Introduction to Life Cycle Options (peptides)Formulation Approaches for DevelopmentExenatide – A Delivery Scientists DreamLife Cycle Programs for Exenatide

PBSS 11 February 2020 San Francisco

LIFE CYCLE PRODUCT DEVELOPMENT

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Discovery Support• Lead molecule profiling• Clinical candidate evaluation• Biologic half-life extension

Drug Product Development• Formulation design • Drug product development• Analytical methods

Device Development• Device identification• Integration with formulation• Development and selection

Leveraging a deep understanding of molecular properties, formulation, and device Integrating delivery system R&D project into your development program

Optimizing target product profile to enhance value proposition

MAXIMIZING TARGET PRODUCT PROFILE: DRUG, FORMULATION, DEVICE INTEGRATION

TECHNOLOGY MARKET PREFERENCE

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Injection Oral

device ---Transdermal --- patchNasalBuccalSublingual

Once per day >>> BID or TID

All Combination Products Except for Oral Tablet Capsule

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Criteria Suggested for ConsiderationRoute of Administration Subcutaneous, Intravenous, Intramuscular

Non-invasive (Nasal, microneedle)

Dose Frequency and Pharmacokinetics

Daily or multiple daily injection (with native PK profile)Weekly, Monthly, Quarterly (with continuous exposure)

Projected Dose Projected 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 Handling Easily injected through a 26G or smaller needleMinimal handling by care giver (simple reconstitution)

Device and Container Closure System

Vial and syringe, pre-filled syringe, dual-chamber syringe, cartridgeMulti-use pen, or auto-injector

Stability In-use 25oC, 1 week to 1 month

Stability for Long Term Storage 2-8oC, minimum 24 months

CRITICAL TARGET PRODUCT PROFILE PARAMETERS AFFECTING USER EXPERIENCE

INJECTION FREQUENCY PREFERENCES

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Daily Injection

Weekly Injection

Monthly Injection

Quarterly Injection

6 to 12 Month Inj

Multiple Daily Inj

Patient Self-Injection product:Product Profile More Critical

Potential for Office Administered Product:‘Good’ Product Profile Not Critical

Product Profile Parameters• Complexity of product handling• Ready-to-use product• Needle size for injection (viscosity)• Injection force (viscosity)• Pain on injection (volume)• Duration of injection (volume)• In-Use stability constraints

Decreasing Injection / Administration Frequency

Properties and device design critical for product performance

HOW DO WE DETERMINE THE RIGHT PRODUCT DEVELOPMENT APPROACH?

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ImplantablesXTEN, ELP, PAS Conjugates

Fc and Albumin Fusion

Microspheres, Gels,Pen

Injectors

Injection / Implantable Systems

Lipid systems

Risk

Reward

Non-Injection Systems

Pulmonary Oral

Microneedle

= Commercialized Products

= Products in Development

NasalDDAVP, sCT, Buserelin, Nafarelin, Oxytocin

Pulmozyme, Insulin

Product Characteristics• Low Dose• Low BA• Variability• Pulsatile Exposure

Product Characteristics• Moderate to High BA• Acceptable Variability• Continuous Exposure

VialSyringe

Risk

Reward

Every option except for Oral requires device integration and product development and CDRH regulatory review

PEGylation, Acylation

LHRH, sandostatin LAR,Bydureon

LIRA, Semaglutide,Omontys

Dulaglutide, albiglutide

LHRH

PTH, glucagon phase 3

Semaglutide

Byetta

FORMULATION CONSIDERATIONS TIED TO DEVELOPMENT STRATEGY

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New PharmacologyNeed clinical data for proof of concept

Well Known Pharmacology / TargetFollow on with new target product profile

Get the drug into the clinic fast to validate new pharmacology

• Speed is most important • Any formulation is fine• Establish proof of concept in

clinic regardless of formulation developability

Pharmacology is well understood and development is likely

• Choose formulation approach that will be developable

• Spend time to optimize formulation

• Ensure attractive commercial product profile

DEVELOPMENT NEED DRIVES PRODUCT CONFIGURATION

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Safety and PK

Preclinical and Phase 1 Clinical

Phase 3 Clinical Studies

Safety and Efficacy

Vial and Syringe• Clear Solution• Single Use• No preservative• Peptide active (mg/ml)• Buffer pH 4.5 to 7.5• Stabilizing excipients• Fallback – frozen, lyophilized

Early Phase Clinical Use Commercial Dosage Form RequiredMulti-use?Preservative needed

Product Configuration Options• Clear Solution Vial and Syringe• Lyophilized powder for reconstitution• Single-use pre-filled syringe• Pen injection device for multi-use

Phase 2a and 2b Clinical Studies

Dose Finding

Human Factors

EXENATIDE - A DELIVERY SCIENTISTS DREAM

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• 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) made

SIMPLE COMBINATION DRUG PRODUCTBYETTA – FIRST GLP-1 AGONIST LAUNCHED

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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)• Launched by Amylin and Eli Lilly Partnership (now owned by Astra Zeneca)• Discovered by John Eng (VA Hospital) 1996

GLP-1S MOVE TO MAXIMIZE CONTINUOUS EXPOSURE TO DRIVE MAXIMUM EFFICACY

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Liraglutide (Victoza)Half-life 13 hrs

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

Byetta (exenatide)Half-life 1-2 hrs

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%

HbA1C Reduction

-1.2%

US 2005EU 2006

EU 2009US 2010 EU 2011

US 2012

COMPLEX COMBINATION DRUG PRODUCTBYDUREON – EXENATIDE MICROSPHERE

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• Bydureon is an exenatide microsphere formulation• Vial and syringe, pen, suspension in auto-injector

Bydureon (EU 2011 US 2012)Once weekly SC injection2 mg per week dose

Bydureon Pen (US 2014)Once weekly SC injection2 mg per week dose

Bydureon Bcise (US 2017)Once weekly SC MS suspension2 mg per week dose

Vial and syringe presentation discontinued Jan 2016 with pen launch

BYDUREON BCISE PRODUCT FIRST MICROSPHERE AS READY-TO-USE

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• Bcise is a MS suspension in Miglyol (MCT) • Single-use auto-injector (‘3 step’)• First microsphere in ready-to-use injectable suspension product• Needle sheath and no needle handling or observation• Store in refrigerator laying flat• May be stored at room temperature for 4 weeks prior to use• Substantial product improvement for diabetic patients

BYDUREON BCISE PRODUCT DRAMATICALLY SIMPLIFIED INSTRUCTIONS

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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

EXENATIDE DRUG DEVELOPMENT PROGRAM FOR INJECTABLE SYSTEMS

John EngVA-Amylin

License

1996 2005Exenatide Solution Injection3 Ph3 Studies (1857 pts)

2000 2012Exenatide Microsphere Suspension

5 Ph3 Studies (918 pts)

ByettaFDA

Approval

AlkermesAmylin

MicrosphereLicense

BydureonFDA

Approval

2009 2014Microsphere

Dual Chamber AmylinDevice Group

BydureonFDA

Approval

2008 2017Microsphere

Suspension in oil

2 Ph3 Studies (350 pts)

AmylinProduct

Development

BydureonBCise FDA Approval

AmylinEli Lilly

Alliance

2003AmylinEli Lilly

MFG Plant

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BYDUREON SINGLE DOSE PK (10 TO 12 WKS)

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18

Dose 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 formulation

SD PK Dose Selection Study 2.5 mg, 6 mg, 7 mg, 10 mg

EXENATIDE LIFE CYCLE OPPORTUNITIES EVALUATED IN AMYLIN-LILLY PROGRAM

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• Nasal formulation taken into clinic• Transdermal microporation taken into clinic• Pulmonary dry powder evaluated in preclinical work• Oral delivery evaluated in preclinical work• All 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 issues

NASAL EXENATIDE HUMAN DATA USING THE NASTECH FORMULATION APPROACH

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Nasal Target Product Profile• Aqueous solution formulation• Simple manufacturing process• Commercially available devices • Nasal peptide products in market• BID or TID administration

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)

Plas

ma

Exen

atid

e (p

g/m

L)Opportunity Abandoned - un-attractive from marketing perspective• 3 or 4X Nasal Spray required to achieve AUC equivalent to SC Injection (and clinical effect)

TRANSDERMAL MICROPORATION HUMAN DATA USING THE ALTEA DELIVERY SYSTEM

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Transdermal 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 achieved

LESSONS FROM EXENATIDE LIFE CYCLE TECHNOLOGY EVALUATION

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• Byetta was launched in a good pen, but, with a refrigeration pack• CMC post-approval supplement was able to achieve RT for 30 days

• Challenges 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 particles

• 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 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 approaches

EXENATIDE ANALOGUES WITH CLINICAL DATA DEMONSTRATING PROMISE

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• Lixisenatide (Zealand technology)• Hanmi exendin-4 analogues with Fc conjugate (Sanofi)• Versartis XTEN exenatide• PhaseBio ELP exenatide• Multiple programs in clinical development for analogues based on

exenatide

NUMEROUS APPROACHES TO LONG ACTING EXENATIDE AND ANALOGUES

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

Successful drug product development is the result of careful integration of

preclinical, clinical, and commercial needswith a deep understanding of drug, formulation and

device properties

PRODUCT DEVELOPMENT AND DELIVERY SYSTEMS OVERVIEW

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GREETINGS FROM SAN DIEGO 26

GLP-1 AGONIST MOLECULAR ENGINEERING APPROACHES IN MORE DETAIL

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Twice Daily Injection Once Daily Injection

Once Weekly Injection

ORAMED EXENATIDE ORAL NANOPARTICLE TARGETING LIVER

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EXENATIDE ALBUMIN BINDING PEPTIDEAMYLIN COLLABORATION WITH AFFIBODY

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IV PK for Analogues in Monkey Oral PK for Analogues in Monkey

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

TARGET PRODUCT PROFILESUBCUTANEOUS SOLUTION INJECTABLE

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Profile Component TargetDosage Form Clear and colorless sterile solutionISR Acceptable injection site reactionLabel claim ≥ TBD mg/mL, ≤1 mL per injectionImpurity profile ICH guidanceStability (2-8⁰C) ≥ 18MStorage RefrigerationPK profile • Acceptable PK profile, immediate release profileExcipients • Prior use for injectables, GRAS, or Novel excipient

Container closure system Vial or pre-filled syringe (or cartridge)

Mfg. process (major steps)• Compounding• Aseptic fill • Pen assembly (if pen device is chosen)

Osmolality < 600 mOsm/kg (preferable 250 to 370 mOsm/kg)Administration route/needle gauge Subcutaneous injection/≤ 29G

Immunogenicity To be determined in later stage tox and human studies