New Data on the Cardiovascular Safety of Prucalopride Presented at 2018 Digestive Disease Week Annual Meeting

• New data from this observational, pharmacoepidemiology safety study included more than 35,000 patients (>90% females; many ≤55 years)¹
• Findings were consistent with no evidence of an overall increase in the risk of major adverse cardiovascular events (MACE) in patients using prucalopride compared with polyethylene glycol (PEG)¹
• Prucalopride is currently under U.S. FDA review for the treatment of chronic idiopathic constipation in adults

Cambridge, Mass. – June 3, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) announced today that new data on the cardiovascular (CV) safety of its investigational-stage candidate, prucalopride, will be shared as an oral presentation at the 2018 Digestive Disease Week (DDW) annual meeting (June 2-5, 2018; Washington, D.C.). Prucalopride, a serotonin type 4 (5-HT4) receptor agonist², is being evaluated by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation (CIC) in adults.

“We are pleased that these data will be shared with physicians at the DDW annual meeting because they demonstrate important results about the cardiovascular safety profile of prucalopride and Shire’s commitment to addressing unmet treatment needs in GI,” said Andreas Busch, Ph.D., Head of Research and Development, Shire. “Chronic idiopathic constipation affects an estimated 35 million people in the U.S.^3,4*, and can potentially impact a person’s life.⁵ If approved, prucalopride will be the only readily available 5-HT4 agonist² in the U.S. to treat adults with CIC.”

Shire sponsored an observational, pharmacoepidemiology safety study to estimate the risk, as measured by the pooled adjusted incidence rate ratio (IRR), of major adverse CV events (MACE) in adult new users of prucalopride compared to adult new users of polyethylene glycol (PEG). MACE included hospitalization for acute myocardial infarction or stroke and in-hospital CV death. Study data was from real-world settings in the United Kingdom and Sweden. This pooled analysis included over 35,000 patients with chronic constipation treated with prucalopride or PEG in a 1- to- 5 ratio. The average total duration of use was over 170 days for prucalopride and over 80 days for PEG. The pooled adjusted IRR for MACE was 0.64 (95% CI, 0.36, 1.13) in this mostly female (>90%) patient population where many were aged 55 years or younger, which was consistent with no evidence of an overall increase in the risk of MACE in patients using prucalopride compared with PEG.¹

“Because prior 5-HT4 agonists have been associated with adverse cardiovascular events in the past, further evaluating the risk of MACE in patients taking prucalopride was important,” said Alicia Gilsenan, Ph.D., Senior Director, Epidemiology, RTI Health Solutions, one of the lead researchers of this study. “Findings from this cohort study have provided us with real-world evidence from a large patient population about the cardiovascular safety profile of prucalopride compared with polyethylene glycol.”

Details for the oral presentation are:

Non-Interventional Cohort Study of the Relative Incidence of Major Cardiovascular Events Among Patients Initiating Prucalopride Versus a Matched Comparator Cohort Initiating Polyethylene Glycol 3350 (PEG)
Sunday, June 3, 2018
2:45 p.m. - 3:00 p.m. 
Session Number: 2530; Presentation Number: 386
Ballroom B - Washington Convention Center

Details for the poster presentations:

In addition to the oral presentation, two posters on chronic idiopathic constipation will be presented, contributing to the body of evidence about CIC, which affects an estimated 35 million people in the U.S.^{3, 4*}:

The Economic Burden of Chronic Idiopathic Constipation in the U.S.: A Systematic Literature Review – Poster Presentation
Monday, June 4, 2018
12:00 p.m. - 2:00 p.m.
Session Number: 7165; Presentation Number: Mo1574

Patterns of Pharmacotherapy in Patients with Chronic Idiopathic Constipation Initiating Treatment with Linaclotide or Lubiprostone – Poster Presentation
Monday, June 4, 2018
12:00 p.m. - 2:00 p.m. 
Session Number: 7165; Presentation Number: Mo1573

About the Oral Presentation
Data for this noninterventional, population-based cohort study were collected from four data sources – three from the United Kingdom and one from Sweden and included over 35,000 patients with chronic constipation treated with prucalopride or PEG. Patients were identified using electronic medical records, administrative claims, or national health-data registers. MACE outcomes in the UK were validated using additional clinical data, as available, and adjudicated by a committee of three clinicians. In Sweden, MACE outcomes were identified using previously validated algorithms. In all data sources, >90% of participants were women, and the proportion of patients aged ≥55 years was 21%-34% for UK data sources and 53% in Sweden.¹

About Prucalopride
Prucalopride, a serotonin type 4 (5-HT4) receptor agonist², is a gastrointestinal prokinetic agent that stimulates colonic peristalsis, increasing bowel motility.^6,7 It is an investigational compound, and has not been approved for use by the U.S. Food and Drug Administration.

Prucalopride is currently approved and available in the European Union (EU) where it is marketed by Shire as Resolor^®, indicated for symptomatic treatment of chronic constipation in adults in whom laxatives fail to provide adequate relief.⁸ Prucalopride is also available in several other countries outside of Europe.

On March 5, 2018, Shire announced that the U. S. Food and Drug Administration (FDA) accepted the submission of a new drug application (NDA) for prucalopride as a potential once-daily treatment option for CIC in adults. The FDA is expected to provide a decision on or around December 21, 2018, the designated Prescription Drug User Fee Act (PDUFA) action date. Prucalopride has been studied in more than 90 clinical trials worldwide over the last 20 years, including five main Phase 3 and one Phase 4 double-blind, placebo-controlled clinical trials along with this observational, pharmacoepidemiology CV safety study, which informed the NDA submission.⁹

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NOTES TO EDITORS

About Shire

Shire is the global biotechnology leader serving patients with rare diseases and specialized conditions. We seek to push boundaries through discovering and delivering new possibilities for patient communities who often have few or no other champions. Relentlessly on the edge of what’s next, we are serial innovators with a diverse pipeline offering fresh thinking and new hope. Serving patients and partnering with healthcare communities in over 100 countries, we strive to be part of the entire patient journey to enable earlier diagnosis, raise standards of care, accelerate access to treatment, and support patients. Our Rare Disease and Neuroscience divisions support our diverse portfolio of therapeutic areas, including Immunology, Hematology, Genetic Diseases, Internal Medicine, Ophthalmics, Oncology, and neuropsychiatry disorders.

Championing patients is our call to action - it brings the opportunity - and responsibility - to change people’s lives.

www.shire.com

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Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, projected revenues, the anticipated timing of clinical trials and approvals for, and the commercial potential of, inline or pipeline products, are forward-looking statements. Such 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, the following:

• Shire’s products may not be a commercial success;
• increased pricing pressures and limits on patient access as a result of governmental regulations and market developments may affect Shire’s future revenues, financial condition and results of operations;
• Shire depends on third parties to supply certain inputs and services critical to its operations including certain inputs, services and ingredients critical to its manufacturing processes. 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 manufacture of Shire’s products is subject to extensive oversight by various regulatory agencies. Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to, among other things, significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the nature of producing plasma-based therapies may prevent Shire from timely responding to market forces and effectively managing its production capacity;
• Shire has a portfolio of products in various stages of research and development. The successful development of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee that these products will receive regulatory approval;
• 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 affect Shire’s revenues, financial conditions or results of operations;
• failure to comply with laws and regulations governing the sales and marketing of its products could materially impact Shire’s revenues and profitability;
• Shire’s products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
• Shire’s patented products are subject to significant competition from generics;
• adverse outcomes in legal matters, tax audits 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 the Shire’s revenues, financial condition or results of operations;
• Shire may fail to obtain, maintain, enforce or defend the intellectual property rights required to conduct its business;
• Shire faces intense competition for highly qualified personnel from other companies and organizations;
• failure to successfully execute or attain strategic objectives from Shire’s acquisitions and growth strategy may adversely affect the Shire’s financial condition and results of operations;
• Shire’s growth strategy depends in part upon its ability to expand its product portfolio through external collaborations, which, if unsuccessful, may adversely affect the development and sale of its products;
• a slowdown of global economic growth, or economic instability of countries in which Shire does business, could have negative consequences for Shire’s business and increase the risk of non-payment by Shire’s customers;
• changes in foreign currency exchange rates and interest rates could have a material adverse effect on Shire’s operating results and liquidity;
• Shire is subject to evolving and complex tax laws, which may result in additional liabilities that may adversely affect the Shire’s financial condition or results of operations;
• if a marketed product fails to work effectively or causes adverse side effects, this could result in damage to Shire’s reputation, the withdrawal of the product and legal action against Shire;
• Shire is dependent on information technology and its systems and infrastructure face certain risks, including from service disruptions, the loss of sensitive or confidential information, cyber-attacks and other security breaches or data leakages that could have a material adverse effect on Shire’s revenues, financial condition or results of operations;
• Shire faces risks relating to the expected exit of the United Kingdom from the European Union;
• Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which has increased its borrowing costs and may decrease its business flexibility;
• Shire's ongoing strategic review of its Neuroscience franchise may distract management and employees and may not lead to improved operating performance or financial results; there can be no guarantee that, once completed, Shire's strategic review will result in any additional strategic changes beyond those that have already been announced;
• the potential uncertainty resulting from the announcement by Takeda Pharmaceutical Company Limited on 8 May 2018 of a recommended offer for Shire under the UK Takeover Code; and

a further list and description of risks, uncertainties and other matters can be found in Shire’s most recent Annual Report on Form 10-K and in Shire’s subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in “ITEM1A: Risk Factors”, and in Shire’s subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire’s website.

All forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of 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.

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

References:

1. Gilsenan A, Fortuny J, Ruigómez EPA, Karlsson P, et al. Non-Interventional Cohort Study of the Relative Incidence of Major Cardiovascular Events Among Patients Initiating Prucalopride Versus a Matched Comparator Cohort Initiating Polyethylene Glycol 3350 (PEG). 2018 Digestive Disease Week Annual Meeting (June 2-5, 2018; Washington, D.C.). Presentation Number 386.
2. Briejer MR, et al. Eur J Pharmacol. 2001;423:71–83.
3. Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis. Am J Gastroenterol. 2011;106:1582-1591.
4. U.S. Census Data. Available at: https://www.census.gov/quickfacts/fact/table/US/PST045216. 2016 (NOTE: estimate of 35 million based on US adult population of 248.71 million divided by CIC incidence of 14% from reference 3).
5. Heidelbaugh JJ, Stelwagon M, Miller SA, et. al. The Spectrum of Constipation-Predominant Irritable Bowel Syndrome and Chronic Idiopathic Constipation: US Survey Assessing Symptoms, Care Seeking, and Disease Burden. Am J Gastroenterol. 2015;110:580–587; doi:10.1038/ajg.2015.67; published online 17 March 2015.
6. Camilleri, M, et al. 2008 A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation. N Engl J Med. 2008;358:2344-2354.
7. Miner, PB, Camilleri, M., Burton, D., et. al. Prucalopride induces high-amplitude propagating contractions in the colon of patients with chronic constipation: a randomized study. Neurogastroenterol Motil. 2016;28:(9):1341-1348.
8. Resolor^® (prucalopride), EU Summary of Product Characteristics, December 2015.
9. U.S. FDA Accepts New Drug Application for Prucalopride (SHP555) for Chronic Idiopathic Constipation. March 5, 2018. Available at: https://www.shire.com/en/newsroom/2018/march/jo7p3e.