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FDA Presentation to the Oncologic Drugs Advisory Committee Tositumomab Therapeutic Regimen Corixa Corporation BLA 1250

FDA Presentation to the Oncologic Drugs Advisory Committee Tositumomab Therapeutic Regimen Corixa Corporation BLA 125011 December 17, 2002. Tositumomab Therapeutic Regimen Review Team. Product/Chairperson: Terrye G. Zaremba, Ph.D. Clinical Reviewers: Stephen Litwin, M.D.

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FDA Presentation to the Oncologic Drugs Advisory Committee Tositumomab Therapeutic Regimen Corixa Corporation BLA 1250

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  1. FDA Presentation to the Oncologic Drugs Advisory Committee Tositumomab Therapeutic Regimen Corixa Corporation BLA 125011 December 17, 2002

  2. Tositumomab Therapeutic Regimen Review Team Product/Chairperson: Terrye G. Zaremba, Ph.D. Clinical Reviewers: Stephen Litwin, M.D. George Mills, M.D. Harvey Luksenburg, M.D. Kaushikkumar Shastri, M.D. Biostatistician: Satish Misra, Ph.D. Pharm/Tox: Martin D. Green, Ph.D. Radiochemistry: Leon Epps, Ph.D. BioResearch Monitor: Mary Andrich, M.D. Facilities Specialist: Deborah Trout, B.S. Project Managers: Karen Jones, B.S. Craig Doty, Pharm. D Michael A. Noska, M.S

  3. SubmissionTime-Line • Sept 14, 2000- BLA 125011 submitted • RIT-II-004- 5/31/2000 study report • RIT-II-000 and 001- final study reports • RIT-II-002 and 003-interim study reports • ISS - 286 subjects • Dec 14, 2000 • CP98-020 interim study report • ISS - 308 subjects

  4. Timeline (2) • March 16, 2001 – FDA Action letter #1 • Multiple requests for info on product characterization and manufacture • Inadequate efficacy database -single pivotal trial with substantially different efficacy in transformed vs. non-transformed, some supportive data submitted as interim reports • Inadequate safety database - substantial missing data for acute heme toxicity and delayed hematologic, thyroid and HAMA events

  5. Timeline (3) • August 27, 2001 • RIT-II-003 second interim report through 12/20/2000 • ISS update – 309 patients • Sept 7, 2001 • Final study report CP97-012 • Amended study report RIT-II-002 - MIRROR panel review, data cut-off Jan. 2001

  6. Timeline (4) • Sept 10, 2001- Corixa response to FDA letter • Dec 11, 2001 • RIT-II-004- amended final study report, data cutoff Jan 2001, MIRROR panel review Sept 2001 • ISS update – 620 patients (includes 387 from expanded access) • Long-term responders- various studies- MIRROR panel review • Additional info for CP98-020

  7. Timeline (5) • March 5, 2002 • ISS update: corrected errors & gave additional hematology data collected from audit at clinical study sites in 620 pts • March 12, 2002- FDA action letter #2 • Need to demonstrate a meaningful therapeutic advance over existing treatment (Zevalin approved Feb. 2002) • Additional safety data needed

  8. Timeline (6) • July 2, 2002 • Case report forms and report tabulations for long-term responder subpopulation • July 11, 2002 • Revised proposed indication • Requested accelerated approval for chemo-refractory and standard approval for Rituximab-refractory pts • Amendment 1 to final study report for CP97-012

  9. Timeline (7) • October 4, 2002 • Amendment 2 to final study report for CP97-012 • October 30, 2002 • Independent review for additional patients with transformed histology in CP 97-012 • October 31, 2002 – Corixa completes response to FDA 3/12/2002 letter

  10. Timeline (8) • December 10, 2002 –Responses to Bi Mo inspectional findings • Outstanding issues on clinical trial • identification of dose delivered vs. dose prescribed for patients in efficacy studies • FDA will need to confirm safety profile of proposed dose

  11. Tositumomab Therapeutic Regimen (TTR)Monoclonal Antibody Characteristics • Tositumomab and I-131-Tositumomab • Tositumomab also called “Anti-B1” • Murine IgG2a, l • Recognizes CD20

  12. Characteristics of CD20 • Transmembrane phosphoprotein with a molecular weight of 33-37 kDa • Present on the surface of pre-B and mature B cells • Expressed on >90% of B-cell lymphomas • Not present on stem cells, mature plasma cells, or other nonlymphoid normal tissues • Is not shed or internalized upon antibody binding

  13. MonoclonalAntibody Characteristics (2) • Manufactured by standard tissue culture and purification techniquees • I-131- Tositumomab radiolabeled by the IODO-GEN® method

  14. TTR Components • Unlabeled: -Tositumomab 3 mL vial: 35 mg @ 14 mg/mL -Tositumomab 20 mL vial: 225mg @ 14 mg/mL

  15. TTR Components (2) • Labeleld (I-131-Tositumomab • Dosimetric vial: not less than 20 mL in a 30 mL vial. Protein concentration between 0.10 and 0.25 mg/mL. Calibrated activity of 12-18 mCi. • Therapeutic vial: not less than 20 mL in a 30 mL vial. Protein concentration between 1.1 and 2.5 mg/mL. Calibrated activity of 112-168

  16. TTR Procedure Step 1 – Imaging • Tositumomab 450 mg in 0.9% NaCl injection in total volume of 50 mL IV over 60 minutes • I-131 Tositumomab (dosimetric) 5 mCi + 35 mg Tositumomab in 0.9% NaCl injection in total volume of 30 mL IV over 20 minutes

  17. TTR Procedure Step 2 - Therapy (7-14 days post imaging) • Tositumomab 450 mg in 0.9% NaCl injection in total volume of 50 mL IV over 60 minutes • I-131-Tositumomab (therapeutic) 35 mg containing the patient-specific dose (mCi) IV over 20 minutes

  18. TTR Procedure • Thyroid protective agent is given beginning at least 24 hours prior to the first infusion of I-131 Tositumomab (dosimetric dose) and continues for 14 days following the last infusion of I-131 Tositumomab (therapeutic dose).

  19. Remaining CMC Issues • A number of manufacturing issues remain to be resolved • One contract facility remains to be inspected

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