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 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. 2 Review of Efficacy and PML

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

4. 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 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. 5 Study 1801 Efficacy FDA Analysis NatalizumabPlacebo Number randomized627315 Number reaching sustained disability progression Absolute difference Hazard ratio p – value 104 (17 %)84 (27 %) 10 % 0.58 0.0002 Annualized relapse rate Absolute difference p – value 0.240.73 0.49 < 0.001

6. 6 Study 1802 Efficacy FDA Analysis Natalizumab + Avonex Placebo + Avonex Number randomized589582 Number reaching sustained disability progression Absolute difference Hazard ratio p – value 129 (22 %)156 (27 %) 5 % 0.76 0.0238 Annualized relapse rate Absolute difference p - value 0.340.75 0.41 < 0.001

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

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

9. 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 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. 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 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. 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 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. 12 Retrospective Safety Analysis Natalizumab Exposure Doses< 12≥ 12≥ 24≥ 36Total MS Safety Trial 718115110532791869 CD / RA Safety Trial 721499285181220

13. 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 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. 14 CDER FDA Review Team Regulatory Project Manager (DNP)Product (DMA) Katherine Needleman, M.S., RACElena 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 LeaderLois Freed, Ph.D.,Team Leader Marc Walton, Ph.D., M.D., Deputy Director Russell Katz, M.D., DirectorLabeling (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 Regulatory Project Manager (DNP)Product (DMA) Katherine Needleman, M.S., RACElena 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 LeaderLois Freed, Ph.D.,Team Leader Marc Walton, Ph.D., M.D., Deputy Director Russell Katz, M.D., DirectorLabeling (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