FDA Presentation

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

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Submission Time-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

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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

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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

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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

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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

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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

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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

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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

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Tositumomab Therapeutic Regimen (TTR)Monoclonal
Antibody Characteristics

• Tositumomab and I-131-Tositumomab
• Tositumomab also called Anti-B1
• Murine IgG2a, l
• Recognizes CD20

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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 gt90 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

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Monoclonal Antibody Characteristics (2)

• Manufactured by standard tissue culture and
  purification techniquees
• I-131- Tositumomab radiolabeled by the IODO-GEN
  method

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TTR Components

• Unlabeled
• -Tositumomab 3 mL vial 35 mg _at_ 14 mg/mL
• -Tositumomab 20 mL vial 225 mg _at_ 14 mg/mL

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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

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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

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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

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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).

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Remaining CMC Issues

• A number of manufacturing issues remain to be
  resolved
• One contract facility remains to be inspected