NDA-22-291-FDA市公開(kāi)課一等獎(jiǎng)?wù)n件名師大賽獲獎(jiǎng)?wù)n件

NDA22-291PROMACTA?(Eltrombopag)FDAReviewAndrewDmytrijuk,MD1ProposedIndication

Eltrombopagisindicatedfortheshort-termtreatmentofpreviously-treatedpatientswithchronicidiopathicthrombocytopenicpurpura(ITP)toincreaseplateletcounts

and

reduceorpreventbleeding.Underlinesaddedforemphasis2EltrombopagBackgroundTablet,administereddailyBindstotransmembraneportionofTPO receptorPreclinicaltestingofEltrombopag:stimulatedplateletsonlyinchimpanzeesinotheranimals(inhighdoses):ChronicprogressivenephropathyLiverabnormalitiesCataractsPreclinicaltestingofanotherTPO receptoragonist:marrowfibrosis3ClinicalDatabase

Eltrombopag(E)exposuren=1088ChronicITP:n=330ThrombocytopeniainhepatitisC:n=56Chemotherapy-inducedthrombocytopenia:n=134Clinicalpharmacology:N=5684ITPProgram“Shortterm”:6weekexposure-Completed:placebocontrolled -773A -773B-On-going,singlearm:“REPEAT” “Longterm”:≥6monthexposure-On-going:placebocontrolled:“RAISE”-On-going:singlearm:“EXTEND”5MajorReviewTopics:“ShortTerm”Efficacy:increaseplateletcountsreduceorpreventbleedingSafety:bleedingrisksfollowingdrugdiscontinuationhepatotoxicity“shortterm”indicationbutlongtermusage -morehepatotoxicity? -potentialmarrowfibrosis?6DataPresentationCompletedstudies(short-term):773A773BOn-goingstudies/interim:REPEAT(cyclesofshort-term)EXTENDRAISE7“ShortTerm”Rationale:

Protocols “ShorttermtreatmentmayincreaseplateletcountsinpatientswithchronicITPscheduledforsurgicalordentalprocedures,wherealowplateletcountcanbeahindranceorevenprohibitiveoftheprocedureduetotheriskofexcessivebleeding.”Underlinesaddedforemphasis8Studies773Aand773B:DesignFeaturesDB,PC,multi-nationalEligibility:-platelets<30Kdespiteatleast1priortherapy-didnotselectpatientsscheduledforproceduresRandomization:-773A:placebooractivedrugat 30mg,50mgor75mgdaily-773B:placebooractivedrugat50mgdaily9773Aand773B:DesignFeatures,continuedDoseadjustment:-dosingterminatedforPltct>200K-773B:couldincreasedoseto75mgatday22Majorbaselineandfollow-upevaluations:

-CBC,clinicalchemistry-WHObleedingscoreEndpoints:-Primary:Pltct≥50Katday43ordrugd/c duetoPltct>200K(“response”)-Other:changeinWHObleedingscore10773Aand773BBaselineCharacteristicsCharacteristicPooled773A&773BPlacebon=6750mgEn=106Age,median46yrs47yrsFemale64%60%Splenectomy42%43%≥2priortx70%75%Pltct,median17K18KAllrandomizedsubjects11773Aand773BDispositionfeaturePooled773A&773BPlacebon=6750mgEn=106Completed6weeks“ontherapy”78%65%Discontinueddrug22%35%-Pltct>200K3%27%-Adverseevent7%5%-Other12%3%12773Aand773B

PrimaryEndpointResults,n(%)*P<0.01forEltrombopag50mgversusplacebostudyPlaceboEltrombopag50mg773A“Responders”3/27(11%)19/27(70%)*773B“Responders”6/38(16%)43/74(58%)*13PrimaryEndpointinSplenectomySubsets,n(%)subsetPooled773A&773BPlacebo50mgESplenectomy4/27(15%)26/44(59%)Nosplenectomy5/37(14%)36/56(64%)14773Aand773B

MaximumPlateletResponsesPlateletcountPlacebon=65Eltrombopag50mgn=101>200K2(3%)29(29%)>400K1(2%)9(9%)>600K03(3%)15WHOBleedingScores

Focuseduponchangefrombaselinebleeding scoreUnclearclinicalmeaningfulnessofchangesin score(e.g.,2to1)“AmethodforobjectivequantificationofbleedingsymptomsinITPhasnotbeenestablished.” BrJHaematol2007;138(2)245-8Investigators:subjectivelyassignedWHOscoreawareofplateletcounts16WHOBleedingScale

GradeDescriptor0Nobleeding1Petechiae2Mildbloodloss3Grossbloodloss4Debilitatingbloodloss17WHOBleedingScoresin773Aand773B

DistributionofChangefromBaselineScoreto“NoBleeding”ScoreatEndofTherapyGroupn,%SubjectsbyBaselineScore01234Eltrombopag35/3990%26/4459%4/1724%2/2-Placebo20/2677%9/2635%3/933%1/3-Pooledplaceboand50mgEltrombopaggroups18“HemostaticChallenges”

in773Aand773BGroupEventPltsRescueMedBloodtransEltrom-bopagGallBlsurg428NoNoGallblsurg369NoNoDental80NoNoMVA491NoNoPlaceboEyesurg12IVIGNoHipsurg25IVIGYesThroatsurg36TxacidNo19AdverseEvents:773Aand773B

Placeboand50mgEltrombopagcohortsEventPlacebon=67Eltrombopagn=106AnyAE35(52%)70(66%)AnySAE8(12%)12(11%)Hemorrhage1(1%)6(6%)VaricoseVrupture*1(1%)0Death01(1%)*noITPrescuemedicationreported20DeathinStudy773A66yearoldman,hxpneumonectomyDay15:increasedALT/ASTDay21:hospitalizedforCOPDexacerbationwith liverandrenaltestabnormalitiesDied~day26of“cardiacfailurecausedby pulmonaryfailure”Autopsy:thromboemboliinlungandliver,RandL ventricularhypertrophyEltrombopag-associatedliver/renaltest abnormalities?21Subject144inStudy773ALiver/renaltestabnormalitiesLabBsLnDay8Day15DrugD/CALTU/L(ULN45)21152741897ASTU/L(ULN40)1512186755Biliμm/L(ULN40)9111453Creatμm/L(ULN110)778497128BUNmm/L(ULN7)---22Platelet,K5104410822MajorSafetySignalsfrom773Aand773B1.Riskforlivertoxicity2.Hemorrhageriskfollowing EltrombopagD/C23Riskforlivertoxicity:EltrombopagundergoeslivermetabolismPreclinicaldatashowlivertoxicityat highdosesOnedeathwithlivertestabnormalities andsmallimbalancesinlivertest abnormalitiesingeneralpopulation24LiverTests,MaxToxicityGrade:773A&773BOutcomeGradePlacebon=67Eltrombopag50mgn=106ALT117(26%)22(21%)21(2%)5(5%)31(2%)2(2%)401(1%)AST112(18%)27(26%)201(1%)31(2%)2(2%)400TotalBili15(8%)15(14%)22(3%)3(3%)31(2%)1(1%)40025HemorrhageriskfollowingEltrombopagD/CComparedtobaseline,worsened thrombocytopeniafollowingTPO-mimetic drugD/CWorsenedthrombocytopenia,comparedto baseline:10%Eltrombopagvs6%placeboImbalanceinserioushemorrhagesfollowing drugD/C26SeriousHemorrhageAdverseEvents:withuseofrescuemedicationsGroupEventPeriodPlateletsERectalHemOffTx~9d<50KEPetechaiaeOffTx~21d<10KEEpistaxisOffTx~32d<10KESubarachHOffTx~30d<20KEMenorrhagOffTx*~14d<10KECerebHemOnTx~11d<10KEGIHemOnTx~15d<20KPlaceboCer&GIHemOnTx~14d<20K*75mgEltrombopag27On-going:REPEATDesign:eligible:platelets≥20Kand≤50K&1priortx3cyclesof6weeksseparatedbyupto30days“offtherapy”P(pán)rimaryendpoint:proportionofsubjectswithplateletresponse,givenaresponseincycle1Limitations:“offtherapy”periodcanbeshortenedUncontrolled,interimdata28REPEAT:PlateletResponseTimeRespondersCycle151/66(77%)Cycle229/33(88%)Cycle313/16(81%)29REPEAT:HemostaticchallengesEventPltsRescueMedsBloodTxSinussurgery83NoNoCardiaccatheterization178NoNoColonoscopy101NoNoDental150NoNoProstate(TURP)126NoNoColonpolypectomy130NoNoDental81NoNo30REPEAT:MajorSafetyFindings

1Serioushemorrhage:epistaxisandear hemorrhage,offtherapy25/66(38%)requiredEltrombopagata timepointbefore30days“offtherapy”due toplatelets<20Korbleedingsymptoms~15%rateoflivertestabnormalities: grade1or2

31On-going:EXTENDDesign:Eligible:completedpriorstudyLongtermexposurewithEltrombopagdoseadjustmentandattempttoreduce/eliminateconcomitantmedsBonemarrowreportsafteroneyearPrimaryendpoint:safetyLimitations:uncontrolled,interimdataPlateletdatan=109Overallsafetyn=20732EXTEND:Exposure:medianof98daysDurationSafetyUpdate,n=207≥6months,n74≥12months,n25≥15months,n9≥24months,n033SafetyData:EXTENDHemostaticchallengesin13subjects:Pre-procedurerescuemedicationsin2subjects

Nobleedingcomplications34SafetyData:EXTEND4Deaths -MVA -GIhemorrhage~55daysafterlastdose -Bronchiectasis/possiblesepsis/DVT -Unwitnesseddeath/fewdetails20subjectswithSAE -3PE -3hemorrhage -2increasedlivertests -isolatedotherevents~15%rateoflivertestabnormalities: mainlygrade1or235BoneMarrowData:EXTENDOtherTPO-mimeticmoleculescause marrowfibrosisinanimalsNomarrowSAEinshorttermEltrombopag studiesAllsubjectsinEXTENDtohavemarrow examafteroneyearEltrombopagMarrowsexaminedbysite pathologists/reportssummarizednocentral/adjudicatedreviewterms/definitionsvariable36BoneMarrowData:EXTENDTodate:19subjectswithmarrowreports17obtained≥10monthsexposure(other after2and8monthsexposure)7/19had“reticulin”documentedinreport1had“reticulinandtrichromestainsshowmoderatefibrosis,moderateincreaseintype3collagen(reticulin)andmildincreaseintype1collagen”1had“myelofibrosisgrade2/3”37On-going:RAISER,DB,PC,sixmonthexposureRemainsblinded,todate197enrolled1deathtodate(CNShemorrhage/nonresponder)26subjectswithSAE“ontherapy”5hemorrhage4cataract3livertestabnormalities2thrombosesotherisolatedevents3subjectswith“post-therapySAE” (bronchitis,PE,CNShemorrhage)38Summary:EfficacyIncreasedplateletcountsin60–70%subjectsBleedingassessedwithscoresateachvisit Incrementalchangesof?meaningfulnessInvestigatorsunblin