Tysabri natalizumab Biogen Idec Inc. BLA 12510415

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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

Center for Drug Evaluation and Research
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Review of Non-PML Safety Issues
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Outline

• Infections other than PML
• Immunogenicity and hypersensitivity reactions
• Carcinogenicity
• Post-marketing reports of serious adverse events
• Summary of major safety concerns

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Infections other than PMLPlacebo-controlled MS
studies

• 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

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Infections other than PMLMS 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)

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Infections other than PMLPlacebo-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

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Infections other than PMLLong-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

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Immunogenicity

• 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

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Immunogenicity

• 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
  

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Immunogenicity

• 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

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Hypersensitivity reactions

• Anaphylactic/ anaphylactoid reactions
• MS placebo-controlled studies 0.4 (6) vs. 0.2
  (2) natalizumab vs. placebo
• CD placebo-controlled studies lt0.1 (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

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CarcinogenicityMS 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

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CarcinogenicityCD 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)

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CarcinogenicityLong-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

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Serious adverse events reported in post-marketing
setting

• Deaths
• Infections
• Herpes CNS infections
• Meningitis and encephalitis
• Malignancies
• Hypersensitivity reactions and other serious
  events

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Summary of key safety issuesNon-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

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Summary of key safety issuesImmunogenicity 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

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Summary of key safety issuesCarcinogenicity

• 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

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Acknowledgements

• 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