銀屑病的生物治療

煩惱有何懼怕，既然躲不掉，就調(diào)好心態(tài)與它共存。心向陽光，何懼風(fēng)霜。

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銀屑病的生物治療

Biologicaltherapiesforpsoriasis

ChronicPlaquePsoriasisT-cellmediateddiseaseMenandwomenaffectedequallyGeneticcomponentCircumscribed,raised,redplaquesScaly,itchy,cracking,bleedingModeratetoseverecharacterizedby>10%bodysurfaceareainvolvement,butcanbeupto98%Life-longdiseasewithnocureConceptbasedon:KruegerJG.JAmAcadDermatol.2002;46:1-23.Cytokine

productionKeratinocyte

hyperproliferationInflammatory

responseT-cellActivation,Proliferation,andCytokineProductionActivatedAPCT-cellImmunologicSynapseICAMLFA-1MHCTCRCD4/CD8LFA-3CD2CD40CD40LB7CD28ICAMLFA-1CostimulatoryMoleculesCD3Costimulatory

SignalsCD11aAntigen-PeptideT-cell

ActivationSignalsT-cellactivationBiologicalTherapiesofPlaquePsoriasisICAMCD11aLFA-3CD2B7CD28

anti-CD11aEfalizumabLFA3-Ig

AlefaceptCTLA4-IgAbataceptT-cellactivationInhibitorCytokine

InhibitorTNFR-IgEternacetAnti-TNFInfliximabHumanizedmAbIgG1

kappahumanframeworkcontainingmurineantibodycomplementarity-determiningregions(CDRs)

(MW150kd)GENENTECHBlocksinteractionbetweenLFA-1onT-cellandintracellularadhesionmolecule(ICAM)onAPC,endotheliumandkeratinocytesEfalizumab（Raptiva）

CharacteristicsHeavychainLightchainHeavychainCDRLightchainCDRCarbohydratesPhaseIstudy(HU9602)Thisstudyinvestigatedsingleintravenous(IV)doses(0.03,0.1,0.3,0.6,1.0,2.0,3.0or10.0mg/kg)ofefalizumabadministeredinadose-escalationmannerto31subjectsmoderatetosevereplaquepsoriasis.PhaseIstudyConclusions

TheIVdosageof0.6mg/kg/wkwasthelowestIVdosagethatconsistentlyproducedthemaximalPDeffect.TheSCdosagewasexpectedtobe1.0mg/kg/wkbasedontheestimateofapproximately50%bioavailabilitywiththeSCdosagerelativetoIVadministration.Theaveraget1/2forSCefalizumab1.0mg/kg/wkis5.5daysAlthoughpeakserumconcentrationafterthelastdose(Cmax)washigherforthe2.0mg/kg/wk(30.9μg/mL)thanforthe1.0mg/kg/wkdosage(12.4μg/mL),noadditionalchangesinPDeffectswereobservedatthehigherdosagesC-EFF-EfalizumabStudy2390:

PivotalPhaseIIIEfficacyStudyRandomizationDay0ScreenPrimaryAnalysisWeek12(Day84)Placebo(n=187)Raptiva1mg/kg(n=369)EntrancecriteriaPlaquepsoriasis≥6monthsBSA≥10%PASI≥12Candidatefor,orhistoryof,systemictherapy9、人的價值，在招收誘惑的一瞬間被決定。2023/2/32023/2/3Friday,February3,202310、低頭要有勇氣，抬頭要有低氣。2023/2/32023/2/32023/2/32/3/20234:57:11PM11、人總是珍惜為得到。2023/2/32023/2/32023/2/3Feb-2303-Feb-2312、人亂于心，不寬余請。2023/2/32023/2/32023/2/3Friday,February3,202313、生氣是拿別人做錯的事來懲罰自己。2023/2/32023/2/32023/2/32023/2/32/3/202314、抱最大的希望，作最大的努力。03二月20232023/2/32023/2/32023/2/315、一個人炫耀什么，說明他內(nèi)心缺少什么。。二月232023/2/32023/2/32023/2/32/3/202316、業(yè)余生活要有意義，不要越軌。2023/2/32023/2/303February202317、一個人即使已登上頂峰，也仍要自強不息。2023/2/32023/2/32023/2/32023/2/3C-EFF-Efalizumab

Study2390:PrimaryEfficacyVariable,thePsoriasisAreaandSeverityIndexPhysician-performedassessmentIndexrangesfrom0to72,higherscoresworsePrimaryanalysisbasedonrateofPASI-75responsePASI-75responder:ApatientwithaPASIpercentimprovementfrombaselineof≥75%PASI-75nonresponder:ApatientwithaPASIpercentimprovementfrombaselineof<75%Extentofpsoriasisandthedegreeofplaqueerythema,thickness,andscalingC-EFF-EfalizumabStudy2390:SecondaryEfficacyEndpointsPhysician-derivedassessmentsPASI-50PASI%improvementfrombaselinePhysician’sGlobalAssessmentsasgiveninbriefingbookPatient-reportedassessmentsDLQI:DermatologyLifeQualityIndex10items,eachrated0=NotatAll,1=ALittle,2=ALot,3=VeryMuch,orNotRelevantOthersasgiveninbriefingbookC-EFF-PASI=45PASI=295%improvementBaselineWeek12EfalizumabAPASI-75ResponseC-EFF-EfalizumabAPASI-50ResponsePASI=43PASI=1467%improvementBaselineWeek12C-EFF-StudyEfalizumabPASI-75RatesatWeek12inPlacebo-ControlledStudies:RaptivaSuperiortoPlaceboinEachStudy******2390

(n=556)2059

(n=597)2058

(n=498)2600

(n=686)*

Fisher’sexacttest,Raptivavs.placebo,ITTanalysis*

p<0.001%ofpatientswithPASI-75C-EFF-EfalizumabPASI-50RatesatWeek12

RaptivaSuperiortoPlaceboinEachStudy******2390

(n=556)2059

(n=597)2058

(n=498)2600

(n=686)*

Fisher’sexacttest,Raptivavs.placebo,ITTanalysisStudy*

p<0.001%ofpatientswithPASI-50C-EFF-EfalizumabConclusionsAboutRaptivaEfficacySignificantefficacyatWeek12OnsetofefficacybyWeek4PsoriasisreturnswhenRaptivastoppedSignificantefficacyonretreatmentEfficacyimproveswithcontinuoustreatmentpast12weeksC-BR-EfalizumabKeySafetyOutcomesExtensivesafetydatabase:2762treatedpatientsMostcommonadverseeventsaremildflu-likesymptomsfollowingfirst2RaptivainjectionsInfrequentcasesofreversiblethrombocytopeniaFavorableoveralladverseeventprofile,

includinginfectionandmalignancyNoevidenceofrenalorhepaticdysfunction

1stextracellular

domainof

humanLFA-3Fcportionof

humanIgG1HHLFA-3LFA-3CH2CH2CH3CH3BindstoCD2Alefacept(LFA3-Ig):

AFullyHumanFusionProteinBiogenAlefaceptMechanismofActionMemoryTCellCD2CD2CD2CD2TCRNaturalKillerCell

FcRIIIGranzymeAntigenPresentingCellMHCLFA3LFA3MemoryTCellapoptosisCD2CD2CD2CD2AlefaceptPhase1Single-DoseStudiesinHealthySubjects:ResultsDecreasedCD2+,CD4+andCD8+cellcountsTransient(<24hrs)neutrophilia(upto>5X)in2/3ofsubjectsLongalefacepteliminationt1/2(250hrs)IM50%lessbioavailablethanIVPhase2and3TrialsAllrandomizeddouble-blindplacebo-controlledC97-708:0.025,0.075,0.15mg/kgIVweeklyx12wkN=229C99-711:7.5mgIVweeklyx12wk(2courses)N=565C99-712:10,15mgIMweeklyx12weeks

N=52612weekspost-treatmentfollowupPrimaryendpointPASI75,2weeksafterlastdosewithoutuseofdisqualifyingmedicationsWeeks1-12DosingWeeks13-24Follow-upPlacebo(n=168)10mg(n=173)15mg(n=166)Phase3IMstudydesignPlaceboAlefaceptAlefaceptScreeningRandomization*21%12%5%Phase3IMPrimaryEndpoint:

PASI75,2WeeksAfterLastDose*P<0.001Phase3IM

PASI50,2WeeksAfterLastDose**42%36%18%*P<0.001Phase3IVStudyDesignCourse1

24WeeksCourse2

24WeeksCohort1

(n=183)Cohort3

(n=186)Cohort2

(n=184)Alefacept

7.5mgAlefacept

7.5mgAlefacept

7.5mgPlaceboPlaceboAlefacept

7.5mgScreeningRandomizationPrimaryendpoint

PASI75,2weeksafterlastdosewithoutuseofdisqualifyingmedicationsCourse2Alefacept7.5mg(Cohort1)48%20%23%Phase3IVStudy

Efficacy,2weeksafterlastdosePASI5038%01020304050ProportionResponding(%)PASI75PGAAlmost

ClearorClear11%14%10%4%4%***** P<0.001** P=0.004Course1Alefacept7.5mg