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 2 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