein purpura (1), increased creatinine (1)**
**SAEs (7) – DVT (1), PE (1), atypical TB (1), increased transaminases (2), cholelithiasis (2)**

## Safety Summary

**Main organs for safety concerns are the kidney and the liver, and the frequency of AEs is greater than with DFO in these organs**
**Adverse effects on the ear/eye appear to be similar in frequency to those seen with DFO**
**Gastrointestinal and dermatological AEs exceed the frequency of those with DFO but are manageable**
**Frequency of uncommon, important AEs is not known because the safety population is small**
**Indefinite use of drug will likely be associated with more frequent and different AEs**

## Sponsor’s Proposed Dosage

**Initiation of Therapy**
**Twenty units of PRBC transfused (****~100 mL/kg)**
**Serum ferritin >1000 ****μ****g/L**
**Starting Dose**
**20 mg/kg/d (but consider both 10 and 30 mg/kg/d based on frequency of transfusion)**
**Maintenance Dose           **
**Adjusted based on monthly monitoring of serum ferritin**

## Comments on Proposed Dosage

**In clinical trials dosing was based on LIC; however, in practice it is doubtful that LIC will be used.  We will ask the Committee for comments regarding appropriate dosing. **
**Transfusion of 100 mL/kg packed red blood cells would be expected to increase the LIC from normal to 7 to 10 mg Fe/g dw.**
**Persistent serum ferritin of >1000 ug/L in a frequently transfused patient is rarely due to a confounding cause.**

## Summary

**Problems with the studies:**
**Dose response for Exjade was not adequately established prior to initiation of the pivotal trial.**
**Most available data for Exjade have been obtained with its use in patients with ****β****-thalassemia.  The experience with other populations with transfusional hemosiderosis is limited. **

## Summary (continued)

**Efficacy:**
**Assessment is based on a single randomized trial and one supportive single-arm trial.**
**The randomized trial did not meet the pre-specified non-inferiority statistical criteria for success.**
**Nevertheless, a treatment effect was observed in the both trials examining change in LIC from baseline with continuing transfusions.  We will be asking the Committee whether this endpoint is acceptable for efficacy.**

## Summary (continued)

**Safety:**
**Evidence for kidney and liver adverse events.**
**Cataracts and hearing adverse effects have been observed.**
**Safety with long-term (life-long) therapy has not been evaluated.**

## Benefit/Risk Assessment

**For patients treated with with an Exjade dose of 20 to 30 mg/kg/day, a mean decrease in LIC was seen during the study with patients continuing to receive transfusions.**
**Exjade has shown clinical adverse events and laboratory abnormalities, mostly non-serious, in clinical studies.  The safety, however, is small.**
**The clinical benefits of Exjade on morbidity/mortality have not been demonstrated.**

## Acknowledgements

**CDER Review Team**
**Suliman Al-Fayoumi, Ph.D., Clinical Pharmacologist, Office of Pharmacology and Biopharmaceutics**
**Sonia Castillo, Ph.D., Statistician, Division of Biometrics II**
**Tamal Chakraborti, Ph.D., Pharmacologist, Division of Gastrointestinal Drug Products**
**Raymond Frankewich, Ph.D., Division of New Chemistry II**
**Charles Ho, Ph.D., Scientific Reviewer, Division of Cardiovascular Devices, CDRH **
**Alice Kacuba, RN, MSN, RAC, Regulatory Health Project Manager**
**Kathy Robie Suh, M.D., Ph.D., Hematology Team Leader, DMIHP**