Fast Tracking Innovation Using Technologies in Oncology...process Low processing temperatures...
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Fast Tracking Innovation Using Technologies in Oncology
©2016 Catalent Pharma Solutions. All rights reserved.
JULIEN MEISSONNIER
VP, SCIENCE & TECHNOLOGY
05.19.16
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Catalent will provide enhanced value by integrating new technologies, products, solutions into simple, easy to access, convergent and integrated offerings
By working with Catalent, molecules will be screened by all the most advanced
TECHNOLOGIES so that
our customers benefit from the most successful outcomes in the market.
i. Drug Design Technologiesii. Enabling Technologiesiii. Drug Delivery Technologies
Drug Design TechnologiesSite-Specific Bioconjugationusing SMARTagTM Technology
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•All natural tag & enzyme modification
•Requires minimal cell line manipulation; supports high production titers
•Supports multiple expression systems
Minimal Cell-Line Engineering
Across Multiple Expression Systems
SMARTag™: Advanced Technology for Development of Optimized Bioconjugates
•C-C bond provides superior stability
•Enables commercial access to payloads
•Library of cytotoxin-linkers available to optimize efficacy by target
Novel Conjugation Chemistry and
Cytotoxin-Linkers
Novel aldehyde tagging technology
•Produces homogenous bioconjugates
•No off target protein reactivity
Site Specific
•Placement flexibility enables “SAR” to optimize efficacy and PK
•Not “location limited”
Programmable Payload
Placement0
SMARTagTM technology: Site-specific protein modification using bioorthogonal chemistry
Sletten EM and Bertozzi CR Angew. Chem. Int. Ed. 2009, 48, 6974-98.Rabuka D Curr. Opin. Chem. Biol. 2010, 14, 790-6
Patterson DM et. al. ACS Chem. Biol. 2014, 9, 592-605.
Site-Specific
Conjugation
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Benefits of site-specific ADC technology
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Enhanced Potency
Improved PK
Increased
Serum Half-Life
CMC Advantages
Reproducible, simplified
Analytics
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Biologic Advantages
Improved
Biophysical
Characteristics
Improved
Payload Stability
Less
TOXICITY
Increased TI
Albers AE, et al. Eur J Med Chem 2014, 88, 3-9
Drake PM, et al. Bioconjugate Chem 2014 25:1331-41
FGEformylglycinegeneratingenzyme(CxPxR specific)
SMARTagTM
ADCSMARTagTM
mAb
standard purification
proteinexpression
SMARTagTM technology: Simple and efficient approach for generating site-specific conjugates
CHO Cell
cysteine(thiol)
formylglycine(aldehyde)
site-specificpayload
placement
conjugation
aldehyde generation
in vivo
Rabuka, D., et al., Nat Protoc. 2012, 7, 1052-67.
The SMARTagTM Platform Enables Optimization Through SAR Exploration
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CytotoxicityPharmacokinetics
EfficacyToxicity
Site Selection
Linker Composition
DAR
The SMARTagTM Platform Summary: Optimizing ADC Components
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PROTEIN PRODUCTIONGPEx® CELL LINE ENGINEERING
SITE SELECTIONMULTIPLE OPTIMIZED PLACEMENTS
SITE-SPECIFIC CONJUGATIONSTABLE, PROPRIETARY CHEMISTRIES
MODULAR LINKERSSOLUBILITY, RELEASE TRIGGER
CYTOTOXINMULTIPLE PAYLOADS
EnablingTechnologiesYour Molecule Has a Soluble Future. We Are Here to Unlock It.
Industry Challenges in Oral Drug Development
“Faster and more cost-effective development of treatments with optimized therapeutic performance.”
Target Product Profile
Understand molecule Physicochemical Properties
Preclinical and clinical proof of concept
Solution for PK/PD challenges
Stability and robustness of formulation
Optimal delivery technology and dose forms
Efficient Development Faster Development Pathway
Better Therapeutic Performance
Optimal Molecule form
Optimized formulation for best bioavailability
Optimized Final Dose Form & Dosing Profile
DESIRED OUTCOME
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Getting to Clinic Faster with a Suitable Formulation is Key to Early Stage Development
CHALLENGES DESIRED SOLUTIONS
Limited amount of material available Ability to handle pre-formulation with minimal amount of material
New molecules present complex bioavailability and formulation challenges not easily overcome by simple methods
Expert advice on formulationoptions and technology expertise tosolve complex bioavailability challenges
Quick and timely entry into toxicity and phase I studies
Speedy execution of product development
Limited funding prior to phase I Efficient and cost effective way to assess development pathway minimizing cash burn
Resource constraints on project management
Getting the right partner for easierand simpler project management
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Only 1 in 10 new molecules in active clinical development
are readily bioavailable
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Bioavailability Challenges Substantially Complicate Achieving Targeted Efficacy
… and even those molecules may not be sufficiently absorbed when
dosed at escalated levels
Pointeaux T et al. , Drug Development and Delivery,2011, 11(8):60-66
Traditional “Powder in Bottle” is Unlikely to Achieve Targeted Efficacy for Most New Oral Molecules
BCS I
BCS III
BCS II
BCS IV
BCS IBCS III
BCS II
BCS IV
R. Lipp; The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities, Am. Pharm. Rev., 2013
Solubility of Pipeline Products (2013)
90%
Several Formulation Technologies Proven to Enhance Bioavailability of BCS Class II/IV Compounds
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Solubilization Literature Growth
Solubilization Innovation TrendSeveral successful bioavailability enhancement formulation technologies have brought 100+ drug products to market.
•Lipid-based formulation •Solid Dispersion•Particle Size Reduction •Salt Form
Source: CPhI Pre-connect, 10/2014
Bridging Drug Compound Properties to Formulation Approaches… Developability Classification System
Courtesy of R. Savla
BCS classification of compounds
BCS Classification
PE
RM
EA
BIL
ITY
H
L
SOLUBILITYH L
16Source: Butler, J. The optimal use of biorelevant media & simple modeling for the prediction of in-vivo oral behaviour (http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf)
I
III IV
Good solubility and permeability
Good solubility Poor permeability
Poor solubility and permeability
IIa
IIbSolubility limited
Dissolution rate limited
Poor solubility Good permeability
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DCS vs. BCS Classification of Compounds
DCS (Developability) vs. BCS Classification
Source: Dr. S. Page, Roche, CRS Meeting July 12-16, 2008, NY
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Russian roulette is a potentially lethal game of chance…
Wikipedia.org
Optimize Outcomes: Why are We Still Playing Russian Roulette With Oncology Drugs ?
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
Black Box Warning for Nilotinib
Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s). Application number: 22-068.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
Nilotinib labeled to be taken fasting
Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
In other words, if you take nilotinib with breakfast, you might die!!!
Tasigna® [package insert]. East Hanover, NJ. Novartis Pharmaceuticals Corp.; 2015
Dr. M. Ratain, 2016, Catalent Fierce Pharma Webinar
Why are We Still Playing Russian Roulette with Protein Kinase Inhibitors…
All listed molecules are solubility limited at target dose
FeSSIF solubility drives a significant change in SLAD
Why are We Still Playing Russian Roulette with Protein Kinase Inhibitors
DrugMarketed
Dose FormDose (mg)
DCSDose/
Solubility Ratio
SLAD (mg)Particle Size
(µm)
Nilotinib Capsule 400 IIb 2,000,000 1 3.5
Ceritinib Capsule 750IIb
11,177 219 63.3
Lapatinib Tablet 1250IIb
192, 308 22 19.7
Erlotinib Tablet 150IIb
32,609 17 16.6
Pazopanib Tablet 800IIb
53,333 53 29.9
Gefitinib Tablet 250 IIa 1,688 535 94,1
Marketed Protein Kinase Inhibitors OverviewFormulation to Differentiate PKIs under Development
Catalent Pharma Solutions data analysis from 29 marketed PKIs, August 2015
82% low
solubility
40%narrow therapeutic
index
31%HAVE A NON
ADEQUATE DOSING REGIMEN
78% non-
optimized DDS
22% milled
API and surfactants
7 Black Labels
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SIMILAR PROPERTIES
SIMILAR FORMULATION RECEIPES
SUBOPTIMALOUTCOMES
Take Abiraterone vs Enzalutamide as an example…is good enough good enough???
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Both Compounds are Highly SimilarNeutral, highly insoluble
Solubility 2 µg/mL
Estimated permeability7,4 x10-4 cm/sec
BCS II, DCS IIb
Highly solubility limited
Recommended max particle size: 11 µm (d90)Solubility Limited Absorbable Dose: 7 mg
Enzalutamide suspension and solid form in early clinical evaluation always below lipid solutions
Lipid solution removes food effect and enables linear escalation up to 600 mg
Phase I-II: Liquid filled hard gelatin capsuleMarket ready: Soft gelatin capsule
Comparability in DCSIIB Formulations PerformanceRp Scherer Softgel vs Spray Dried Dispersions
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Reference: PCT/US2013/059223
SPEED NOT HASTE
SIMPLE MODELS vs
SIMPLE PATTERNS
OPTIFORM® SOLUTION SUITEEnhanced Bioavailability in 12 Weeks
1ASSESS
2 ENHANCE
3 DELIVER
Lipid Formulation
Particle SizeReduction
Solid Dispersion
• Molecule Characterization
• Assess Salt Form Benefits
• Preliminary Consultation to select formulation technologies for ENHANCE
• Expert Consultation
• Extensive analytical data report
• 1-4 animal PK study material1. Lipid system2. Solid dispersion 3. Micronized Material4. Salt Form (optional) C
USTO
MER C
ON
DU
CTS A
NIM
AL S
TU
DIE
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Salt Form Optimization
Catalent Enabling Technologies for a Soluble Future
Drug Delivery TechnologiesUnlocking Biomolecules Potential using OptiGel BioTM
and Zydis Bio Technologies
Review from Hassani L et al. , Drug Delivery and Formulation Conference, 2016
Summary of Technological Approaches
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OptiGel™ Bio TechnologyDuodenal Delivery with a GRAS Formulation
OptiGel™ Bio technology incorporates enteric coating and permeation enhancers to first deliver active macromolecules to the absorption site and then pass through the absorption site to enter circulation
Targeted Delivery
Enteric Coating
Delivery of active macromolecule to absorption sites critical to achieve therapeutic levels
Protection from the degradation in harsh gastric environment
Absorption & Permeability
Chemical Modifications
Modification to API can improve absorption in the small intestine
Permeation Enhancers
Incorporation with a wide variety of permeation enhancers in formulation improves transport through the tight junctions of the lumen
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CATALENT CONFIDENTIAL - FOR INTERNAL USE ONLY
OptiGel™ Bio Softgel Formulation Enhances Macromolecule Drug Stability and Absorption
OptiGel™ Bio softgel capsule is a novel multiparticulate system filled with liquid GRAS (Generally Recognized As Safe) formulations releasing in-situ permeation enhancers
DrugStability
In the Final Dose Form
Lipid environment reduces local water activity
At the Point Of Delivery
Enteric delivery (pH ~ 6.0)Colonic delivery (pH ~ 7.4)Multiparticulate system avoids variabilityLipid environment offers protection against protease
Drug Uptake
Biological Barrier
GRAS formulations evolves in permeation enhancers in-vivo High local concentrations of permeation enhancers
DeliveryMultiparticulate liquid systems offer options for systemic and local delivery
Zydis® Bio TechnologySublingual/Buccal Delivery with GRAS Ingredients
Zydis® ODT (orally disintegrating tablet) is a lyophilized oral solid dosage form that disperses almost instantly in the mouth without water required.
Zydis® Bio technology is an advanced ODT formulation designed to deliver macromolecules to the oral mucosa for systemic absorption.
Targeted delivery
Orally Disintegrating Tablet
Direct delivery of macromolecule to the oral mucosa.
Avoids degradation in the harsh environment of the GIT (e.g. pH, enzymatic activity, GI fluid interactions).
Avoids first pass hepatic metabolism
Presents high local concentration of macromolecule in well dispersed form.
Absorption & Permeability
Biological Barrier
Largely non-keratinised, stratified squamous epithelium; good blood supply.
Regional variations in epithelium thickness (e.g. sublingual 100 – 200 µm vs buccal 500 – 800µm).
Permeable to macromolecules with molecular weight < 5000 Daltons
Potential for AbsorptionEnhancement
Incorporation of absorption enhancers
Formulation with bioadhesives33
Zydis® Bio TechnologySublingual / Buccal Delivery
Zydis® Bio technology presents active macromolecules in a robust, convenient and fast-dispersing form with the potential to avoid cold-chain storage.
Drug Stability
Lyophilized process
Low processing temperatures
Formulation options to optimise in-process stability (matrix component selection, pH adjustment)
Long Term Stability
Low water activity in the dried product
Aluminium packaging provides high moisture barrier and good environmental protection
Acceptable room temperature storage demonstrated for multiple peptide / protein compounds
Site of Absorption
No extreme pH exposure in oral cavity (salivary pH ~6.8 dependent on flow rate); no relevant proteases
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CATALENT CONFIDENTIAL - FOR INTERNAL USE ONLY
DRUG DELIVERY SOLUTIONS
OPTIFORM® SOLUTION SUITE BIO
OptiForm® Solution Suite Bio3-step Structured Process with Flexible Options at Any Stage
1ASSESS
2 ENHANCE
3 DELIVER
• Biological candidate drugability
• Assess the possibility to reach exposure with the right barrier
• Assess stability issues
• Analytical data and Expert Recommendation
• PK results in upper animal species
• Accelerated stability data (optional)
FU
RTH
ER D
EVELO
MEN
T S
TEPS
• Viable and optimized dose form prototypes for Phase I and beyond
• CMC and Analytical
• Clinical and Commercial supply
Lipid formulation screening: OptiGel™ Bio technology
Lyophilized tablets prototype screening: Zydis® Bio technology
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Parallel Screening ExampleSalmon Calcitonin Case Study
Fully conscious Beagle dogs moving freely with free access to food and waterASSESS Baseline Assessment
ENHANCE Formulation Screening
ASSESS: Candidates Screening Selection
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Male Sprague Dawley Rats (~400 grams)
Surgically Cannulated
• IJC or IDC (intra jejunal or duodenal) > Compound Administration
• FAC (femoral artery) > blood sampling
• FVC (femoral vein) > iv dosing
Studies are conducted in fully
conscious rats that are freely
moving in specialized study
boxes/cages.
FAC Femoral arteryBlood sampling
IJC/IDC Jejunal or duodenalDosing
Sodium caprate (50 to 100 mg/kg bw) utilized as a surrogate
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ASSESS: Candidates Screening Selection (Lipidization Example)
Easier Enabling Technologies
Molecule specific integrated solutions to unlock molecules potential.
Simpler Drug DeliveryTechnologies
Advanced technologies with a simplified regulatory pathway.
Differentiated Drug Design Technologies
Maximizing novel biomolecules clinical outcomes.
Acknowledgements
Dr. Finn K. Hansen – University DüsseldorfDr. Marc Ratain (MD) – Chicago HospitalDr. Christian Gachet – INSERM U949Dr. Maurice Petitou – Endotis PharmaGuy Dubreucq – Endotis Pharma
David Rabuka – Catalent EmeryvilleGregory Bleck – Catalent MadisonVincent Plassat – Catalent BeinheimRosie McLaughlin – Catalent SwindonMarc Mejias – EM Lyon
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