Exjade

1
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
2
Sponsors 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

3
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

4
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.

5
Outline of Presentation

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

6
Studies Reviewed

7
Study 0107

• Pivotal trial with non-inferiority design with
  DFO as comparator
• Randomized, open-label, parallel group,
  multi-institutional
• Enrollment 586 patients with ß-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

8
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

9
Study 0107Dosing 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
• gt3 to 7 mg Fe/g dw 10
  25 to 35
• gt7 to 14 mg Fe/g dw 20
  35 to 50
• gt14 mg Fe/g dw 30
  50
• Patients previously receiving DFO could
  remain on their previous dose.

10
Study 0107Definition of Success
11
Study 0107Non-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.

12
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
  studys 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 studys end

13
Study 107Demographics

• 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)
• lt6
  30 (10.1) 28 (9.7)
• 6 - lt12 67
  (22.6) 68 (23.4)
• 12 - lt16 57
  (19.3) 49 (16.9)
• 16 - lt50 142
  (48.0) 144 (49.7)
• 50 - lt65 0
  (0.0) 1 (0.3
• Sex, n ()
• Male 140
  (47.3) 142 (49.0)
  
• Female 156
  (52.7) 148 (51.0)

14
Study 107Dose Cohorts

• Subgroup
  Exjade
  DFO
• 
  N296
  N290
• Baseline LIC dosing category, n ()
• lt3 mg Fe/g/dw
  15 (5.1) 14
  (4.8)
• gt3 - 7 mg Fe/g dw
  78 (26.4) 79 (27.2)
• gt7 - 14 mg Fe/g dw
  84 (28.4) 91
  (31.4)
• gt14 mg Fe/g dw
  119 (40.2) 106
  (36.6)
• Dose cohort (based on initial dose), n ()
• 5 mg/kg Exjade / lt25 mg/kg DFO
  15 (5.1) 7 (2.4)
• 10 mg/kg Exjade / 25-lt35 mg/kg DFO 78
  (26.4) 40 (13.8)
• 20 mg/kg Exjade / 35-lt50 mg/kg DFO 84
  (28.4) 119 (41.0)
• 30 mg/kg Exjade / gt50 mg/kg DFO 119
  (40.2) 124 (42.8)
• Average daily dose (mg/kg) during study (mean
  median)
• lt3 mg Fe/g/dw
  6.2 5.0
  33.9 30.0
• gt3 - 7 mg Fe/g dw
  10.2 10.0 36.7
  35.0
• gt7 - 14 mg Fe/g dw
  19.4 20.0 42.4
  40.8

15
Study 107 Disposition of Patients

• 
  Exjade DFO
• 
  N296 N290
• 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)

16
Study 0107Primary Efficacy Analysis (PP-1)

• Exjade
  DFO
• 
  N276 N277
• Success rate () 52.9
  66.4
• Difference and 95 CI -13.5
  -21.6,-5.4

17
Study 0107Change in LIC from Baseline (PP-2)

• Liver Iron
  Concentration (LIC), mg Fe/g dw
• Baseline
  End-of-Study Change
• Exjade (N268)
• Mean 14.1
  11.7 -2.4
• DFO (N273)
• Mean 13.2
  10.4 -2.9

18
Study 0107Change 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 (N185)
• Mean 18.5
  13.1 -5.3
• significant change from baseline, plt0.001

19
Study 0107 Changes in serum ferritin from
baseline to end of study

20
Supportive Study 0108

• Single arm, open label, multi-institutional
  treatment with Exjade for 48 weeks
• Enrollment 85 subjects with
• ß-thalassemia, 99 subjects with rare anemias
• Exjade dosing same as in Study 0107
• Evaluated change in LIC from baseline to end of
  study

21
Study 0108Change 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 (N147)
• Mean 18.0
  13.8 -4.2
• All Patients with Who Received 20 or 30 mg/kg/day
  (initial dose) (N126)
• Mean 20.2
  14.8 -5.5

22
Study 0108Change 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 (N76)
• Mean 19.3
  14.6 -4.7
• ?-Thal Patients who received Exjade 20 or 30
  mg/kg/day (initial dose) (N67)
• Mean 21.2
  15.1 -6.1

23
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

24
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.

25
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

26
Safety Populations

• 
  Patients receiving gt1 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) ß-thalassemia
• Clinical pharmacology studies 237
  --
  
• (volunteers and ß-thalassemia)

27
Study 0107 Deaths

28
Study 0107Discontinuations Due to Adverse Events

• Event
  Exjade DFO
• 
  N296 N290
• 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)

29
Study 0107 Serious Adverse Events (N, )

• Primary Organ System Class
  Exjade DFO
• 
  N296
  N290
• 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)

30
Study 0107Adverse Events Occurring in gt5 of
Patients (N, )

• Preferred Term Exjade
  DFO
• 
  N296 N290
• 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)

31
Study 0107 Notable Differences in Adverse Events
for Exjade vs. DFO

• 
  Exjade DFO
• 
  N296
  N290
• 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 gt0.6mg/mg 55
  (18.6) 21 (7.2)

32
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

33
Adverse Events - Liver

• Study 0107
• Increased transaminases (gt5x 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

34
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

35
DeathsDuring 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

36
Notable Adverse Events Extension Studies

• Combined population 426 patients (ß-thal, 360
  rare anemias, 66)
• Length of studies mostly 72-96 weeks
• Deaths (ß-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)

37
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

38
Sponsors Proposed Dosage

• Initiation of Therapy
• Twenty units of PRBC transfused (100 mL/kg)
• Serum ferritin gt1000 µg/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

39
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 gt1000 ug/L in a
  frequently transfused patient is rarely due to a
  confounding cause.

40
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 ß-thalassemia. The
  experience with other populations with
  transfusional hemosiderosis is limited.

41
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.

42
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.

43
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.

44
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