Shire - Jefferies 2014 Global Healthcare Conference

Shire: Repositioned for Continued Growth

Flemming Ornskov, MD Chief Executive Officer

Jefferies Healthcare Conference June 2, 2014

To be as brave as the people we help.

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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 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 Rare Diseases 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 subject to lengthy review an 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 U.S. Securities and Exchange Commission, including its most recent Annual Report on Form 10-K.


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We have created a platform to deliver sustainable growth and superior patient outcomes

Sustainable Growth

Operational Efficiency;

Commercial Excellence;

Scalable Model

Leading Franchises; Innovative Portfolio;

Disciplined M&A

Simple Structure and High Performing Management

Superior Patient

Outcomes


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We have accelerated our growth

1 Product sales are from continuing operations, and exclude DERMAGRAFT which is treated as a discontinued operation following divestment in January 2014.

Internal Medicine

GI

Neuro- science

Rare Diseases

Q1 2014

1,308

Q1 2013

1,098

1Q 2014 Product sales growth1

$ Million; Percent growth

+19%

+39%

+16%

+17%

(11)%

Improved Rare Diseases competitive performance

Added ViroPharma, including CINRYZE in Rare Diseases

Management actions

Sharpened Neuroscience customer focus

Achieved #1 position in 5-ASA market

Divested DERMAGRAFT to a more natural owner


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Q1 2014: Strategy delivers strong results

• Serve patients with high unmet needs in select, commercially attractive specialty therapeutic areas

• Drive optimum performance of our In-line marketed products

• Build our pipeline of innovative treatments through both R&D and BD activities

• Ensure efficient use of resources through a simplified corporate structure

Our refined strategy

2014 Q1 EBITDA 41%

2014 Q1 Revenue 19%

2014 Q1 Cash Generation 29%

Full-year 2014 earnings guidance upgraded following Q1 results


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Human Genetic Therapies

Specialty Pharmaceuticals

Regenerative Medicine

Organizational transition

1Q 2013

One Shire

Current

4x commercially focused business units

1x integrated R&D organization

Significant operating leverage

1x international infrastructure with presence in 50+ countries

Core components

Streamlined supporting functions

Rapid transition to simplified structure has increased accountability and agility


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Significant increase in 1Q EBITDA margin(1)

$ Million; Percent of product sales Program details

(1) Results exclude DERMAGRAFT which is treated as a discontinued operation following divestment in January 2014. (2) Excluding royalties and other revenues.

Integrating R&D under a single leadership team

Created a single, consolidated international structure

Streamlined other corporate functions

Halted programs that did not fit strategy or commercial criteria

Divested underperforming businesses (DERMAGRAFT)

SG&A

EBITDA(2)

100%

R&D

COGS

Q1 2014

1,308

Q1 2013

1,098

We have created a step change in efficiency


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S&P 500

FTSE 100

BioPharma Peers

Source: Company reports, Capital IQ as of 15 May 2014 (1) Median of peers including Alexion, Allergan, Amgen, Biogen, BioMarin, Celgene, Gilead, Merck KGaA, Novo Nordisk, UCB, Valeant and Vertex.

Driving material share price outperformance Total shareholder return from May 1, 2013 to May 15, 2014

(1)

Accelerated growth

Increased efficiency

Disciplined M&A

Immediate impact

Enhanced pipeline

These initiatives have had an immediate impact on share price performance


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$30 billion global market(7)

Market growth estimated to be 5% from 2013-20(7)

#1 position in 5-ASA market(8)

#2 sales force as ranked by U.S. GI’s(8)

Sample Pipeline Programs:

Leading positions in attractive therapeutic areas

Shire’s largest business unit ~$75 billion market size

(orphan drug sales) allows for significant headroom(4)

Market growth estimated to be 11-12% from 2012-17(4)

#1 position in HAE market(5)


$8 billion U.S. ADHD market We expect product sales to

double by 2020 through BED, SHP465 and geographic expansion(6)


VPRIV (Japan) Gaucher

SHP611 MLD

CINRYZE IV (low vol)

HAE Prophylaxis

SHP609 Hunter CNS

SHP610 Sanfilippo A

SHP613

Acute Vascular Repair

LDX* BED

INTUNIV (Japan) ADHD

INTUNIV® (EU) ADHD

SHP465 ADHD

LUM 001 Cholestatic Liver

Disease

LUM 002 Non-Alcoholic Steatohepatitis

SHP555 (US) Chronic

Constipation

$2B in Rare Diseases(1) $1.6B in Neuroscience(2) $0.8B in GI(3)

* Lisdexamfetamine dimesylate, active ingredient in VYVANSE/ELVANSE. (1) 2013 product sales on a pro-forma basis including CINRYZE (2) 2013 product sales exclude ADDERALL XR sales, which is managed in our Internal Medicine BU (3) 2013 product sales

(4) Kalorama Worldwide Market for Orphan Drugs (5) Seeking Alpha “Dyax And ViroPharma: An Overview Of HAE Space” (6) Subject to FDA approval for BED and SHP465 (7) Evaluate Pharma (8) IMS


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Multiple drivers of double digit sales performance

• CINRYZE delivered $86m since Jan 24 • Over 1,100 patients on therapy in the US

• FIRAZYR sales +80% • Strong US growth continues – more than 1,800 patients have

used FIRAZYR since launch

• ELAPRASE sales +13% • Driven by continued growth in the number of treated patients

• LIALDA strong performance continues, +28% • Continued market share gains in the US • Strong TRx performance continues through 1Q 2014

• VYVANSE sales +18% • US growth driven by price and volume • International sales show strong growth

Operational Discipline


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BED – Under diagnosed and undertreated patient population with significant morbidity • Approximately 3MM(1) patient in the US suffering with the disorder • In a survey of US adults, less than 7% of BED patients reported receiving

treatment over a 12 month period(1) • Per DSM-5: Condition is characterized by marked distress • No FDA approved treatment

Targeting 2nd half of 2015 launch - Substantive market analysis is well underway • Phase 3 studies complete – achieved primary endpoint in both trials • On track for a 2nd half of 2014 NDA submission

Binge Eating Disorder – a significant growth opportunity for VYVANSE

(1) Hudson et al,, 2012, National Comorbidity Survey Replication 2001-2003

Commercial Excellence


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SHP465: A new product to meet an adult ADHD market need

• Demonstrated efficacy at 16 hours post-dosing in registration trials • Planning for a launch in the first half of 2015 • We expect SHP465 to have 3-years of Hatch-Waxman exclusivity and we expect to have

at least two patents listed in the Orange Book expiring as late as May 2023

SHP465

We believe with SHP465 as part of our portfolio we can add 3%-5% to our existing share of the overall ADHD market



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Lifitegrast for dry eye disease - next steps

Following FDA meeting, preparing for a Q1 2015 filing

Complete remaining chemistry and manufacturing work

Build BU / Finalize commercial strategy

2016 Launch (subject to FDA approval)

Assess the need for gathering additional clinical data in support of the US filing and potential

international regulatory submissions

Strategy Shift


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CINRYZE IV (low vol)

HAE Prophylaxis

LUM 001 Rare Hepatic

Diseases LUM002 NASH

SHP607 (PREMIPLEX®) Prevention of ROP

SHP606 (lifitegrast)

Dry eye disease

Reinforce Core TAs

M&A Strategy

Expand into high value adjacent TAs

Rationale Recent examples

• Existing infrastructure or expertise creates “ownership” advantage

• Generate synergies (revenue, cost, operational) to substantiate control premium and value creation

• Informed entry into adjacent TAs with long-term growth potential where Shire has expertise or can build core competencies

Disciplined M&A strategy focused on acquiring in-line and pipeline assets in core and adjacent TAs

Strategy Shift


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ViroPharma: integration progressing successfully

Drive revenue from marketed products

Ensure uninterrupted supply

Realize cost and revenue synergies

Leverage talent

Extract value from pipeline programs

• Cinryze proforma revenue growth Q1 +16% • Sales force in US integrated with minimal turnover; driving strong

new patient growth

• Resolving outstanding manufacturing issues • Leveraging Shire’s manufacturing expertise

• Leveraging opportunities in HAE • Integration of ViroPharma into One Shire organization • Rapid transition of G&A activities; Commercial and R&D over

longer-term; on track to deliver $150M in savings in 2015

• Leveraging ViroPharma expertise in HAE and strength in patient advocacy area

• Pipeline programs reviewed and key decisions made

5 key success factors:



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FSGS has severe consequences for patients and significant societal costs • ~75,000 patients with primary FSGS in the G6 • Affects children and adults of all ages and

races; increased risk in people of African ancestry

• In children, it is the second most common cause of nephropathic syndrome and the second leading cause of kidney failure

• 60-75% of patients are nephrotic at diagnosis and eventually progress to ESRD, typically in about 8 years

• ~25% of patients relapse after treatment • High recurrence rates in patients receiving

kidney transplants (30% in adults, up to 80% in children)

The human face of FSGS

“We have a massive unmet medical need, but we are stuck with histological diagnosis and working with steroids” - FSGS KOL

Sources: KOL interview; http://www.nephcure.org/fsgs-facts - site accessed Jan 11th 2014

FSGS is a rare renal disorder affecting both children and adults and has significant commercial opportunity given high unmet need

Strategy Shift

http://www.nephcure.org/fsgs-facts�


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• Expands Shire’s pipeline with a novel clinical stage anti-fibrotic agent • Strengthens our growing and innovative portfolio targeting renal and

fibrotic diseases • FT011, the lead molecule, targets an innovative, novel and previously

undescribed mechanism of action and is currently completing a phase 1b trial in patients with renal impairment

• A phase 2 trial is planned for 2015 in patients with Focal Segmental Glomerulosclerosis (FSGS), a rare fibrotic kidney disease with high unmet medical need

• The acquisition also diversifies our pipeline, giving us access to Fibrotech’s library of novel molecules that are engineered to target fibrotic mechanisms across multiple indications of high unmet need

Fibrotech: strategic step in strengthening Shire’s Rare Disease pipeline

Strategy Shift


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Pedi

atric

Alagille Syndrome (ALGS)

• Present at 3 months

• No approved therapy

• ~13% bile diversion surgery, 21-31% liver transplant

• Very intense pruritus

Progressive Familial Intrahepatic Cholestasis (PFIC)

• Present at 3-6 months


• ~35% bile diversion surgery, ~50% liver transplant

• Very intense pruritus

• Without surgery, fatal by 2nd decade

Adul

t

Primary Biliary Cirrhosis (PBC) • >40 years old, 90% female

• Ursodeoxycholic acid (UDCA) approved for therapy – only ~50% patients respond

• Obeticholic acid (OCA; Intercept) in Ph 3 (but increases pruritus & CV issues have been reported)

• Slow progression

• Intense pruritus

Primary Sclerosing Cholangitis (PSC) • Mean age at diagnosis: 40 years, 70% Male


• Intense pruritus

• Aggressive, life expectancy 8-10 years from diagnosis

LUM001 for Cholestatic Liver Disease Strategy

Shift


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ALGS PFIC Before

Surgery(1) After

Surgery(1) Before

Surgery(2) After

Surgery(2)

Bile Acids (µmol/L) 115 28 Bile Acids (µmol/L) 337 11

Bilirubin (mg/dL) 2.4 1.6 Bilirubin (mg/dL) 2.4 1.5

Itching (0 no scratching- 4 cutaneous mutilation)

4 1 Itching (0-4) 3 1

Rationale for an ASBTi in Cholestasis Lowering Bile Acids Results in Significant Clinical Benefit

Emerick, BMC Gastroenterology (2008), Emeriick, Hepatology (2002), Schukfeh, J Ped Surgery (2012) (1) Mean (2) Median

Removing bile acids through surgical intervention: Reduces serum bile acids Improves biochemical markers of liver disease Rapidly reduces itching Slows disease progression x Disfiguring and associated with serious complications

Strategy Shift


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Replenishing our pipeline and pursuing further strategic deals

Acquired first and only protein replacement therapy being investigated for Dystrophic Epidermolysis Bullosa (pre-clinical)

Acquired Dry Eye Disease asset (phase 3), which could provide the basis for a larger ophthalmology business

Acquired Retinopathy of Prematurity (ROP) asset (phase 2), providing entry point into neonatology

Announced deal adds significant scale to rare disease portfolio with on- market hereditary angioedema (HAE) product complementary to FIRAZYR®

Expands our portfolio with clinical stage anti-fibrotic agent (rare & renal diseases)

Expands GI and Rare Disease portfolio with clinical assets for Cholestatic Liver Diseases

Well positioned for future M&A

• Strong cash generation • $1.8 billion in 2013

• Balance sheet flexibility • Net Debt of $1.4 billion • Increased corporate debt

ceiling to $12 billion

• Developing integration as a core strength, for rapid realization of synergies

Strategy Shift

Note: Fibrotech & Lumena deals have been signed but are still subject to closure.


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Further refine therapeutic area strategy

Strengthen our portfolio organically and via M&A

Integrate ViroPharma

Maintain discipline and continue One Shire program to drive further operational leverage


Strategy Shift

2014 Priorities: continue to reposition Shire for future growth


Explore new opportunities to drive growth from in-line portfolio

Maintain commercial focus to deliver continued sales growth

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

Q&A Breakout: Broadway Room, 10AM

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

Investor relations contacts

Europe: Sarah Elton-Farr Souheil Salah T: +44 1256 894157 T: +44 1256 894160 E: [email protected] E: [email protected]

North America: Jeff Poulton T: +1 781 482-0945 E: [email protected]

Investor Relations

Shire - Jefferies 2014 Global Healthcare Conference