ThePharmaceuticalTechnologySpecialists

www.drugdeliveryexperts.com

ChristopherA.Rhodes,PhD,President,CEO,Founder

FormulationChallengesandOpportunitiesforPeptideDrugProductCPCSymposium,11OCT2017

2

PeptideProductDevelopmentConsiderations

• WhatMakesaProductDevelopmentScientist?• IntroductionandDeliverySystemPreferences• TheImportanceofTargetProductProfile• Exenatide LifeCycleProgram• Questions

HowDidIGetHere?LotsofHelp!

YERhodes- DISchuster- CSFoote- JIBerson --- SSSteiner- WCVincek - ABaron-- DBradbury-- FriendsandColleagues

MentorsandInfluencesandExperiencesPhysicalOrganicChemistryPhotochemicalandThermalRearragementsSingletOxygenandElectronTransferRxns

Small,Mid-sizeBiotech,DrugDeliveryLabandteamstartupsFunctionalleaderandteamleader

StartupsandConsultingCTO,HeadR&DDrugDeliveryExperts

1981 1992 2011 2014

4

CenterofExcellenceforPeptideDrugProduct

MissionBringingOurGlobalPartners

theBestDrugProductSolutions

VisionChangingLivesThrough

LeadershipinDrugDeliverySystems

SpecialistsincombinationdrugproductdevelopmentComplexformulationdesignanddeviceintegrationDeepexperienceinpeptidedrugdevelopment30highlyexperiencedPhDandBSscientists

AchievingTargetProductProfileRequiresADeepUnderstandingofActive,Formulation,Device

DiscoverySupport• Leadmoleculeprofiling• Clinicalcandidateevaluation• Biologichalf-lifeextension

DrugProductDevelopment• Formulationdesign• Drugproductdevelopment• Analyticalmethods

DeviceDevelopment• Deviceidentification• Integrationwithformulation• Developmentandselection

Leveragingadeepunderstandingofmolecularproperties,formulation,anddeviceIntegratingdeliverysystemR&Dprojectintoyourdevelopmentprogram

Optimizingtargetproductprofiletoenhancevalueproposition

5

6

MarketPreferenceforNon-invasiveDelivery

Injection Oral

device---Transdermal--- patchNasalBuccalSublingual

Onceperday>>>BIDorTID

7

DailyInjection

WeeklyInjection

MonthlyInjection

QuarterlyInjection

6to12MonthInj

MultipleDailyInj

PatientSelf-InjectionCommon:ProductProfileMoreCritical

PotentialforOfficeAdministeredProduct:GoodProductProfileNotCritical

ProductProfileParameters• Complexityofproducthandling• Ready-to-useproduct• Needlesizeforinjection(viscosity)• Injectionforce(viscosity)• Painoninjection(volume)• Durationofinjection(volume)• In-Usestabilityconstraints

DecreasingInjection/AdministrationFrequency

InjectionFrequencyPreferences

8

LimitedExamplesofCommerciallyTestedSystemicDeliverySystemsforPeptides

NewPolymer

Scaffolds

PEGylation

MicrosphereswithReconstitution

PenInjectors

VialandSyringe

InjectionSystems

Lipidsystems

Risk

Reward

Non-Invasive

Pulmonary Oral

Transdermal

Risk

Reward

=CommercializedProducts

=ProductsinDevelopment

Nasal

DDAVP,sCT,Buserelin,Nafarelin,Oxytocin

Pulmozyme,Insulin

Characteristics:• LowDose• LowBA• Variability• PulsatileExposure

Characteristics:• ModeratetoHighBA• AcceptableVariability• ContinuousExposure

9

ImportanceofTargetProductProfileMostParametersAffecttheUserExperience

Criteria SuggestedforConsiderationRouteofAdministration Subcutaneous, Intravenous,Intramuscular

Non-invasive(Nasal,microneedle)

Dose FrequencyandPharmacokinetics

Daily ormultipledailyinjection(withnativePKprofile)Weekly,Monthly,Quarterly(withcontinuousexposure)

Projected Dose Projectedhuman,animal,toxicitydoses(drivesconcentrationindosageform)

DoseVolume < 1mL forsubcutaneousinjection(alsodrivesconcentrationindosageform)

EaseofUseandHandling Easilyinjectedthrougha26GorsmallerneedleMinimalhandling bycaregiver(simplereconstitution)

DeviceandContainerClosureSystem

Vialandsyringe, pre-filledsyringe,dual-chambersyringe,cartridgeMulti-usepen,orauto-injector

StabilityIn-use 25oC,1week to1monthStabilityfor LongTermStorage

2-8oC,minimum24months

10

InSitu Gel-FormingSystem

Suspension

Liposome

Microsphere

Implant

DailyInjection

WeeklyInjection

MonthlyInjection

IncreasingDrugPotency

Non-AqueousSolution/Suspension

QuarterlyInjection

Atrigel

Sustained ReleaseFormulationApproaches

11

Exenatide Properties– ADeliveryScientistsDream

Highlypotentdrug– 10to20microgramsperdayHighlywatersolublepeptides– 100smg/mlGoodstabilityinaqueoussolutionGoodmetabolicstabilityHalf-lifeof1to2hoursinhumansChoicesfordeliverysystemarevirtuallyunlimitedYet,mistakescanbe(andwere)made

12

DrugProductProfileExample:Exenatide

Exenatide Drug Substance• 39 amino acid peptide

Disposable Pen-injector• 5 mcg or 10 mcg per injection• Storage : 2 year shelf-life• In-use: 30 day period at RT

Container Closure System• 1.2 & 2.4 mL cartridge for pen• 0.25 mg/mL strength

Byetta (exenatide injection)• LaunchedbyAmylinandEliLillyPartnership(nowownedbyAstraZeneca)• DiscoveredbyJohnEng (VAHospital)1996

13

GLP-1sMovetoMaximizeContinuousExposure

Liraglutide (Victoza)Half-life 13 hrs

Kothare P A et al. J Clin Pharmacol2008;48:1389-1399

Byetta (exenatide)Half-life 1-2 hrs

KimDetal.Dia Care2007;30:1487-1493

0 4 8 12 16 20 24 280

50100150200250300350400450500550

Last Injection

Active Treatment Period Follow-Up Period

Time (wk)

Pla

sma

Exe

natid

e (p

g/m

L)

Bydureon (exenatide MS)

-0.9%

-1.5%

HbA1CReduction

-1.2%

US2005EU2006

EU2009US2010 EU2011

US2012

14

MicrospherestoAchieveContinuousExenatide

Exenatide WeeklyPLGAMicrospheres(SEM)

LicensePLGATechnologyfromAlkermes (2000)(Neutropin Depot)wasprecedentforwork

15

Exenatide MicrosphereManufactureandQC

Exenatide MSReleaseandPolymerDegradation Exenatide MSParticleSizeDistribution

PolymerType,FormulationandProcess

ControlsReleaseProfileAndPharmacokinetics

ParticleSizeisControlledbyProcessand

DictatesDeviceandNeedleGuage

16

Exenatide Microsphere(Bydureon)LifeCycle

• Bydureon isanexenatide microsphereformulation• Vialandsyringe,pen,suspensioninauto-injector• MSinjectablesuspensiontobesubmittedbyAZ20172018?

Bydureon (EU2011US2012)OnceweeklySCinjection2mgperweekdose

Bydureon Pen(US2014)OnceweeklySCinjection2mgperweekdose

Bydureon Suspension(US2018?)OnceweeklySCMSsuspension2mgperweekdose

VialandsyringepresentationdiscontinuedJan2016withpenlaunch

17

Bydureon:SingleDosePKProfile(10to12weeks)

SDPKDoseSelectionStudy2.5mg,6mg,7mg,10mg DoseSelectionStudy0.8mgand2mgexenatide

• Initialreleaseinfirstdaysubjectofsignificantformulationandclinicalwork• Targetproductprofilewasoncepermonthinjection– couldnotbeachievedduetoinitialrelease• 300pg/mlwasachievablewithlowinitialreleasebyweeklyinjectionofthesameformulation

18

Exenatide DeliveryOpportunitiesEvaluated

• Nasalformulationtakenintoclinic• Transdermalmicroporation takenintoclinic• Pulmonarydrypowderevaluatedinpreclinicalwork• Oraldeliveryevaluatedinpreclinicalwork• AlloftheseformulationssufferedfromPKissues

• Lowbioavailability,variability,shorterexposuretimesthanSCinjection

19

NasalExenatide HumanData(Nastech Formulation)

NasalTargetProductProfile:• Aqueoussolutionformulation• Simplemanufacturingprocess• Commerciallyavailabledevices• Nasalpeptideproductsinmarket• BIDorTIDadministration

0 60 120 180 240 300 360 420 4800

100

200

300

400 5 ug SC600 ug IN

10 ug SC(previous study)

Time (min)Pl

asm

a Ex

enat

ide

(pg/

mL)

OpportunityAbandoned- un-attractivefrommarketingperspective• 3or4XNasalSprayrequiredtoachieveAUCequivalenttoSCInjection(andclinicaleffect)

20

TransdermalMicroporation HumanData(Altea)

TransdermalTargetProductProfile:• Simplebandaid-likeproductadministeredwdevice• Nopainonadministration• Continuous24hourexposure(Bydureon-like)• Onceperdayadministration(twiceasfallback)

OpportunityAbandoned- duetosignificantinvestmentrequied (device,patch,manufacturing)• Onceperday24hourcontinuousexposurenearlyachieved

21

Exenatide Lessons

• Byetta waslaunchedinagoodpen,but,witharefrigerationpack• CMCpost-approvalsupplementrequiredtogetRTfor30days

• Challengesofmicrospheresustainedreleaseformulationnotwellunderstood• Initialinterestinaoncemonthlyproduct• Weeklyproductwasacompromiseduetoinitialreleasefromparticles

• Bydureon waslaunchedinavialandsyringe• Importanceofdevicewasrecognizedtoolate

• Bydureon dualchamberpenwasdifficultandtooktoolong• Atlaunch,inferiortootherweeklyGLP-1productsonthemarket

• Bydureon MSsuspensioncouldhavebeencompletedearlier($!)• DecisiontobuildMSplantinsteadofworkingwithCMOs($$$)• SingularfocusonMSinvestmentpreventedothermeaningfulapproaches

MoleculeDesign• Peptide,proteinvariants• Conjugatesforhalf-life

DeliverySystemDesign• Aqueousornon-aqueousvehicle• Sustainedreleaseformulation• Triggeredortargetedsystems

DrugProductDesign• Pen,auto-injector• Pre-filledsyringe• Nasal,oculardropsorspray

TechnologyTransferGMPMfg

ProcessDevelopmentScaleUp

FormulationDevelopment

AnalyticalResearch

DevelopmentAssessment

LeadMoleculeDesign

AnalyticalMethods

Qualification

DevelopmentStability

AnalyticalDevelopment

Preformulation

DeliverySystemFeasibility

FormulationPKScreening

LeadMoleculeSelection

DeliverySystemSelection DrugProductDevelopment

DeviceSelectionandDevelopment

TestArticleSupplyforPreclinicalandToxicityStudies

22

ActivitiesRequiredtoAchieveTargetProductProfile

23

TakeHomeMessageforDrugProductDevelopment

Integrationofmolecularproperties,formulation,anddeviceiskeytoachievingthedesiredproductprofile

Productuseandself-administrationcontraints drivedeviceconfiguration,formulationdesign,molecularproperties

24

HaveFunandAskQuestions

ThePharmaceuticalTechnologySpecialists

www.drugdeliveryexperts.com

26

GLP-1AGONIST MOLECULAR ENGINEERING

GLP-1dimer

97%homologytoGLP-1Ex-4pluspolyLys

LiraplusoptimizedAlbuminbinder

TwoGLP-1sonFcfragment

CARhodesGSK-CRS18APR2017

TwiceDailyInjection OnceDailyInjection

OnceWeeklyInjection

27

LIRAGLUTIDE AND SEMAGLUTIDE

• Lipidated GLP-1analoguesbasedonNovolipidation system• Liraglutide is97%homologoustoGLP-1• Albuminbindingbylipidforhalf-lifeextension• Semaglutide hasanoptimizedalbuminbindingsidechain

LiraglutideApprovedEU2009/US2010DailySCinjection1.2to1.8mgperdose

CARhodesGSK-CRS18APR2017

1mgatsteadystate

SemaglutideNDA2016WeeklySCInjection1-2mgperdose