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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