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1、Tysabrie(natalizumab)BiogenIdecInc.BLA125104/15PeripheralandCentralNervousSystemDrugsAdvisoryCommitteeGaithersburg,MarylandMarch7-8,2006AliceHughes,ML.D:.DivisionofNeurologyProducts人CenterforDrugEvaluationandResearchReviewofNon-PMLSafetylssues门共F5洁errolheroussyetempnugsAdvisonyconmittee酊EE9Outline。I
2、nfectionsotherthanPML。Immunogenicityandhypersensitivityreactions。Carcinogenicity。Post-marketingreportsofseriousadverseevents。Summaryofmajorsafetyconcerns月共18133338PonrolheroussyelemprgsAdvisoryconmittee匹uInfectionsotherthanPML:Placebo-controlledMSstudies。Natalizumab-andplacebo-treatedpatientshadsimi
3、larincidencesof:-infectionsoverall:73.796vs.73.996(natalizumabvs:.placebo)一seriousinfections:2.4?6vs.2.3*Natalizumab-andplacebo-treatedpatientshadsimilarincidencesof:一upperrespiratorytractinfections:59.6%vs.59.8?%一UTls:21.5?6vs.21.4?6a怀L达c一理一gastroenteritis:9.1%6vs.9.0?%月共18133338Ponrolheroussyelemp
4、rgsAdvisoryconmittee匹March78,2006粤InfectionsotherthanPML:MSstudies*Incidencesofspecificinfectionsinplacebo-controlledstudies:-alllowerrespiratorytractinfections:13.3?%6vs.12.296(natalizumabvs.placebo)seriouspneumonias:0.496vs.0.296vaginalinfections:7.5?%6vs.6.2?EbityoitouEi友人浩一人gingivalinfections:1.
5、1%6vs.0.5%*Atypicalinfections、cryptosporidialgastroenteritiswithprolongedcourse(inmonotherapyStudy1801罗acuteCMVinfectionwithtransaminitis(inopen-labelStudy1808)月共18133338ConrolheroussyelemprgsAdvisoryconmittee辽March78,20069InfectionsotherthanPML:Placebo-controlledCDstudies国圆ULihyusweu一40.4?4vs.35.8%
6、(natalizumabvs.placebo)*Incidenceofseriousinfections:园渡25园圆Lt团圆口E沥人国洁口H北史水沥一团洁ciEtyuet吴一河一一allherpesinfections:1.69%vs.1.096一perianalabcesses:1.1%6vs.0.6“4一seriousviralmeningitides:0.2?4(2)vs.0一seriousUTls:0.2%(2)vs.0OneseriousCMVinfection(CMVcolitis)一Patientalsoreceivingazathioprine月共11519338Ponrol
7、heroussyelemprgsAdvisoryconmittee辽March7.8,20069InfectionsotherthanPML:Long_termCDstudiesAtypicalInfections*SixseriousatypicallowerrespiratorytractinfectionsE浩u胡-PulmonaryaspergillosisPneumocystiscariniipneumonia-Varicellapneumonia=Mycobacteriumaviumintracellularecomplexpneumonia=Burkholderiacepacia
8、infection*PossibletuberculosisinfectionUnclearroleofconcomitantimmunosuppressiveyimmunomodulatoryagentsandintercurrentilInesses月共18133338ConrolheroussyelemprgsAdvisoryconmittee辽March78,20060Immunogenicity*Antinatalizumabantibodyformationassessedevery12weeksinPhase3MSStudiesandselectedCDstudies一1096o
9、fpatientshadapositiveantibodytiteratleastE,496ofpatientsweretransientlypositiveand6?6werepersistentlypositiveinMSStudiesIncidenceofanti-natalizumabantibodyformationrieTtedSiT人余人5-Intermittent(irregular)infusionsmayleadtohigherincidenceofantibodyformation月共11519338PonrolheroussyelemprgsAdvisoryconmit
10、tee辽March7.8,20069Immunogenicity*Antinatalizumabantibodyformationstronglyassociatedwithinfusionreactionsandhypersensitivityreactlons一Infusionreactionsoccurredin77%ofpersistentlyantibody-positivepatientsvs.20?6ofantibody-negativepatientsinMSStudies1801and1802Mostfrequentinfusionreactionsinantibody-po
11、sitivepatients:rigors,nausea,headache,urticariaflushing,E沥E沥Aanaphy_擅c藿oidUecusleueeouoeantibody-positivepatientsvs.0antibody-negativepatientsinEl沥=Anaphylactic/anaphylactoidreactionsoccurredin1.3%ofantib。d寓-ositivepatientsvs.0antibody-negativepatientsinselectedCDstudies月共18133338Conrolheroussyelemp
12、rgsAdvisoryconmittee匹March78,2006Immunogenicity*MSrelapsesreportedmorefrequentlyasadverseeventsinantibody-positivepatients(vs.transientlypositiveandantibody-negativepatients)园芒河i人振2spatients)*Incidenceofinfectionslowerinantibody-positivepatients(vs.transientlypositiveandantibody-negativepatients)-OverallinfectionsinMSpatients:69?%vs.8296(antibody-positivevs.antibody-negativepatients)一HerpesinfectionsinMSpatients:2.796vs.8.496月D共18133838PonrolheroussyelemprgsAdvisoryconmittee匹March7.8,2006E
