ThePharmaceuticalTechnologySpecialists

www.drugdeliveryexperts.com

ChristopherA.Rhodes,PhD,President,CEO,Founder

Exenatide andItsLifeCycleEuroTIDES,08NOV2017

AchievingTargetProductProfileRequiresADeepUnderstandingofActive,Formulation,Device

DiscoverySupport• Leadmoleculeprofiling• Clinicalcandidateevaluation• Biologichalf-lifeextension

DrugProductDevelopment• Formulationdesign• Drugproductdevelopment• Analyticalmethods

DeviceDevelopment• Deviceidentification• Integrationwithformulation• Developmentandselection

Leveragingadeepunderstandingofmolecularproperties,formulation,anddeviceIntegratingdeliverysystemR&Dprojectintoyourdevelopmentprogram

Optimizingtargetproductprofiletoenhancevalueproposition

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3

MarketPreferenceforNon-invasiveDelivery

Injection Oral

device---Transdermal--- patchNasalBuccalSublingual

Onceperday>>>BIDorTID

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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

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CommerciallyApprovedDeliveryTechnologiesforSystemicDeliveryofPeptides

XTEN,ELP,PASconjugates

FcandAlbuminfusion

PEGylation,Acylation

Microspheres

PenInjectors

VialandSyringe

InjectionSystems

Risk

Reward

Pulmonary

Non-Invasive

Oral(Systemic)

Microneedle

Risk

Reward

=CommercializedProducts

=ProductsinDevelopment

Nasal

DDAVP,sCT,Buserelin,Nafarelin,Oxytocin

Pulmozyme,Insulin

Characteristics:• LowDose• LowBA• Variability• PulsatileExposure

Characteristics:• ModeratetoHighBA• AcceptableVariability• ContinuousExposure

PTH,glucagonphase3

LHRH,sandostatin LAR,Bydureon

LIRA,Semaglutide,Omontys

Dulaglutide,albiglutide

Implantables LHRH

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ImportanceofTargetProductProfileMostParametersAffecttheUserExperience

Criteria SuggestedforConsideration

RouteofAdministration Subcutaneous, Intravenous,IntramuscularNon-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 to1month

Stabilityfor LongTermStorage

2-8oC,minimum24months

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InSitu Gel-FormingSystem

Suspension

Liposome

Microsphere

Implant

DailyInjection

WeeklyInjection

MonthlyInjection

IncreasingDrugPotency

Non-AqueousSolution/Suspension

QuarterlyInjection

Atrigel

Sustained ReleaseFormulationApproaches

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ConjugateApproachesforHalf-LifeExtension

PEGylation

AlbuminorFcFusion(FcRn recycling)

DailyInjection

WeeklyInjection

MonthlyInjection

IncreasingDrugPotency

PolyAminoAcidFusions

Acylation(albuminbinder)

VariousincludingreversiblePEG

Carbohydrateanalogues

HESylation,Glycosylation

XTEN,ELP,PASylation

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Exenatide Properties– ADeliveryScientistsDream

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

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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

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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

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MicrospherestoAchieveContinuousExenatide

Exenatide WeeklyPLGAMicrospheres(SEM)

LicensePLGATechnologyfromAlkermes (2000)(Neutropin Depot)wasprecedentforwork

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Exenatide MicrosphereManufactureandQC

Exenatide MSReleaseandPolymerDegradation Exenatide MSParticleSizeDistribution

PolymerType,FormulationandProcess

ControlsReleaseProfileAndPharmacokinetics

ParticleSizeisControlledbyProcessand

DictatesDeviceandNeedleGuage

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Exenatide Microsphere(Bydureon)LifeCycle

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

Bydureon (EU2011US2012)OnceweeklySCinjection2mgperweekdose

Bydureon Pen(US2014)OnceweeklySCinjection2mgperweekdose

Bydureon Bcise (US2017)OnceweeklySCMSsuspension2mgperweekdose

VialandsyringepresentationdiscontinuedJan2016withpenlaunch

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ImportanceofBydureon Bcise ApprovalProductPrecedentforMicrosphereBasedProducts

• Bcise isaMSsuspensioninMiglyol (MCT)• Single-useauto-injector(‘3step’)• Firstmicrosphereinready-to-useinjectablesuspensionproduct• Needlesheathandnoneedlehandlingorobservation• Storeinrefrigeratorlayingflat• Maybestoredatroomtemperaturefor4weekspriortouse• Substantialproductimprovementfordiabeticpatients

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DramaticallySimplifiedInstructions-for-Use

Shake the autoinjector hard for at least 15 seconds until the medicine is well mixed

Medicine must be fully mixed before unlocking. Unlock device and firmly unscrew orange cap

Push the autoinjector against the skin and hold it there for 15 seconds to get full dose

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Bydureon TimelineForDevelopment

JohnEngVA-AmylinNCELicense

1996 2005Exendin-4R&D

2000 2012Exen MSR&D

ByettaFDA

Approval

AlkermesAmylin

MSLIcense

BydureonFDA

Approval2009 2014

MSDualChamberPen

AmylinDeviceGroup

BydureonFDA

Approval

2008 2017

MSSuspensionR&DAmylinProduct

Development

BydureonBcise FDAApproval

AmylinEliLillyAlliance

2003AmylinEliLillyMSPlant

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Bydureon:SingleDosePKProfile(10to12weeks)

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

• Initialreleaseinfirstdaysubjectofsignificantformulationandclinicalwork• Targetproductprofilewasoncepermonthinjection– couldnotbeachievedduetoinitialrelease• 300pg/mlwasachievablewithlowinitialreleasebyweeklyinjectionofthesameformulation

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Exenatide DeliveryOpportunitiesEvaluatedwithinAmylinLillyAlliance(2000to2011)

• Nasalformulationtakenintoclinic• Transdermalmicroporation takenintoclinic• Pulmonarydrypowderevaluatedinpreclinicalwork• Oraldeliveryevaluatedinpreclinicalwork• AlloftheseformulationssufferedfromPKissues

• Lowbioavailability,variability,shorterexposuretimesthanSCinjection

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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)

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TransdermalMicroporation HumanData(Altea)

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

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

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Exenatide Lessons

• Byetta waslaunchedinagoodpen,but,witharefrigerationpack• CMCpost-approvalsupplementrequiredtogetRTfor30days

• Challengesofmicrospheresustainedreleaseformulationnotwellunderstood• Initialinterestinaoncemonthlyproduct• Weeklyproductwasacompromiseduetoinitialreleasefromparticles

• Bydureon waslaunchedinavialandsyringe• Importanceofdevicewasrecognizedtoolate

• Bydureon dualchamberpenwasdifficultandtooktoolong• Atlaunch,inferiortootherweeklyGLP-1productsonthemarket

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

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Exenatide AnalogueswithClinicalData

• Lixisenatide (Zealandtechnology)• Hanmi exendin-4analogueswithFcconjugate(Sanofi)• Versartis XTENexenatide• PhaseBio ELPexenatide• Multipleprogramsinclinicaldevelopmentforanalogues

basedonexenatide

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NumerousApproachesforLong-ActingFormulationsandAnalogues

Drug Design, Development and Therapy 2013:7 963–970

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GLP-1AGONIST MOLECULAR ENGINEERING

GLP-1dimer

97%homologytoGLP-1Ex-4pluspolyLys

LiraplusoptimizedAlbuminbinder

TwoGLP-1sonFcfragment

CARhodesGSK-CRS18APR2017

TwiceDailyInjection OnceDailyInjection

OnceWeeklyInjection

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Exenatide OralFormulationApproachesOramed LipidNanoparticleLiverTargetting

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Exenatide AlbuminBindingPeptideAmylinCollaborationwithAffibody Ab

Levy OE, Jodka CM, Ren SS, Mamedova L, Sharma A, et al. (2014) Novel ExenatideAnalogs with Peptidic Albumin Binding Domains: Potent Anti-Diabetic Agents with Extended Duration of Action. PLoS ONE 9(2): e87704. doi:10.1371/journal.pone.0087704

OralPKforAnaloguesinMonkeyIVPKforAnaloguesinMonkey

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TakeHomeMessageforDrugProductDevelopment

Integrationofmolecularproperties,formulation,anddeviceiskeytoachievingthedesiredproductprofile

Productuseandself-administrationcontraints drivedeviceconfiguration,formulationdesign,molecularproperties

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HaveFunandAskQuestions

ThePharmaceuticalTechnologySpecialists

www.drugdeliveryexperts.com