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1、TysabriTysabri (natalizumab)(natalizumab)Biogen Idec Inc.Biogen Idec Inc.BLA 125104BLA 125104/15/15Peripheral and Central Nervous System Peripheral and Central Nervous System Drugs Advisory Committee Drugs Advisory Committee Gaithersburg, MarylandGaithersburg, MarylandGaithersburg, MarylandMarch 7-8
2、, 2006March 7-8, 2006March 7-8, 2006Alice Hughes, M.D.Alice Hughes, M.D.Alice Hughes, M.D.Division of Neurology ProductsDivision of Neurology ProductsDivision of Neurology ProductsCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and Research 1Peripheral and Central Nervous System Dr
3、ugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Review of Non-PML Safety Issues2Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006
4、OutlineInfections other than PMLImmunogenicity and hypersensitivity reactionsCarcinogenicityPost-marketing reports of serious adverse eventsSummary of major safety concerns3Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMar
5、ch 7-8, 2006March 7-8, 2006Natalizumab- 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% v
6、s. 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 studies4Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Infe
7、ctions other than PML:MS studiesIncidences 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:
8、1.1% vs. 0.5%Atypical infectionscryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801)acute CMV infection with transaminitis (in open-label Study 1808)5Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory Commit
9、teeMarch 7-8, 2006March 7-8, 2006Infections other than PML:Placebo-controlled CD studiesIncidence 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
10、.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. 0serious UTIs: 0.2% (2) vs. 0One serious CMV infection (CMV colitis)Patient also receiving azathioprine6Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral an
11、d Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Infections other than PML:Long-term CD studiesAtypical InfectionsSix serious atypical lower respiratory tract infectionsPneumonia with lung abscessPulmonary aspergillosisPneumocystis carinii pneumoniaVaricella pneumoniaMy
12、cobacterium avium intracellulare complex pneumoniaBurkholderia cepacia infectionPossible tuberculosis infectionUnclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illnesses7Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervou
13、s System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006ImmunogenicityAnti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies10% of patients had a positive antibody titer at least once4% of patients were transiently positive and 6% were persis
14、tently positive in MS StudiesIncidence 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 formation8Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Ner
15、vous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006ImmunogenicityAnti-natalizumab antibody formation strongly associated with infusion reactions and hypersensitivity reactionsInfusion reactions occurred in 77% of persistently antibody-positive patients vs. 20% of antibody-negative pat
16、ients in MS Studies 1801 and 1802Most frequent infusion reactions in antibody-positive patients: rigors, nausea, headache, urticaria, flushing, pruritus, dyspneaAnaphylactic/ anaphylactoid reactions occurred in 5.3% of antibody-positive patients vs. 0 antibody-negative patients in MS Studies 1801 an
17、d 1802Anaphylactic/ anaphylactoid reactions occurred in 1.3% of antibody-positive patients vs. 0 antibody-negative patients in selected CD studies 9Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 20
18、06ImmunogenicityMS 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 pos
19、itive 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%10Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory C
20、ommitteeMarch 7-8, 2006March 7-8, 2006Hypersensitivity reactionsAnaphylactic/ anaphylactoid reactionsMS placebo-controlled studies: 0.4% (6) vs. 0.2% (2) natalizumab vs. placeboCD placebo-controlled studies: 0.1% (1) vs. 0Long-term CD studies: 1 additional case of anaphylaxis (during first infusion
21、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 eventsMost hypersensitivity events occurred during or immediately after second in
22、fusion; some occurred laterOne case of anaphylaxis associated with 13th infusion11Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Carcinogenicity:MS studiesMalignancies balanced in natalizumab-
23、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 CABasal cell CACervical CAColon CAMelanomaSquamous cell CAPituitary adenomaPapillary thyroid CA12Peripheral and Centr
24、al Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Carcinogenicity:CD studiesMalignancies more frequently reported for natalizumab-treated patients in placebo-controlled studies (0.6% vs. 0.2%)Types of neoplasms obser
25、ved in natalizumab-treated patients in all CD studies: Breast CALung CABladder CAColorectal CAMalignant melanomaUterine CABasal cell CASquamous cell CAUterine CARenal cell CA (clear cell)MeningiomaCraniopharyngioma (suspected)Lymphoma (B-cell)13Peripheral and Central Nervous System Drugs Advisory Co
26、mmitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Carcinogenicity:Long-term CD studiesB-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-mercapt
27、opurine therapyHad submandibular lymphadenopathy during 9/04 screening examination; not apparent on subsequent examPresented with painful lymphadenopathy August, 2005 and was diagnosed (CT; biopsy) with B-cell lymphoma14Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Cen
28、tral Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Serious adverse events reported in post-marketing settingDeathsInfectionsHerpes CNS infections Meningitis and encephalitisMalignanciesHypersensitivity reactions and other serious events15Peripheral and Central Nervous System D
29、rugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Summary of key safety issues:Non-PML infectionsTypes of infections suggest possible compromise in cell-mediated immunityHerpes infections, lower respiratory tract infections (especially
30、 those caused by atypical pathogens), and viral meningitides are of particular concernRole of concomitant medications and intercurrent illnesses in pathogenesis of infections is unclearRelative risks for infections similar in MS Studies 1801 (monotherapy) and 1802 (combination therapy)No clear assoc
31、iation between increasing number of natalizumab infusions and risk for infections16Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006Summary of key safety issues:Immunogenicity and hypersensitivit
32、yAnti-natalizumab antibodies formed in approximately 10% of patientsPersistently positive anti-natalizumab antibodies associated with infusion reactions, hypersensitivity reactions, increased MS relapse/ CD exacerbations, decreased incidence of infectionsAnaphylactoid reactions occurred in 0.4% of n
33、atalizumab-treated MS patients overall and in 5% of antibody-positive patientsHypersensitivity reactions most common with second infusion but may occur much later17Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2
34、006March 7-8, 2006Summary of key safety issues:CarcinogenicityNo evident increase in risk for malignancies in MS studiesOne lymphoma (B-cell) in patient in long-term CD trialconcomitant 6-mercaptopurine therapy and history of infliximab therapyNo leukemiasLonger exposures will be needed before risk
35、for malignancies can be adequately assessed18Peripheral and Central Nervous System Drugs Advisory CommitteePeripheral and Central Nervous System Drugs Advisory CommitteeMarch 7-8, 2006March 7-8, 2006AcknowledgementsTysabri Review TeamRegulatory Project Manager (DNP) Product (DMA)Katherine Needleman,
36、 M.S., RAC Elena Gubina, Ph.D. Chana Fuchs, Ph.D. Team LeaderClinical (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 LeaderMarc Walton, M.D., Ph.D., Deputy DirectorRussell 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 LeaderStatistics (OPSS) Sharon Yan, Ph.D.Kun Jin, Ph.D., Team Leader 19
