Research Overview and Technology Platformsinvestors.shire.com/~/media/Files/S/Shire-IR/... · • Research ventures • Internal • BD/Alliance Novel Project Concepts • Access

Our purpose We enable people with life-altering conditions to lead better lives.

Research Overview and Technology Platforms Albert Seymour, PhD, Head of Research and Nonclinical Development

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The “SAFE HARBOR” Statement Under the Private Securities Litigation Reform Act of 1995

Statements included in this announcement that are not historical facts are forward-looking statements. Forward-looking statements can be identified by words such as “aspiration”, “will”, “expect”, “forecast”, “aspiration”, “potential”, “estimates”, “may”, “anticipate”, “target”, “project” or similar expressions suitable for identifying information that refers to future events. Forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that: Shire’s products may not be a commercial success; revenues from ADDERALL XR are subject to generic erosion and revenues from INTUNIV will become subject to generic competition starting in December 2014; the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire's products may impact future revenues,

financial condition and results of operations; Shire conducts its own manufacturing operations for certain of its products and is reliant on third party contractors to manufacture other products and to provide goods and services.

Some of Shire’s products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time.

the development, approval and manufacturing of Shire’s products is subject to extensive oversight by various regulatory agencies. Submission of an application for regulatory approval of any of our product candidates, such as our planned submission of a New Drug Application to the FDA for Lifitegrast as a treatment for the signs and symptoms of dry eye disease in adults, may be delayed for any number of reasons and, once submitted, may be subjected to lengthy review and ultimately rejected. Moreover, regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;

the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely impact Shire’s revenues, financial conditions or results of operations;

investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s activities in the highly regulated markets in which it operates may result in the distraction of senior management, significant legal costs and the payment of substantial compensation or fines;

adverse outcomes in legal matters and other disputes, including Shire’s ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on Shire’s revenues, financial condition or results of operations;

Shire faces intense competition for highly qualified personnel from other companies, academic institutions, government entities and other organizations. Shire is undergoing a corporate reorganization and the consequent uncertainty could adversely impact Shire’s ability to attract and/or retain the highly skilled personnel needed for Shire to meet its strategic objectives;

failure to achieve Shire’s strategic objectives with respect to the acquisition of ViroPharma Incorporated may adversely affect Shire’s financial condition and results of operations; and other risks and uncertainties detailed from time to time in Shire’s filings with the US Securities and Exchange Commission, including its most recent Annual Report on Form 10-K.

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Today’s R&D Sessions

Albert Seymour, PhD Research Overview and Technology Platforms mRNA, Protein Replacement, Gene Therapy, Antibody Platforms

9:25-10:00

Rare Diseases: GI / Metabolic SHP625 (LUM001), SHP626 (LUM002)

Ciara Kennedy, PhD David Piccoli, MD

10:00-10.45

Rare Diseases: Ophthalmics SHP607 / ROP, SHP630 / BIKAM

Norman Barton, MD, PhD 11:15-11:45

Rare Diseases: Complement Biology and Renal / Fibrotic SHP616 / Cinryze new uses

Howard Mayer, MD 1:15-1:30

Rare Diseases: CNS SHP609 / Hunter CNS, SHP610 / Sanfilippo A, SHP611 / MLD, Armagen

Howard Mayer, MD 1:30-2:00

Late-Stage Update SHP606 / Lifitegrast, BED, SHP465 / ADHD

Howard Mayer, MD Randall Brenner Joe Tauber, MD

2:00-2:45

Z

Z

Z

Z

Z

Topic Speaker Time (EST)

4

Rare Diseases Leadership Underpins Multiple TAs

Rare Diseases Leadership

• SHP625 • (ALGS, PSC, • PFIC, PBC) • HemeA / B • UCD

• Firazyr / Cinryze • Firazyr ACE-I • Cinryze SC • Cinryze new uses

• Maribavir • Cinryze AMR • IGAN • Fibrotech (FSGS) • DEB • CF

• BED • SHP465

• Hunter CNS • Sanfilippo A • MLD • Armagen • HTT

• SHP626 (NASH) • SHP 555 • ROP

• adRP

• Lifitegrast

GI / Metabolic

Ophthalmics

CNS

Complement Biology

Renal / Fibrotic

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Genetic-based Drug Discovery & Development

Patients and

Families

Description of Phenotype and Unmet Medical

Need

Identification of Underlying

Genes and Disease Biology

Characterizing Mechanism of

Disease Biology

Drug Discovery and Early

Development

Genetic Research

Cycle

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Research Model for Delivering the Portfolio in Rare Diseases

• TIGEM • BCH • Research ventures • Internal • BD/Alliance

Novel Project Concepts

• Access to tool reagents to test mechanism

• Pre-defined criteria • Data driven

decisions

Hypothesis Driven Go/No Go Decisions

• DEB • HEMB • RP • Hunter CNS • CF • UCD • HTT

Delivery from Research to

Early Development

1. Research portfolio built around high confidence targets in diseases with significant unmet medical need

2. Culture of rapid and clear data driven go/no go decisions

3. Efficient and focused team integrating internal and external flexible model to deliver early alignment with process and clinical development

4. ~26 active programs with a goal of delivering 3 programs from research to early development per year with a focus on quick to clinical POC

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Identifying Rare Diseases Opportunities

Follow the biology to select the right target and focus on diseases with high unmet medical need and well-understood disease pathophysiology

Strategic Focus

ELICIT PHARMACOLOGY

TARGET ENGAGED

EXPOSURE IN TARGET TISSUE

UNMET MEDICAL NEED

UN

DER

STAN

DIN

G O

F D

ISEA

SE M

ECH

ANIS

M

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External Innovation is Core to Research

Development Opportunities

Early Stage Opportunities • Translate existing science into diseases of interest • Develop lead assets • Build relationships

Co-Investment • Externally fund programs and manage

research and develop • Create novel investment structures

http://www.xconomy.com/wordpress/wp-content/images/2011/03/Nimbus.png

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Rare Disease Leadership through Innovative Technology Platforms – Internal and External

TARGET CONCEPT

BIOLOGY Best modality to affect Biology

POC Quickest way to test POC

Reagent antibodies to test mechanism

Therapeutic antibodies

TECHNOLOGY PLATFORMS

Reagent mRNA to test mechanism

Therapeutic mRNA

Reagent tools to test mechanism

Therapeutic lead molecules

Internal expertise to manage outsourced

expertise

Therapeutic delivery of cDNA

for gene correction

Gene editing

Reagent protein constructs

Therapeutic delivery of novel proteins

Antibody MRT Small Molecule Gene Therapy Proteins

Des

crip

tion

Part

ners

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DNA, RNA, and Protein Technology Platforms

• Reagent mRNA to test mechanism • Therapeutic mRNA

• Therapeutic delivery of cDNA for gene correction

• Gene editing

• Reagent protein constructs • Therapeutic delivery of novel

proteins

Gene Therapy

MRT

Proteins

Technology platforms Description

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Gene Therapy Transformational Therapy for Monogenic Diseases


Therapeutic mRNA

Therapeutic delivery of cDNA for gene

correction

Gene editing


Therapeutic delivery of novel proteins D

escr

iptio

n Pa

rtne

rs

Res

earc

h Pr

ogra

ms • Hemophilia A / B

Gene Editing Huntington Mutant Allele Repression

• Cystic Fibrosis Citrullinemia

• Dystrophic Epidermolysis Bullosa

MRT Gene Therapy Proteins

1

2

3

4

5

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Shire – Sangamo Collaboration

Goal: Using Zinc Finger Protein (ZFP) Technology as Disease Therapeutics

• Shire innovative approach to address root-cause of life-threatening diseases • Entry into gene editing therapies

Milestone-driven agreement

• Cross-functional collaboration aimed to deliver multiple therapeutics • Technology affords exploration of multiple approaches for disease-modifying therapies • Initial focus on Hemophilia and Huntington Disease

Agreement announced in

Feb 2012

Gene Therapy

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Engineered ZFPs Enables Sequence Specificity and Function

ZFP attached to a functional domain or nuclease

• Regulation of target gene expression (up-regulation or repression)

• Double strand break in the DNA (gene disruption or correction)

Gene Therapy

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• Rare hereditary disorder in which the ability of patients' blood to clot is impaired due to impaired FIX or FVIII production – leads to excessive and uncontrolled internal bleeding, pain and eventual permanent damage to joints and muscles

• Epidemiology: 1 / 5000 male births (~8 out of 10 people who have hemophilia have type A)

• Disease severity: severe, moderate, mild – dependent on percentage of FVIII / FIX level in blood, (<1%, 1-5%, >5%)

MECHANISM

DISEASE

Gene Therapy 1 Gene Therapy in Albumin Safe Harbor Locus: Factor VIII & Factor IX

1

15

Systemic Delivery of ZFP Therapeutics® via AAV Vectors ZFN Pair and

Corrective Gene Nucleic Acids Coding for

ZFNs and Corrective Gene in AAV Vectors

Peripheral IV Administration

AAV Traffics to Liver And Permanently

Corrects Gene

Liver Cells Secrete Corrected Protein In Vivo Protein

Replacement (e.g. Factor IX)

ZFN

ZFN

Homology Corrective Gene Homology

AAV Vectors

Gene Therapy 1 1 1

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Factor IX Gene Therapy Development Candidate for Hemophilia B: Murine POC

Factor 9 Expression Elevated

n.s.

**

Clotting Time Reduced

Duration of Expression Beyond 60 Weeks

Gene Therapy 1 1 1

17

TranscriptionStart Site

Exon 1

TranscriptionStart Site

Exon 1ATGTranscriptionStart Site

Exon 1ATG

Huntington’s Disease: Selective Inhibition of Disease Causing Mutation

• Huntington’s disease is an autosomal dominant neurodegenerative disease characterized by cognitive, behavioral and motor dysfunction. It is a progressive disease initiating typically at mid-life, with an average death 15 years after onset.

• Caused by expansion of a CAG nucleotide repeat within the first exon of the huntington gene causing a misfolding and pathologic conformation of the huntington protein

• Epidemiology: 8 / 100,000 (prevalence)

MECHANISM

DISEASE

Mutant allele selectively inhibited

Gene Therapy 2

2

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CURRENT DATA

*** P < 0.001

Nor

mal

ized

Ex

pres

sion

%GFP qPCR

NS

Mouse Htt

102

ZFP GFP

***

R6/2 Transgene

39

ZFP GFP

Statistical longitudinal analysis: Generalized Estimated Equation (GEE)

* GFP vs. ZFP = OR 2.4, p = 0.015

AAV-ZFP delivery

Huntington’s Disease Gene Therapy: Murine POC

61% knock-down of HD mutant allele in ZFP-treated striata 7 weeks after injection

Reduced clasping (primary motor phenotype) In HD model

Prop

ortio

n of

m

ice

show

ing

clas

ping

in 3

0s

Gene Therapy 2 2

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mRNA Replacement Therapy (MRT) MRT for Monogenic Diseases


Therapeutic mRNA


correction

Gene editing



escr

iptio

n Pa

rtne

rs

Res

earc

h Pr

ogra

ms


• Hemophilia A / B Gene Editing Huntington Mutant Allele Repression



1

2

3

4

5

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• Rapid normalization of clinical biomarkers in liver disease models • Successful delivery of therapeutic protein to lungs via nebulization in pulmonary model • Successful delivery of mRNA in mouse models via intrathecal, intra-ocular and intra-articular

administration; efficient production of therapeutic antibodies

• Novel therapeutic – Messenger RNA designed to enable the in vivo production of both intracellular and secreted proteins – ability to treat diseases that cannot be addressed with current technologies

• “Plug-and-play” platform with ability to use same reagents, same cell-free production process and same proprietary delivery vehicle – rapid, cost-effective, small footprint manufacturing

• Protected by extensive IP portfolio: 26 patent families & 70+ pending applications • Repeat dosing treatment algorithm – no need to define new commercial model

(e.g., gene therapy “one-and-done”)

• As patient’s own cells produce endogenous protein, downstream processes (e.g., glycosylation, protein processing and trafficking) remain unaffected

• Unlike gene therapy, does not alter the genome • Potent, dose-dependent pharmacology is reversible upon cessation of treatment in animal models

Transformational Technology

Scalable Manufacturing In Place

Other

Proof-of-Principle In Multiple Disease

Models

Broad Applicability

mRNA Therapeutics Platform Overview MRT

21

OTC CFTR

MRT Technology

MRT has demonstrated Potential for Broad Therapeutic Applicability

Proteins produced

systemically

Proteins produced

locally

0

500

1000

1500

2000

2500

3000

3500

4000

3h 6h 12h 24h 48h 72h

Mea

n Fa

ctor

IX P

rote

in in

Ser

um (n

g/m

L)

Time (Post-Administration)

MRT demonstrated across species: Mouse, Rat, Rabbit, Pig, Non-human Primate

Factor IX EPO AGAL

0

200

400

600

800

1000

1200

ng M

RT-e

ncod

ed p

rote

in/m

g To

tal

Prot

ein

Time (Post-Administration)n= 4 per group

Cytoplasmic

ASS1

MRT

Mean Human EPO Protein in Mouse Serum(Single IV Injection)

0

2

4

6

8

10

12

14

16

1 2 4 6 8 24 48

Time (h)

Mea

n Hu

man

EPO

Pro

tein

(ug/

mL)

GLA Expression In Mouse Serum Over TimeAfter Treament via GLA MRT

0

1000

2000

3000

4000

5000

6000

3 6 12 24 48 72

Time Post-Treatment

ng G

LA/m

L Ser

um

Mitochondrial Transmembrane-Lung

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• Autosomal recessive disorder

• DF508 is most common mutation (>70% of patient population)

• Results in improper folding and mis-trafficking of protein away from membrane surface

• Results in clogging of the airways due to mucus build-up

INCIDENCE / PREVALENCE & TREATMENT OPTIONS

DISEASE Human CFTR Protein

• ~60,000 Patients in US and EU

• Recent treatments focus on small subset of patients

• Significant unmet medical need remains

MRT MRT CFTR: Development Candidate to Treat Cystic Fibrosis

3

3

23

Pulmonary Delivery: Functional Translation of CFTR MRT In Vitro and In Vivo in mice Nanoparticle delivered hCFTR mRNA can be observed in target epithelial cells in vivo1…

…and creates functional ion channels in vitro2

1High magnification (40x) representation of in situ hybridization analysis of lungs from CFTR KO mice treated with hCFTR mRNA nanoparticles. hCFTR mRNA is observed in apical cytoplasm of target epithelial cells within bronchus. Tissues were harvested 24 hours post-administration.

2Current-voltage plot comparing chloride ion-generated current of various treated HEK293T cells 24 hours after transfection of hCFTR mRNA. The light blue represents cells that have been transfected with hCFTR mRNA 24 hours prior, followed by treatment with activator 8-Br-cAMP (4 min prior to analysis). The dark blue line represents similarly treated cells which were subjected to further exposure of 10 mM CFTRinh-172. The black line represents untreated HEK 293T cells (untreated).

MRT 3 3

24

Animal Proof-of-Principle for Lung Delivery of CFTR Shows Broad Biodistribution of Functional Protein

Firefly luciferase (FFL) MRT used as a measure of

biodistribution in pig lung tissue MRT

aerosolized for delivery

to Lung epithelia

CFTR expression detected in FFL + lung tissue

Demonstration of exogenous expression of CFTR in a large animal model system

+ Cont Untreated

mg tissue loaded 300 697 163

Pig #

1 1

CFTR C-band

Dorsal View of the Pig Lung

Color Bar Min = 750 Max = 27,000

MRT 3 3

25

IHC in Normal Pig Lung: Anti-hCFTR Antibody Detection of MRT-Derived hCFTR

Immunohistochemistry images of one representative pig from either vehicle treated (A) or 10 mg human CFTR mRNA dose group (B)

MRT 3

Positive stain

Vehicle 10 mg human CFTR mRNA

3

A) B)

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Summary of Pulmonary Delivery Results

• CFTR MRT offers potential for disease modification in an area of significant unmet medical need

• Pulmonary delivery and expression of hCFTR:FFL to the porcine lung by nebulized mRNA formulation was demonstrated

• Tissue regions with expression of Luciferase also co-expressed hCFTR • Luciferase negative regions lacked hCFTR expression

• Provides evidence that target lung tissue, i.e. bronchial epithelial cells, expresses hCFTR following mRNA delivery

• Tolerance to 5 doses at weekly intervals in pigs demonstrated • No tissue pathology detected • No adverse clinical signs observed • No increase in liver enzymes or inflammatory cytokines detected

• Early development to date has demonstrated: • Strong preclinical data package • Clear development strategy

MRT 3 3

27

• Citrullenemia is an autosomal recessive metabolic disorder

• Due to mutations in argininosuccinate synthetase (ASS1)

• ~14% of all urea cycle disorders

• Results in high levels of plasma ammonia, leading to lethargy, vomiting, seizures, and failure to thrive


DISEASE

• 1: 57,000 live births

• Expressed in liver and kidney

• No disease modifying therapies available

MRT MRT ASS1: Development Candidate to Treat Citrullinemia

4

4

Human urea cycle pathway

28

Immunohistochemical (IHC) Detection of Human ASS1 Protein Encoded by MRT

• IHC staining of MRT-encoded protein

• Positive staining in hepatocytes and Kupffer cells

• Widespread distribution in liver

• Protein detectable up to 1 week post-dose

3h 6h

24h

72h

12h 48h

30 min

1 Week Untreated

Pharmacokinetic profile studied after single dose of MRT 1.0 mg / kg MRT, single dose, IV, WT mice

MRT 4 4

29

0.00

100.00

200.00

300.00

400.00

500.00

600.00

700.00

1

Pre-Dose 24 hr Day 8 Day 15 (pre-dose)Day 16 (24h post dose) Day 22 Day 29 (pre-dose) Day 30

Evidence of Efficacy in Citrullinemia Mouse Model Initial efficacy study performed in ASS1 deficiency model; hypomorphic mutation with ~10% of normal ASS1 activity • Single dose (1.0 mg / kg) of either ASS1 mRNA loaded LNP or empty LNP (control) • Measure plasma ammonia levels pre- & post-dose • Compare model with WT levels

MRT 4 4

Ass1 fold (T389I) mutant

Wild Type

D0 D15 D29

N=6 / group

Plas

ma

NH

3 (µm

ol/L

)

ASS1 MRT

Plasma Ammonia Levels Pre- & Post-Treatment with ASS1 MRT

30

Summary of Intravenous MRT for Urea Cycle Diseases • We have focused initially on urea cycle defects for IV MRT as they

allow rapid clinical proof-of-concept and compelling market opportunity • Clinical path clarity • High unmet need in a sizeable market • Clear MRT advantage

• Mouse model results demonstrate approximately 50-100% of normal liver ASS1 and ammonia reduction following MRT • Human ASS1 mutational spectrum in Citrullinemia suggests activity

>10% would be disease-modifying

MRT 4 4

31

mRNA Replacement Therapy (MRT) MRT for Monogenic Diseases


Therapeutic mRNA


correction

Gene editing



escr

iptio

n Pa

rtne

rs

Res

earc

h Pr

ogra

ms


• Hemophilia A / B Gene Editing Huntington Mutant Allele Repression



1

2

3

4

5

32

Novel Therapeutics via Protein Engineering Proteins

33

• Rare genetic disease: fragile blistering skin, deformed limbs, numerous co-morbidities, early death

• Mutations in gene encoding Collagen Type VII (C7): autosomal dominant (DDEB) & autosomal recessive (RDEB)

• Aberrant function / absence of C7 at dermal-epidermal junction affect attachment of epidermis to dermis


HYPOTHESIS

DISEASE

IV rC7 as protein replacement therapy will:

• Reach the lamina densa at dermal-epidermal surfaces

• Incorporate into matrix to normalize function

• Correct blistering abnormalities and complications

• ~5000 diagnosed patients: 2,000 addressable patients (base case) with IV protein replacement therapy; all genders and races affected

• No disease modifying treatment available: only recurrent, symptomatic treatments; painful and costly disease

Proteins Human rCollagen 7: Development Candidate to Treat Dystrophic Epidermolysis Bullosa (DEB)

5

5

34

rC7 Forms Anchoring Fibrils Critical for Dermal-Epidermal Adhesion in Animal Models

• C7 forms anchoring fibrils, attachment structures in the basement membrane zone (BMZ) responsible for adhering the epidermis to the dermis

• Loss-of-function mutations in COL7A1 lead to abnormal, decreased or absent anchoring fibrils

Recombinant C7 (rC7) incorporates into basement membrane zone forming anchoring

fibrils, reversing separation of dermal-epidermal junction in animal models

Normal DEB Recessive

Formation of anchoring fibrils

Proteins 5 5

35

Shire Collagen 7 was Distributed to the Proper Location within the Dermal-Epidermal Junction in Multiple Tissues in Mouse Models Control WT Shire CHO-C7

Shire Collagen 7 treatment

No treatment

Shire Collagen 7 Reversed Dermal-Epidermal Separation in a Dose-Dependent Manner in Mouse Models

Mice Treated with a Single Injection of Recombinant Collagen 7 Lived Longer

Shire CHO-C7

Shire Fibroblast-C7

Proteins Tissue Distribution of Shire Collagen 7 5 5

DEB (Control)

** p<0.01, vs. PBS

** *

DEB (Shire Collagen 7)

36

Research Model for Delivering the Portfolio in Rare Diseases

• TIGEM • BCH • Research ventures • Internal • BD/Alliance

Novel Project Concepts

• Access to tool reagents to test mechanism

• Pre-defined criteria • Data driven

decisions

Hypothesis Driven Go/No Go Decisions

• DEB • HEMB • RP • Hunter CNS • CF • UCD • HTT

Delivery from Research to

Early Development

1. Research portfolio built around high confidence targets in diseases with significant unmet medical need

2. Culture of rapid and clear data driven go/no go decisions

3. Efficient and focused team integrating internal and external flexible model to deliver early alignment with process and clinical development

4. ~26 active programs with a goal of delivering 3 programs from research to early development per year with a focus on quick to clinical POC

Documents

Research Overview and Technology Platformsinvestors.shire.com/~/media/Files/S/Shire-IR/... · • Research ventures • Internal • BD/Alliance Novel Project Concepts • Access