WIXLIB

LIFE CYCLE PRODUCT DEVELOPMENTIntroduction to Life Cycle Options (peptides)Formulation Approaches for DevelopmentExenatide – A Delivery Scientists DreamLife Cycle Programs for ExenatidePBSS 11 February 2020 San FranciscoPBSS 11FEB20203

MAXIMIZING TARGET PRODUCT PROFILE:DRUG, FORMULATION, DEVICE INTEGRATIONLeveraging a deep understanding of molecular properties, formulation, and deviceIntegrating delivery system R&D project into your development programOptimizing target product profile to enhance value propositionDiscovery Support Lead molecule profilingClinical candidate evaluationBiologic half-life extensionPBSS 11FEB2020Drug Product Development Formulation designDrug product developmentAnalytical methodsDevice Development Device identificationIntegration with formulationDevelopment and selection4

TECHNOLOGY MARKET PREFERENCEInjectionAll CombinationProducts Except forOral Tablet CapsuleOraldevice ---Transdermal --- patchNasalBuccalSublingualOnce per day BID or TIDPBSS 11FEB20205

CRITICAL TARGET PRODUCT PROFILEPARAMETERS AFFECTING USER EXPERIENCECriteriaSuggested for ConsiderationRoute of AdministrationSubcutaneous, Intravenous, IntramuscularNon-invasive (Nasal, microneedle)Dose Frequency andPharmacokineticsDaily or multiple daily injection (with native PK profile)Weekly, Monthly, Quarterly (with continuous exposure)Projected DoseProjected human, animal, toxicity doses (drives concentration in dosage form)Dose Volume 1mL for subcutaneous injection (also drives concentration in dosage form)Ease of Use and HandlingEasily injected through a 26G or smaller needleMinimal handling by care giver (simple reconstitution)Device and Container ClosureSystemVial and syringe, pre-filled syringe, dual-chamber syringe, cartridgeMulti-use pen, or auto-injectorStability In-use25oC, 1 week to 1 monthStability for Long Term Storage2-8oC, minimum 24 monthsPBSS 11FEB20206

INJECTION FREQUENCY PREFERENCESDecreasing Injection / Administration FrequencyMultipleDaily InjDailyInjectionProduct Profile Parameters Complexity of product handlingReady-to-use productNeedle size for injection (viscosity)Injection force (viscosity)Pain on injection (volume)Duration of injection (volume)In-Use stability constraintsPBSS njection6 to 12Month InjPatient Self-Injection product:Product Profile More CriticalPotential for Office Administered Product:‘Good’ Product Profile Not CriticalProperties and device design critical forproduct performance7

HOW DO WE DETERMINE THE RIGHTPRODUCT DEVELOPMENT APPROACH?Every option except for Oral requires device integration and productdevelopment and CDRH regulatory reviewInjection / Implantable SystemsImplantablesNon-Injection SystemsLHRHXTEN, ELP, PAS ConjugatesLipid systemsPEGylation, AcylationPenInjectorsMicrospheres, Gels,ByettaVialSyringeRewardPBSS 11FEB2020Dulaglutide, albiglutideLIRA, Semaglutide,OmontysLHRH, sandostatin LAR,BydureonSemaglutideOralPulmozyme, InsulinRiskRiskFc and Albumin FusionPulmonaryNasalMicroneedlePTH, glucagon phase 3DDAVP, sCT, Buserelin, Nafarelin, OxytocinProduct Characteristics Moderate to High BA Acceptable Variability Continuous Exposure Commercialized Products Products in DevelopmentRewardProduct Characteristics Low Dose Low BA Variability Pulsatile Exposure8

FORMULATION CONSIDERATIONS TIED TODEVELOPMENT STRATEGYNew PharmacologyWell Known Pharmacology / TargetGet the drug into the clinic fast tovalidate new pharmacology Speed is most important Any formulation is fine Establish proof of concept inclinic regardless of formulationdevelopabilityPharmacology is well understoodand development is likely Choose formulation approachthat will be developable Spend time to optimizeformulation Ensure attractive commercialproduct profile9Need clinical data for proof of conceptPBSS 11FEB2020Follow on with new target product profile

DEVELOPMENT NEED DRIVESPRODUCT CONFIGURATIONPreclinical andPhase 1 ClinicalSafety and PKEarly Phase Clinical UsePhase 2a and 2bClinical StudiesDose FindingMulti-use?Preservative neededVial and Syringe Clear Solution Single Use No preservative Peptide active (mg/ml) Buffer pH 4.5 to 7.5 Stabilizing excipients Fallback – frozen, lyophilizedPBSS 11FEB2020HumanFactorsPhase 3Clinical StudiesSafety and EfficacyCommercial Dosage Form RequiredProduct Configuration Options Clear Solution Vial and Syringe Lyophilized powder for reconstitution Single-use pre-filled syringe10 Pen injection device for multi-use

EXENATIDE - A DELIVERY SCIENTISTS DREAM Highly potent drug – 10 to 20 micrograms per day Highly water soluble peptide – 100s mg/ml Good stability in aqueous solution Good metabolic stability Half-life of 1 to 2 hours in humans Choices for delivery system are virtually unlimited Yet, mistakes can be (and were) madePBSS 11FEB202011

SIMPLE COMBINATION DRUG PRODUCTBYETTA – FIRST GLP-1 AGONIST LAUNCHEDByetta (exenatide injection) Launched by Amylin and Eli Lilly Partnership (now owned by Astra Zeneca) Discovered by John Eng (VA Hospital) 1996Exenatide Drug Substance 39 amino acid peptidePBSS 11FEB2020Container Closure System 1.2 & 2.4 mL cartridge for pen 0.25 mg/mL strengthDisposable Pen-injector 5 mcg or 10 mcg per injection Storage : 2 year shelf-life In-use: 30 day period at RT12

GLP-1S MOVE TO MAXIMIZE CONTINUOUSEXPOSURE TO DRIVE MAXIMUM EFFICACYByetta (exenatide)Half-life 1-2 hrsHbA1CReduction-0.9%Liraglutide (Victoza)Half-life 13 hrs-1.5%-1.2%Last InjectionBydureon(exenatideMS)Follow-Up PeriodActive Treatment Period550Plasma Exenatide (pg/mL)500Kothare P A et al. J Clin Pharmacol2008;48:1389-139935030025020015010050US 2005EU 20060EU 2009US 2010PBSS 11FEB20204504000481612Time (wk)EU 2011US 201220132428

COMPLEX COMBINATION DRUG PRODUCTBYDUREON – EXENATIDE MICROSPHERE Bydureon is an exenatide microsphere formulation Vial and syringe, pen, suspension in auto-injectorBydureon (EU 2011 US 2012)Once weekly SC injection2 mg per week doseBydureon Pen (US 2014)Once weekly SC injection2 mg per week doseBydureon Bcise (US 2017)Once weekly SC MS suspension2 mg per week doseVial and syringe presentationdiscontinued Jan 2016 with pen launchPBSS 11FEB202014

BYDUREON BCISE PRODUCTFIRST MICROSPHERE AS READY-TO-USE Bcise is a MS suspension in Miglyol (MCT)Single-use auto-injector (‘3 step’)First microsphere in ready-to-use injectable suspension productNeedle sheath and no needle handling or observationStore in refrigerator laying flatMay be stored at room temperature for 4 weeks prior to useSubstantial product improvement for diabetic patientsPBSS 11FEB202015

BYDUREON BCISE PRODUCTDRAMATICALLY SIMPLIFIED INSTRUCTIONSShake the autoinjector hardfor at least 15 seconds untilthe medicine is well mixedPBSS 11FEB2020Medicine must be fully mixedbefore unlocking. Unlock deviceand firmly unscrew orange capPush the autoinjector against theskin and hold it there for 15seconds to get full dose16

EXENATIDE DRUG DEVELOPMENTPROGRAM FOR INJECTABLE SYSTEMS1996John EngVA-AmylinLicenseExenatide Solution Injection3 Ph3 Studies (1857 FDAApprovalExenatide Microsphere Suspension5 Ph3 Studies (918 pts)2003AmylinEli LillyAlliance2009AmylinEli LillyMFG BSS dureonDual ChamberFDAApprovalMicrosphereSuspension in oil2 Ph3 Studies (350 pts)2017BydureonBCise FDA17Approval

BYDUREON SINGLE DOSE PK (10 TO 12 WKS)SD PK Dose Selection Study 2.5 mg, 6 mg, 7 mg, 10 mgDose Selection Study 0.8 mg and 2 mg exenatide Initial release (first 24 hours) was a subject of significant formulation and clinical work Target product profile was once per month injection – could not be achieved due to initial release 300 pg/ml was achievable with low initial release by weekly injection of the same formulationPBSS 11FEB20201818

EXENATIDE LIFE CYCLE OPPORTUNITIESEVALUATED IN AMYLIN-LILLY PROGRAM Nasal formulation taken into clinicTransdermal microporation taken into clinicPulmonary dry powder evaluated in preclinical workOral delivery evaluated in preclinical workAll of these formulations suffered from unacceptable PK issues Low bioavailability and high variability Shorter exposure times than SC injection (no absorption phase) GLP-1 peptides have significant Cmax tolerability issuesPBSS 11FEB202019

Nasal Target Product Profile Aqueous solution formulation Simple manufacturing process Commercially available devices Nasal peptide products in market BID or TID administrationPlasma Exenatide (pg/mL)NASAL EXENATIDE HUMAN DATA USINGTHE NASTECH FORMULATION APPROACH600 ug IN5 ug SC10 ug SC(previous study)4003002001000060120180240300Time (min)360420480Opportunity Abandoned - un-attractive from marketing perspective 3 or 4X Nasal Spray required to achieve AUC equivalent to SC Injection (and clinical effect)PBSS 11FEB202020

TRANSDERMAL MICROPORATION HUMANDATA USING THE ALTEA DELIVERY SYSTEMTransdermal Target Product Profile Simple bandaid-like product administered w device No pain on administration Continuous 24 hour exposure (Bydureon-like) Once per day administration (twice as fall back)Opportunity abandoned due to significant investment required (device, patch, manufacturing) Once per day 24 hour continuous exposure nearly achievedPBSS 11FEB202021

LESSONS FROM EXENATIDE LIFE CYCLETECHNOLOGY EVALUATION Byetta was launched in a good pen, but, with a refrigeration pack CMC post-approval supplement was able to achieve RT for 30 daysChallenges of microsphere sustained release formulation not well understood Initial interest in a once monthly product Weekly product was a compromise due to initial release from particlesBydureon was launched in a vial and syringe Importance of device was recognized too lateBydureon dual chamber pen was difficult and took too long At launch, inferior to other weekly GLP-1 products on the marketBydureon MS suspension could have been completed earlier ( !)Decision to build MS plant instead of working with CMOs ( )Singular focus on MS investment prevented other meaningful approachesPBSS 11FEB202022

EXENATIDE ANALOGUES WITH CLINICALDATA DEMONSTRATING PROMISE Lixisenatide (Zealand technology)Hanmi exendin-4 analogues with Fc conjugate (Sanofi)Versartis XTEN exenatidePhaseBio ELP exenatideMultiple programs in clinical development for analogues based onexenatidePBSS 11FEB202023

NUMEROUS APPROACHES TO LONGACTING EXENATIDE AND ANALOGUESDrug Design, Developmentand Therapy 2013:7 963–970PBSS 11FEB202024

PRODUCT DEVELOPMENT AND DELIVERYSYSTEMS OVERVIEWSuccessful drug product developmentis the result of careful integration ofpreclinical, clinical, and commercial needswith a deep understanding of drug, formulation anddevice propertiesPBSS 11FEB202025

GREETINGS FROMSAN DIEGO26

GLP-1 AGONIST MOLECULAR ENGINEERINGAPPROACHES IN MORE DETAILTwice Daily InjectionOnce Daily InjectionOnce Weekly InjectionPBSS 11FEB202028

ORAMED EXENATIDE ORAL NANOPARTICLETARGETING LIVERPBSS 11FEB202029

EXENATIDE ALBUMIN BINDING PEPTIDEAMYLIN COLLABORATION WITH AFFIBODYIV PK for Analogues in MonkeyOral PK for Analogues in MonkeyLevy OE, Jodka CM, Ren SS, Mamedova L, Sharma A, et al. (2014) Novel ExenatideAnalogs with Peptidic Albumin Binding Domains: Potent Anti-Diabetic Agents withExtended Duration of Action. PLoS ONE 9(2): e87704.doi:10.1371/journal.pone.0087704PBSS 11FEB202030

TARGET PRODUCT PROFILESUBCUTANEOUS SOLUTION INJECTABLEProfile ComponentDosage FormISRLabel claimImpurity profileStability (2-8⁰C)StoragePK profileExcipientsTargetClear and colorless sterile solutionAcceptable injection site reaction TBD mg/mL, 1 mL per injectionICH guidance 18MRefrigeration Acceptable PK profile, immediate release profile Prior use for injectables, GRAS, or Novel excipientContainer closure systemVial or pre-filled syringe (or cartridge) Compounding Aseptic fill Pen assembly (if pen device is chosen) 600 mOsm/kg (preferable 250 to 370 mOsm/kg)Mfg. process (major steps)OsmolalityAdministration route/needlegaugeImmunogenicityPBSS 11FEB2020Subcutaneous injection/ 29GTo be determined in later stage tox and human studies31

Feb 11, 2020 · Bydureon was launched in a vial and syringe Importance of device was recognized too late Bydureon dual chamber pen was difficult and took too long At launch, inferior to other weekly GLP-1 products on the market Bydureon