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Tysabri natalizumab Biogen Idec Inc. BLA 12510415

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Anti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS ... MS studies ... Persistently positive anti-natalizumab antibodies associated with infusion ... – PowerPoint PPT presentation

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Title: Tysabri natalizumab Biogen Idec Inc. BLA 12510415


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

Center for Drug Evaluation and Research
2
Review of Non-PML Safety Issues
3
Outline
  • Infections other than PML
  • Immunogenicity and hypersensitivity reactions
  • Carcinogenicity
  • Post-marketing reports of serious adverse events
  • Summary of major safety concerns

4
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

5
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)

6
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

7
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

8
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

9
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

10
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

11
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

12
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

13
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)

14
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

15
Serious adverse events reported in post-marketing
setting
  • Deaths
  • Infections
  • Herpes CNS infections
  • Meningitis and encephalitis
  • Malignancies
  • Hypersensitivity reactions and other serious
    events

16
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

17
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

18
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

19
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
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