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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am

ount

Lot 1

1 2 3 4 5 6 7 8

Enhanced Potency

Improved PK

Increased

Serum Half-Life

CMC Advantages

Reproducible, simplified

Analytics

6

0

am

oun

t

Lot 2

1 2 3 4 5 6 7 8 0

am

oun

t

Lot 3

1 2 3 4 5 6 7 8

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

S

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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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