医学交流课件：Pearl Co-SuspensionTM Metered Dose Inhalers Platform and PT010 Overview

PearlCo-SuspensionTM

MeteredDoseInhalersPlatformandPT010OverviewCONFIDENTIAL08/09July2016COPDandAsthma–ProgressiveDiseasesRequireEscalatingInterventionswithDecreasingPulmonaryFunctionFletcherandPeto,BMJ,1977,RennardandVestbo,PATS,2008Langeetal.,NEJM339(1998)1194Femalenon-smokers(similartrendsformales,andsmokers)2Priceetal.StudyPriceetal.RespMed2011;105:1457-66MDIFormulationChallenge4MicronizedDrugCrystalsMDISuspensionCohesionAdhesionSettlingDrug-DruginteractionPorousParticles:ConstructionandProperties

Extensivenon-clinicalandclinicalsafetydataAerodynamicallyLightConstructionPerforatedScaffoldingStructureCONFIDENTIALApril7,2023AdaptedfromVehringRetal.Langmuir2012;28:15015−23;Non-clinicalandclinicalsafetyevidenceonfileatPearlDistearoylphosphatidylcholine5InstantlycollapseatairwaytemperatureandhumidityStableatroomtemperatureParticleTypesinCo-suspensionMDIsDrugCrystalsStable,purePorousParticlesStable,buoyant4g~1.4g/cc~0.25g/ccCo-SuspensionTM:FoundationofaPipeline

Rapidandsimpletransitionacrossproducts

HFAsuspensiondropletMonotherapyDualCombinationTripleCombination*Notdrawntoscale.ActualmorphologymayvaryMonotherapyCo-SuspensionTM:DoseRanging

TunabilityandprecisionatnanogramdoselevelsDrugFineParticleMassAdaptedfromNogaBetal.PresentedatERS2013April7,2023CONFIDENTIALDualCo-SuspensionTM–InVitroDoseRanging

No‘co-formulation’effectAdaptedfromevidencepublishedbyNogaetal,ERS2013;

InvitrolaboratorytestdataonfileatPearl.April7,2023Co-SuspensionTM:Mono,Dual,andTriple

NoevidenceofinteractionbetweendrugtypesReisneretal,ERS2014:slidefrompodiumpresentation.CONFIDENTIALApril7,2023TripleCo-SuspensionTM–InVitroDoseRanging

BudesonideDoseswithFixedBackdropofLAMAandLABAReisneretal,ERS2014:slidefrompodiumpresentation.CONFIDENTIALApril7,202311PT003PT010BudesonidePKfromTriple–DoseProportionalDrugDelivery

EvidencesupportsprogressionoftriplecombinationtoPhase3studiesGeometricMeanPlasmaConcentration-TimeProfileofBudesonide(Semi-LogScale)0123451067981112MeanPlasmaBudesonideConcentration

(LogScale)(pg/mL)Time(hr)BGFMDI320/14.4/9.6µgSymbicortMDI320/9µgBGFMDI160/14.4/9.6µgSymbicortMDI160/9µgBGFMDI80/14.4/9.6µg1000100101Reisneretal,ERS2014;PT010001study(NCT01980615)CONFIDENTIALApril7,2023Co-SuspensionTMMDIs

AsimplebasisofabroadpipelineTripleCombination(PT010)Overview

InhaledProductDevelopmentforCOPDBGFMDI(PT010)Single1-yearexacerbationstudyandsingle24-Weeklungfunctionandsxsstudy

ofBGFMDIvsBFFMDIandGFFMDIGFFMDI(PT003)PhaseIIIGFFMDIvsPlacebo,FFMDI,GPMDIBFFMDI(PT009)24-weekLFstudyand52-weekexacerbationstudyofBFFvsFFMDI,BDMDI,andSymbicortTBH*GPMDI(PT001)PhaseIIIGPMDIvsPlaceboFFMDI(PT005)PhaseIIIFFMDIvsPlaceboBDMDI(PT008)DoseSelectionBasedonPKtomatchSymbicortTBH*April7,2023ConfidentialandProprietary15*SymbicortTBHisnotFDAapproved16GOLD1GOLD2GOLD3GOLD4mMRC0-1CAT<10mMRC≥2CAT≥10012CDBAExacerbationsperyearPT010LABA/LAMA/ICSLAMAPT003LABA/LAMALAMABudesonide++PT010studies–positioningofPT010005andPT010006PT010005PT010006PrimaryendpointAnnualCOPDexacerbationsTroughFEV1Patientpopulation65%PN≥FEV1≥25%PN≥1moderateorsevereCOPDexacerbationsinprevious12months80%PN>FEV1≥25%PNSamplesize500Chinese/Total8000400Chinese/Total

1800Treatmentduration1year6monthsNewDrugApplicationLabelupdateInitialregistrationPT010targetsgroupDpatientsImprovelungfunctionReduceexacerbationsAdjustedMeanChange(±SE)fromBaselineinMorningPre-doseTroughFEV1(L)OverTime-PT003007ConfidentialandProprietary17PT003008:AdjustedMeanPeakChange(±SE)fromBaselineinFEV1

(L)OverTime18PT003011mITTPopulation:FEV1(L)±SEover24HoursonDay29

ConfidentialandProprietary19AdjustedMeanChangefromBaselineinMorningPre‑doseTrough

FEV1(L)+/-SEOverTimeforFF

MDIandPlaceboMDI

StudyPT003006(ITTPopulation)20N=392N=370AdjustedMeanChangefromBaselineinFEV1(L)+/-SEOverthe12‑HourPost‑doseIntervalatDay1andWeek

12forFFMDIandPlaceboMDI–PFT

Sub‑Study

StudyPT003006(ITTPopulation)21Day1Week12RelativeBioavailabilityofBudesonide

BGFMDI320/14.4/9.6µgvsSymbicortMDI320/9µgRatio(%)ofGeometricLSMeans±90%CI220-12lastmax22PT009001–BFFDoseRangingStudy

MeanChangefromBaselineFEV1(L)onDay2923Budesonide/Glycopyrronium/FormoterolFumarate(BGF)ClinicalDevelopmentProgram24PT010ClinicalProgramOverviewPT010005–52weekExacerbationStudythatincludesa24-weeklungfunction/symptomssub-studyPT010006–24weekLungFunctionStudythatinludesaHPA-axissub-studyPT010008-28-weekextensionstudyofStudyPT010006toevaluateoverallsafetyincludingocularandbonemineraldensity25AssessingtripleTHErapyinobstructiveluNgdiseAse26sophostelos

EfficacyandsafetyoftripleTHerapyinObstructivelungdiSeaseKeyassessmentoftRipletherapyOnluNgfunctioninObstructivelungdiSease

StudyOfthePreventionofExacerbationsandimprovingHealthOutcomesinObstructivelungdiSeaseTrialtoEvaluateLungfunctioninObstructivelungdiSeaseBGF(PT010)BGF(PT009)StudyPT010005ExacerbationStudyDesign28ConfidentialWeekVisit56121654785212,34-4048Double-blindBGF320/14.4/9.6µg (n=~2,000*)BFF320/9.6µg (n=~2,000*)

GFF14.4/9.6µg (n=~2,000*)Follow-upRANDOMIZATIONBGF=budesonide,glycopyrronium

andformoterolfumarateBFF=budesonideandformoterolfumarateGFF=glycopyrroniumandformoterolfumarateBGF160/14.4/9.6µg (n=~2,000*)912361113442028AssessBDresponseScreening241014*=Potentialblindedsamplesizere-estima