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

2. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 2 Review of Non-PML Safety Issues

3. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 3 OutlineOutline Infections other than PML Immunogenicity and hypersensitivity reactions Carcinogenicity Post-marketing reports of serious adverse events Summary of major safety concerns Infections other than PML Immunogenicity and hypersensitivity reactions Carcinogenicity Post-marketing reports of serious adverse events Summary of major safety concerns

4. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 4 Natalizumab- and placebo-treated patients had similar incidences of: –infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo) –serious infections: 2.4% vs. 2.3% Natalizumab- and placebo-treated patients had similar incidences of: –upper respiratory tract infections: 59.6% vs. 59.8% –UTIs: 21.5% vs. 21.4% serious UTIs: 0.6% vs. 0.5% –gastroenteritis: 9.1% vs. 9.0% Natalizumab- and placebo-treated patients had similar incidences of: –infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo) –serious infections: 2.4% vs. 2.3% Natalizumab- and placebo-treated patients had similar incidences of: –upper respiratory tract infections: 59.6% vs. 59.8% –UTIs: 21.5% vs. 21.4% serious UTIs: 0.6% vs. 0.5% –gastroenteritis: 9.1% vs. 9.0% Infections other than PML: Placebo-controlled MS studies

5. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 5 Infections other than PML: MS studies Incidences of specific infections in placebo-controlled studies: –all lower respiratory tract infections: 13.3% vs. 12.2% (natalizumab vs. placebo) serious pneumonias: 0.4% vs. 0.2% –vaginal infections: 7.5% vs. 6.2% –all herpes infections: 7.0% vs. 6.1% –gingival infections: 1.1% vs. 0.5% Atypical infections cryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801) acute CMV infection with transaminitis (in open-label Study 1808) Incidences of specific infections in placebo-controlled studies: –all lower respiratory tract infections: 13.3% vs. 12.2% (natalizumab vs. placebo) serious pneumonias: 0.4% vs. 0.2% –vaginal infections: 7.5% vs. 6.2% –all herpes infections: 7.0% vs. 6.1% –gingival infections: 1.1% vs. 0.5% Atypical infections cryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801) acute CMV infection with transaminitis (in open-label Study 1808)

6. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 6 Infections other than PML: Placebo-controlled CD studies Incidence of infections overall: –40.4% vs. 35.8% (natalizumab vs. placebo) Incidence of serious infections: –2.5% vs. 2.6% Incidences of selected infections: –URIs: 27% vs. 21% –UTIs: 2.9% vs. 2.0% –vaginal infections: 2.1% vs. 1.6% –all herpes infections: 1.6% vs. 1.0% –perianal abcesses: 1.1% vs. 0.6% –serious viral meningitides: 0.2% (2) vs. 0 –serious UTIs: 0.2% (2) vs. 0 One serious CMV infection (CMV colitis) –Patient also receiving azathioprine Incidence of infections overall: –40.4% vs. 35.8% (natalizumab vs. placebo) Incidence of serious infections: –2.5% vs. 2.6% Incidences of selected infections: –URIs: 27% vs. 21% –UTIs: 2.9% vs. 2.0% –vaginal infections: 2.1% vs. 1.6% –all herpes infections: 1.6% vs. 1.0% –perianal abcesses: 1.1% vs. 0.6% –serious viral meningitides: 0.2% (2) vs. 0 –serious UTIs: 0.2% (2) vs. 0 One serious CMV infection (CMV colitis) –Patient also receiving azathioprine

7. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 7 Infections other than PML: Long-term CD studies Atypical Infections Six serious atypical lower respiratory tract infections –Pneumonia with lung abscess –Pulmonary aspergillosis –Pneumocystis carinii pneumonia –Varicella pneumonia –Mycobacterium avium intracellulare complex pneumonia –Burkholderia cepacia infection Possible tuberculosis infection Unclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illnesses Atypical Infections Six serious atypical lower respiratory tract infections –Pneumonia with lung abscess –Pulmonary aspergillosis –Pneumocystis carinii pneumonia –Varicella pneumonia –Mycobacterium avium intracellulare complex pneumonia –Burkholderia cepacia infection Possible tuberculosis infection Unclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illnesses

8. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 8 ImmunogenicityImmunogenicity Anti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies –10% of patients had a positive antibody titer at least once 4% of patients were transiently positive and 6% were persistently positive in MS Studies Incidence of anti-natalizumab antibody formation was higher in Study 1802 (12%) than in 1801 (9%) –Intermittent (irregular) infusions may lead to higher incidence of antibody formation Anti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies –10% of patients had a positive antibody titer at least once 4% of patients were transiently positive and 6% were persistently positive in MS Studies Incidence of anti-natalizumab antibody formation was higher in Study 1802 (12%) than in 1801 (9%) –Intermittent (irregular) infusions may lead to higher incidence of antibody formation

9. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 9 ImmunogenicityImmunogenicity Anti-natalizumab antibody formation strongly associated with infusion reactions and hypersensitivity reactions –Infusion reactions occurred in 77% of persistently antibody- positive patients vs. 20% of antibody-negative patients in MS Studies 1801 and 1802 Most frequent infusion reactions in antibody-positive patients: rigors, nausea, headache, urticaria, flushing, pruritus, dyspnea –Anaphylactic/ anaphylactoid reactions occurred in 5.3% of antibody-positive patients vs. 0 antibody-negative patients in MS Studies 1801 and 1802 –Anaphylactic/ anaphylactoid reactions occurred in 1.3% of antibody-positive patients vs. 0 antibody-negative patients in selected CD studies Anti-natalizumab antibody formation strongly associated with infusion reactions and hypersensitivity reactions –Infusion reactions occurred in 77% of persistently antibody- positive patients vs. 20% of antibody-negative patients in MS Studies 1801 and 1802 Most frequent infusion reactions in antibody-positive patients: rigors, nausea, headache, urticaria, flushing, pruritus, dyspnea –Anaphylactic/ anaphylactoid reactions occurred in 5.3% of antibody-positive patients vs. 0 antibody-negative patients in MS Studies 1801 and 1802 –Anaphylactic/ anaphylactoid reactions occurred in 1.3% of antibody-positive patients vs. 0 antibody-negative patients in selected CD studies

10. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 10 ImmunogenicityImmunogenicity MS relapses reported more frequently as adverse events in antibody-positive patients (vs. transiently positive and antibody-negative patients) –57% vs. 35% (antibody-positive vs. antibody-negative patients) Incidence of infections lower in antibody-positive patients (vs. transiently positive and antibody-negative patients) –Overall infections in MS patients: 69% vs. 82% (antibody-positive vs. antibody-negative patients) –Herpes infections in MS patients: 2.7% vs. 8.4% MS relapses reported more frequently as adverse events in antibody-positive patients (vs. transiently positive and antibody-negative patients) –57% vs. 35% (antibody-positive vs. antibody-negative patients) Incidence of infections lower in antibody-positive patients (vs. transiently positive and antibody-negative patients) –Overall infections in MS patients: 69% vs. 82% (antibody-positive vs. antibody-negative patients) –Herpes infections in MS patients: 2.7% vs. 8.4%

11. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 11 Hypersensitivity reactions Anaphylactic/ anaphylactoid reactions –MS placebo-controlled studies: 0.4% (6) vs. 0.2% (2) [natalizumab vs. placebo] –CD placebo-controlled studies: <0.1% (1) vs. 0 –Long-term CD studies: 1 additional case of anaphylaxis (during first infusion in CD251; 300 days after receiving 4 infusions in prior CD study) Skin and subcutaneous tissue disorder infusion reactions in MS placebo-controlled studies: 4.6% vs. 1.9% Urticaria: 1.6% vs. 0.3% Delayed hypersensitivity events Most hypersensitivity events occurred during or immediately after second infusion; some occurred later –One case of anaphylaxis associated with 13th infusion Anaphylactic/ anaphylactoid reactions –MS placebo-controlled studies: 0.4% (6) vs. 0.2% (2) [natalizumab vs. placebo] –CD placebo-controlled studies: <0.1% (1) vs. 0 –Long-term CD studies: 1 additional case of anaphylaxis (during first infusion in CD251; 300 days after receiving 4 infusions in prior CD study) Skin and subcutaneous tissue disorder infusion reactions in MS placebo-controlled studies: 4.6% vs. 1.9% Urticaria: 1.6% vs. 0.3% Delayed hypersensitivity events Most hypersensitivity events occurred during or immediately after second infusion; some occurred later –One case of anaphylaxis associated with 13th infusion

12. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 12 Carcinogenicity: MS studies –Malignancies balanced in natalizumab- and placebo- treated patients in placebo-controlled studies (0.7% natalizumab vs. 1.3% placebo) –Types of malignancies observed in natalizumab-treated patients in all MS studies: Breast CA Basal cell CA Cervical CA Colon CA Melanoma Squamous cell CA Pituitary adenoma Papillary thyroid CA –Malignancies balanced in natalizumab- and placebo- treated patients in placebo-controlled studies (0.7% natalizumab vs. 1.3% placebo) –Types of malignancies observed in natalizumab-treated patients in all MS studies: Breast CA Basal cell CA Cervical CA Colon CA Melanoma Squamous cell CA Pituitary adenoma Papillary thyroid CA

13. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 13 Carcinogenicity: CD studies –Malignancies more frequently reported for natalizumab-treated patients in placebo-controlled studies (0.6% vs. 0.2%) –Types of neoplasms observed in natalizumab-treated patients in all CD studies: Breast CA Lung CA Bladder CA Colorectal CA Malignant melanoma Uterine CA Basal cell CA Squamous cell CA Uterine CA Renal cell CA (clear cell) Meningioma Craniopharyngioma (suspected) Lymphoma (B-cell) –Malignancies more frequently reported for natalizumab-treated patients in placebo-controlled studies (0.6% vs. 0.2%) –Types of neoplasms observed in natalizumab-treated patients in all CD studies: Breast CA Lung CA Bladder CA Colorectal CA Malignant melanoma Uterine CA Basal cell CA Squamous cell CA Uterine CA Renal cell CA (clear cell) Meningioma Craniopharyngioma (suspected) Lymphoma (B-cell)

14. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 14 Carcinogenicity: Long-term CD studies B-cell lymphoma (1) –49 yo man who received 6 infusions of natalizumab in Studies 307 and 351 (9/04 – 2/05) –History of infliximab therapy (8 doses ) –Concomitant 6-mercaptopurine therapy –Had submandibular lymphadenopathy during 9/04 screening examination; not apparent on subsequent exam –Presented with painful lymphadenopathy August, 2005 and was diagnosed (CT; biopsy) with B-cell lymphoma B-cell lymphoma (1) –49 yo man who received 6 infusions of natalizumab in Studies 307 and 351 (9/04 – 2/05) –History of infliximab therapy (8 doses ) –Concomitant 6-mercaptopurine therapy –Had submandibular lymphadenopathy during 9/04 screening examination; not apparent on subsequent exam –Presented with painful lymphadenopathy August, 2005 and was diagnosed (CT; biopsy) with B-cell lymphoma

15. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 15 Serious adverse events reported in post-marketing setting Deaths Infections –Herpes CNS infections Meningitis and encephalitis Malignancies Hypersensitivity reactions and other serious events Deaths Infections –Herpes CNS infections Meningitis and encephalitis Malignancies Hypersensitivity reactions and other serious events

16. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 16 Summary of key safety issues: Non-PML infections Types of infections suggest possible compromise in cell- mediated immunity Herpes infections, lower respiratory tract infections (especially those caused by atypical pathogens), and viral meningitides are of particular concern Role of concomitant medications and intercurrent illnesses in pathogenesis of infections is unclear Relative risks for infections similar in MS Studies 1801 (monotherapy) and 1802 (combination therapy) No clear association between increasing number of natalizumab infusions and risk for infections Types of infections suggest possible compromise in cell- mediated immunity Herpes infections, lower respiratory tract infections (especially those caused by atypical pathogens), and viral meningitides are of particular concern Role of concomitant medications and intercurrent illnesses in pathogenesis of infections is unclear Relative risks for infections similar in MS Studies 1801 (monotherapy) and 1802 (combination therapy) No clear association between increasing number of natalizumab infusions and risk for infections

17. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 17 Summary of key safety issues: Immunogenicity and hypersensitivity Anti-natalizumab antibodies formed in approximately 10% of patients Persistently positive anti-natalizumab antibodies associated with infusion reactions, hypersensitivity reactions, increased MS relapse/ CD exacerbations, decreased incidence of infections Anaphylactoid reactions occurred in 0.4% of natalizumab- treated MS patients overall and in 5% of antibody-positive patients Hypersensitivity reactions most common with second infusion but may occur much later Anti-natalizumab antibodies formed in approximately 10% of patients Persistently positive anti-natalizumab antibodies associated with infusion reactions, hypersensitivity reactions, increased MS relapse/ CD exacerbations, decreased incidence of infections Anaphylactoid reactions occurred in 0.4% of natalizumab- treated MS patients overall and in 5% of antibody-positive patients Hypersensitivity reactions most common with second infusion but may occur much later

18. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 18 Summary of key safety issues: Carcinogenicity No evident increase in risk for malignancies in MS studies One lymphoma (B-cell) in patient in long-term CD trial –concomitant 6-mercaptopurine therapy and history of infliximab therapy No leukemias Longer exposures will be needed before risk for malignancies can be adequately assessed No evident increase in risk for malignancies in MS studies One lymphoma (B-cell) in patient in long-term CD trial –concomitant 6-mercaptopurine therapy and history of infliximab therapy No leukemias Longer exposures will be needed before risk for malignancies can be adequately assessed

19. Peripheral and Central Nervous System Drugs Advisory Committee March 7-8, 2006 19 AcknowledgementsAcknowledgements Tysabri 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 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, M.D., Ph.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 Tysabri 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 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, M.D., Ph.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