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Exjade ® Novartis NDA 21-882

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.

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Exjade ® Novartis NDA 21-882

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  1. 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

  2. Iron Metabolism • Body iron balance – input vs output • Iron highly conserved • Normal TBI - 3-5 gm • Normal LIC - <1.5 mg Fe/gm dw • TBImg/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

  3. 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

  4. 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

  5. Studies Reviewed

  6. 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

  7. 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) <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%)

  8. Study 107Dose Cohorts • Exjade dose prespecified according to baseline LIC • DFO dose • prespecified according to baseline LIC or • Patients could continue on prior effective DFO dose

  9. Study 0107Primary 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]

  10. Study 0107Change 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

  11. 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 (N=185) Mean 18.5 13.1 -5.3* * significant change from baseline, p<0.001

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

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

  14. 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.

  15. 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

  16. 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 (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

  17. Safety Populations Patients receiving >1 Dose of _________________________ PopulationExjadeDFO -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)

  18. Pediatric Safety PopulationAll 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

  19. 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)

  20. 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

  21. 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

  22. 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)

  23. 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

  24. 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

  25. 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

  26. 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.

  27. 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

  28. Exjade • Discussion and questions: Considerations for PMC protocol development • Long term use in pediatric patients • Use among patients with lower LIC • Cardiac effects

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