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Tysabri ® (natalizumab) Biogen Idec Inc. BLA 125104 /15

Tysabri ® (natalizumab) Biogen Idec Inc. BLA 125104 /15. Peripheral and Central Nervous System Drugs Advisory Committee Gaithersburg, Maryland March 7-8, 2006 Susan S. McDermott, M.D. Division of Neurology Products. Center for Drug Evaluation and Research. Review of Efficacy and PML.

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Tysabri ® (natalizumab) Biogen Idec Inc. BLA 125104 /15

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  1. Tysabri® (natalizumab)Biogen Idec Inc.BLA 125104/15 Peripheral and Central Nervous System Drugs Advisory Committee Gaithersburg, Maryland March 7-8, 2006 Susan S. McDermott, M.D. Division of Neurology Products Center for Drug Evaluation and Research

  2. Review of Efficacy and PML

  3. Outline • Regulatory background • Pivotal trials • Efficacy results • Anti-natalizumab antibodies • Progressive multifocal leukoencephalopathy (PML) • Retrospective safety evaluations

  4. Regulatory Background • Accelerated approval (11/23/04) • 21 CFR 601.40 - 46 • Natalizumab effect at one year reasonably likely to predict effect at two years • Primary endpoints for MS therapy trials • Relapse rate • Disability accumulation

  5. Study 1801 EfficacyFDA Analysis

  6. Study 1802 EfficacyFDA Analysis

  7. Anti-natalizumab Antibodies • 6% of subjects developed persistent anti-natalizumab antibodies • Persistent antibody development was associated with less efficacy, compared to antibody-negative subjects

  8. Efficacy Summary • Efficacy • Relapse rate • Disability progression • Add-on therapy • Immunogenicity

  9. PML Case 1 • 46 year old woman with RRMS in Study 1802 who received natalizumab infusions April 2002 through January 2005 (37 doses) • November 2004: PML symptoms began, and were initially thought to be worsening MS • December 2004: MRI changes atypical for MS; received 2 short courses of steroids • February 2005: Positive CSF JC virus; subject died

  10. PML Case 2 • 46 year old man with RRMS in Study 1802 who received a total of 28 doses from October 2002 through December 2004 • October 2004: atypical frontal lesion on routine MRI • November 2004: behavioral changes seen • December 2004: worsening symptoms and new MRI lesions consistent with PML • Natalizumab stopped mid-December 2004 • February 2005: JC virus was found in serum, CSF, and brain tissue; Avonex stopped • Subject continued to decline, now disabled

  11. PML Case 3 • 60 year old man with Crohn’s disease died after taking a total of 8 natalizumab doses • Subject was on natalizumab monotherapy when his initial PML symptoms developed, but had a complicated history of intermittent concomitant immunosuppressant use • Originally diagnosed as an astrocytoma, but retrospective tumor pathology review revealed PML • Retrospective analysis: banked serum samples became positive for JC virus two months prior to symptom development

  12. Retrospective Safety AnalysisNatalizumab Exposure

  13. PML Summary • Three cases of PML identified • Other than natalizumab, additional risk factors were not identified • Relationship between concomitant immunosuppression and PML is unclear; risk of monotherapy v. combination therapy is unclear

  14. CDER FDA Review Team Regulatory Project Manager (DNP)Product (DMA) Katherine Needleman, M.S., RAC Elena Gubina, Ph.D. Chana Fuchs, Ph.D., Team Leader Clinical (DNP) Susan S. McDermott, M.D. Pharm/Tox (DNP) Alice Hughes, M.D.Barbara Wilcox, Ph.D. Wilson Bryan, M.D., Team Leader Lois Freed, Ph.D.,Team Leader Marc Walton, Ph.D., M.D., Deputy Director Russell Katz, M.D., Director Labeling (DDMAC) Catherine Gray, Pharm.D. Clinical Pharmacology (OCBP) Iftekhar Mahmood, Ph.D. RiskMAP Review Team (ODS) Hong Zhao, Ph.D., Team Leader Statistics (OPSS) Sharon Yan, Ph.D. Kun Jin, Ph.D., Team Leader

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