Prucalopride (SHP555) Update for Global Investors

March 7, 2018

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Prucalopride - Introduction

U.S. FDA Accepts New Drug Application for Prucalopride (SHP555) for Chronic Idiopathic Constipation (CIC) • Prucalopride is an investigational product for the treatment of chronic idiopathic constipation in adults in the U.S.

• The product is investigational. The U.S. FDA accepted submission of Shire’s NDA and the PDUFA date is on or around December 21, 2018

• Shire does not know when or if FDA will approve prucalopride

• Shire cannot predict the content of the labeling for prucalopride in the event of FDA approval

• This presentation updates investors on Shire’s current development plan for prucalopride

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STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Prucalopride - Summary

U.S. FDA Accepts New Drug Application for Prucalopride (SHP555) for Chronic Idiopathic Constipation (CIC)

• Reinforces Shire’s long-standing heritage in gastrointestinal (GI) conditions and deep customer relationships and in-house capabilities

• Strong addition to GI franchise, which includes LIALDA, GATTEX and provides bridge to pipeline assets such as SHP621 and SHP647 • If approved, prucalopride will be the only readily available 5-HT4 agonist1 in the U.S. to treat CIC in adults • CIC affects an estimated 35 million people in the U.S.2,3* Many patients are dissatisfied with or do not respond to current therapies4 • Efficacy and safety evaluated in five main Phase 3 and one Phase 4 double-blind, placebo-controlled clinical trials5,6 • NDA submission includes real-world evidence from an observational, pharmacoepidemiology cardiovascular safety study7

*This represents ~14% of the U.S. population as of July 1, 2016 Census Bureau Data.

1. Briejer MR et al. Eur J Pharmacol. 2001;423(1):71-83. 2. Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis. The American Journal of Gastroenterology. 2011;106:1582-1591. 3. US Census Data. Quick Facts. Available at: https://www.census.gov/quickfacts/fact/table/US/PST045216. 2016/. 4. Johanson JF & Kralstein J Aliment Pharmacol Ther 2007;25:599–608. 5. Clinical Trials and Related Publications (Prucalopride). 6. Annex H1 Resolor 7. SPD555-802: Cohort Study of the Relative Incidence of Major Cardiovascular Events Among Patients Initiating Prucalopride Versus a Matched Comparator Cohort. Protocol. www.encepp.eu/encepp/viewResource.htm;jsessionid=j3GBA4ZCMy2HD6FQGiS_s43JWSa-jy3p4-Vrz4U3e3vZyNDJOc4x!-53086593?id=22643. 3

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Prucalopride Overview

• A serotonin type 4 (5-HT4) receptor agonist1 Mode of action • A gastrointestinal prokinetic agent thought to stimulate colonic peristalsis, increasing bowel motility1 • If approved by FDA*, it would be the only readily available gastrointestinal prokinetic drug available for adults with chronic idiopathic constipation in the U.S. Clinical • Approved in EU and several other International markets with cumulative experience patient exposure of approximately 283k person years of treatment2 • Studied in more than 90 clinical trials worldwide over the last 20 years, including six main randomized, controlled clinical trials3 Timing • PDUFA action date of December 21, 2018 with FDA noting that timelines are flexible and subject to change based on workload and identification of potential review issues • Patents have already expired; 5 years NCE exclusivity from U.S. launch

1. Wong BS, Manabe N, Camilleri M. Role of prucalopride, a serotonin (5-HT4) receptor agonist, for the treatment of chronic constipation. Clinical and Experimental Gastroenterology. 2010;3:49-56. 2. PSUR for Reporting Period: 15 Oct 2016 to 14 Oct 2017: Cumulative and Interval Exposure from Marketing Experience (section 5 of the PSUR). 3. Clinical Trials and Related Publications (Prucalopride). 4 * Shire does not yet know what the final labeling will be for prucalopride, if approved, or if there will be post-marketing requirements or commitments.

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY U.S. CIC market and unmet need

• A common and often debilitating medical problem, with a demonstrated impact on quality of Disease life, and associated with a substantial economic burden1 • There are many causes, and one of the possible underlying problems is an impairment or dysfunction of the gut’s ability to move, by contracting and releasing, naturally.2

2,3* U.S. market • 35M patients in the U.S. with CIC • Published population based surveys indicate ~25 – 40 % of patients were actively seeking treatment with an HCP for CIC1,4 • The value of the Novel Rx constipation market in US is ~$1.7billion (IMS Gross revenue), and growing strongly >20% (2017 vs 2016)5

1 Unmet need • Many patients are dissatisfied with or do not respond to current therapies • Current treatment consists of Rx therapies and OTC laxatives • Prucalopride, a serotonin type 4 (5-HT4) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis, increasing bowel motility6 and should address an unmet need in adults suffering from CIC

“CIC is a commonly-occurring condition that affects nearly one in eight people in the United States. Many patients use over-the-counter and prescription medicines, including laxatives, but continue to have constipation symptoms.” William D. Chey, MD, Professor of Gastroenterology & Nutrition Sciences, Director of the GI Nutrition & Behavioral Wellness Program, University of Michigan Health System, Ann Arbor.

* This represents ~14% of the U.S. population as of July 1, 2016 Census Bureau Data.

1. Johanson JF & Kralstein J Aliment Pharmacol Ther 2007;25:599–608. 2. Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis. The American Journal of Gastroenterology. 2011;106:1582-1591. 3. US Census Data. Quick Facts. Available at: https://www.census.gov/quickfacts/fact/table/US/PST045216. 2016/. 4. Heidelbaugh et al. Am J Gastroenterol 2015; 110:580– 587. 5. IMS Data on file. 6. Wong BS, Manabe N, Camilleri M. Role of prucalopride, a serotonin (5-HT4) receptor agonist, for the treatment of chronic constipation. Clinical and Experimental Gastroenterology. 2010;3:49-56. 5

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Prucalopride targets 5-HT4 receptors to increase motility

COLON

Thought to stimulate 5-HT4 receptors on intrinsic sensory neurons1–3

Triggers peristaltic reflex and colonic mass movement3

RECTUM

1. Briejer MR et al. Eur J Pharmacol. 2001;423(1):71-83. 2. Grider JR et al. Gastroenterology. 1998;115(2):370-380. 3. Prins NH et al. Br J Pharmacol. 2000;131(5):927-932. 6

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Key efficacy results1

Impact on • Integrated analysis of over 2000 patients from four continents demonstrated bowel prucalopride was efficacious in the treatment of individuals with CIC function • Normalization of bowel movements (average of ≥3 SCBMs per week over 12 weeks) in 27.8% of adults versus 13.2% on placebo (P<0.001) • Clinically meaningful improvement in bowel function (average increase of ≥1 SCBMs per week over 12 weeks) in 47.0% of adults on prucalopride versus 29.9% on placebo (P<0.001)

• Significant reduction in the time to first SCBM Additional endpoints • Significant reductions in rescue medication for both mean number of tablets and mean days of use with prucalopride (P<0.001)

Note: SCBMs = spontaneous complete bowel movements); PAC-SYM = patient assessment of constipation symptoms questionnaire; PAC-QOL: patient assessment of constipation quality of life questionnaire.

1. Camilleri M et al. Dig Dis Sci. 2016;61(8):2357-2372. 7

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Key safety results1

• Overall, 806 patients (63.3%) in the prucalopride group and 682 patients (53.3%) in the placebo group experienced ≥1 TEAE • The majority of TEAEs experienced by patients in both treatment groups were mild or moderate in severity • Most common adverse events were similar in both men and women and included gastrointestinal disorders (nausea, diarrhea, and abdominal pain) and headache • Fewer men than women experienced TEAEs (prucalopride group, 47.2 versus 68.5%; placebo group, 38.5 versus 58.0%, respectively) • The proportion of patients who experienced any adverse cardiovascular events was low and comparable between groups (1.8% for placebo versus 2.0% for prucalopride) • TEAEs led to permanent discontinuation for 3.4% of subjects in the placebo group and 5.2% of subjects in the prucalopride group

1. Camilleri M et al. Dig Dis Sci. 2016;61(8):2357-2372. 8

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY Supporting gastroenterologists to manage patients with different GI conditions

Lialda (Mesalamine) Gattex SHP555* US Pentasa/US only - SHP647* (teduglutide SHP621* Shire (Mesalamine) [rDNA origin])

Anti MAdCAM GLP-2 analog Topical steroid

5-HT4 receptor agonist

Inflammatory Bowel Chronic Idiopathic Ulcerative Colitis (UC) Disease (IBD) Short Bowel Eosinophilic Constipation (CIC) (mild to moderate) (moderate to severe) Syndrome (SBS) Esophagitis (EOE)

20-30% IBD of patients undergo surgery

Specialty GI Rare GI

* Investigational compound in the US and has not been approved for use by the US Food and Drug Administration. 9

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY “Safe Harbor” Statement Under The Private Securities Litigation Reform Act Of 1995

Statements included herein that are not historical facts, including without limitation statements • inability to successfully compete for highly qualified personnel from other companies concerning future strategy, plans, objectives, expectations and intentions, the anticipated timing and organizations; of clinical trials and approvals for, and the commercial potential of, inline or pipeline products, • failure to achieve the strategic objectives, including expected operating efficiencies, are forward-looking statements. Such forward-looking statements involve a number of risks and cost savings, revenue enhancements, synergies or other benefits at the time anticipated uncertainties and are subject to change at any time. In the event such risks or uncertainties or at all with respect to Shire’s acquisitions, including NPS Pharmaceuticals Inc., Dyax materialize, Shire’s results could be materially adversely affected. The risks and uncertainties Corp. or Baxalta Incorporated may adversely affect Shire’s financial condition and include, but are not limited to, the following: results of operations; • Shire’s growth strategy depends in part upon its ability to expand its product portfolio • Shire’s products may not be a commercial success; through external collaborations, which, if unsuccessful, may adversely affect the • increased pricing pressures and limits on patient access as a result of governmental development and sale of its products; regulations and market developments may affect Shire’s future revenues, financial condition • a slowdown of global economic growth, or economic instability of countries in which and results of operations; Shire does business, as well as changes in foreign currency exchange rates and interest • Shire conducts its own manufacturing operations for certain of its products and is reliant on rates, that adversely impact the availability and cost of credit and customer purchasing third party contract manufacturers to manufacture other products and to provide goods and and payment patterns, including the collectability of customer accounts receivable; services. 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Fluctuations in buying or distribution patterns by such customers can adversely Form 10-Q, in each case including those risks outlined in “ITEM 1A: Risk Factors”, and affect Shire’s revenues, financial conditions or results of operations; in subsequent reports on Form 8-K and other Securities and Exchange Commission • Shire’s products and product candidates face substantial competition in the product markets filings, all of which are available on Shire’s website. in which it operates, including competition from generics; • adverse outcomes in legal matters, tax audits and other disputes, including Shire’s ability to All forward-looking statements attributable to us or any person acting on our behalf are enforce and defend patents and other intellectual property rights required for its business, could expressly qualified in their entirety by this cautionary statement. Readers are cautioned have a material adverse effect on the Company’s revenues, financial condition or results of not to place undue reliance on these forward-looking statements that speak only as of operations; the date hereof. Except to the extent otherwise required by applicable law, we do not undertake any obligation to update or revise forward-looking statements, whether as a result of new information, future events or otherwise. 10

STATEMENTS REGARDING PRUCALOPRIDE SUBJECT TO REGULATORY APPROVAL - INTENDED FOR INVESTOR AUDIENCE ONLY