FDA Advisory Committee Recommends Approval of Shire’s Prucalopride (SHP555) for Chronic Idiopathic Constipation

Intended for U.S. Audience

FDA Advisory Committee Recommends Approval of Shire’s Prucalopride (SHP555) for Chronic Idiopathic Constipation

If FDA grants approval, prucalopride will be the only readily available 5-HT4 receptor agonist¹ in the U.S. for chronic idiopathic constipation in adults; FDA is anticipated to make a final decision by the end of December

Cambridge, Mass. – October 18, 2018 – Shire plc (LSE: SHP, NASDAQ: SHPG) announced today that the U.S. Food and Drug Administration (FDA) Gastrointestinal Drugs Advisory Committee voted unanimously (10 to 0) that the risk-benefit profile of prucalopride supports the approval of this New Drug Application (NDA). The FDA will take the advisory committee’s recommendation into consideration when the agency makes a final determination. The Prescription Drug User Fee Act (PDUFA) action date for prucalopride is December 21, 2018.

The advisory committee also voted unanimously (10 to 0) that the potential risk of cardiovascular adverse events with the use of prucalopride in adults with CIC has been adequately addressed by Shire. Prucalopride, a serotonin type 4 (5-HT4) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis, increasing bowel motility.^{2,[3],[4],[5]} Drugs similar to prucalopride have been associated with adverse cardiovascular (CV) events in the past.

“We are pleased with the advisory committee’s vote today supporting prucalopride for the treatment of adults with chronic idiopathic constipation in the U.S., and will continue working with the FDA during the final stages of its review,” said Andreas Busch, Ph.D., Head of Research and Development at Shire. “This investigational compound reinforces Shire’s long-standing heritage in gastrointestinal conditions and deep in-house capabilities in the category.”

Prucalopride has been studied in more than 90 clinical trials worldwide over the last 20 years, including six key studies by which the advisory committee made its recommendation today. The advisory committee reviewed data included in the prucalopride NDA, specifically five main Phase 3 and one Phase 4 double-blind, placebo-controlled clinical trials. An integrated analysis of these six main randomized, controlled clinical trials evaluated the global efficacy and safety of prucalopride 2 mg daily in men and women with chronic constipation; study designs across the trials were similar. Overall, there were 2,484 adult patients included in the integrated efficacy analysis and 2,552 adult patients included in the integrated safety analysis; all patients included received prucalopride less than or equal to 2 mg daily or placebo.⁶

The committee also reviewed results from an observational, pharmacoepidemiology safety study that Shire sponsored 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.⁷

For the observational, pharmacoepidemiology safety study, the pooled adjusted IRR for MACE was 0.64 (95% CI, 0.36, 1.14)⁸ in this mostly female (>90%) patient population where many were aged 55 years or younger, which excluded a threefold increase risk of MACE in patients using prucalopride compared with PEG. The average total duration of use was over 170 days for prucalopride and over 80 days for PEG.⁷

There are an estimated 35 million adults in the U.S. with chronic idiopathic constipation.^9,[10]* The condition is characterized by difficult, infrequent or incomplete passage of stools over a prolonged period and a range of symptoms, which may include abdominal pain and/or bloating.¹¹ 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.¹²

Supporting Clinical Data
In the integrated analysis of the six main clinical trials, significantly more patients treated with prucalopride versus placebo (27.8% vs 13.2%; p<0.001) achieved an average of three or more spontaneous, complete bowel movements (SCBMs) per week over the 12-week treatment period. The most common (greater than or equal to 5%) treatment-emergent adverse events (TEAEs) in the prucalopride group were diarrhea, headache, abdominal pain, and nausea. The proportion of patients who experienced any adverse cardiovascular CV events were comparable between groups (1.8% for placebo vs. 2.0% for prucalopride). Serious TEAEs were reported in 1.6% of patients who received prucalopride versus 2.4% of patients who received placebo. No fatal TEAEs occurred.⁶

About Prucalopride
Prucalopride, a selective serotonin type 4 (5-HT4) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis, increasing bowel motility.^2,3,4,5 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.¹³ Prucalopride is also available in several other countries outside of Europe.

For further information please contact:

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 diverse portfolio of therapeutic areas includes Immunology, Hematology, Genetic Diseases, Neuroscience, Internal Medicine, and Ophthalmics.
 
Championing patients is our call to action - it brings the opportunity - and responsibility - to change people’s lives.

www.shire.com

Forward-Looking Statements

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 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 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 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;
• the potential uncertainty among our employees, customers, suppliers, and other business partners resulting from the announcement by Takeda Pharmaceutical Company Limited on May 8, 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, 2017 Census Bureau Data.

¹ Briejer MR et al. Eur J Pharmacol 2001;423:71–83.

² Camilleri, M, et al. 2008 A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation. N
  Engl J Med. 2008;358:2344-2354.

³ 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.

⁴ DeSchryver, et. al. The effects of the specific 5HT4 receptor agonist, prucalopride, on colonic motility in
  healthy volunteers. Aliment Pharmacol Ther. 2002; 16: 603-612.

⁵ Tack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L. Prucalopride (Resolor) in the
  treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 2009;58 (3):357-65

⁶ Camilleri M, et al. Efficacy and Safety of Prucalopride in Chronic Constipation: An Integrated Analysis of
   Six Randomized, Controlled Clinical Trials. Digestive Diseases and Sciences. 2016.61:2357-2372.

⁷ 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) Gilsenan, Alicia et al. Gastroenterology, Volume 154, Issue 6, S-92 - S-93. Abs #386.

⁸ Shire Errata to Shire’s FDA Briefing Document. October 18, 2018.

⁹ U.S. Census Data. Available at: https://www.census.gov/quickfacts/fact/table/US/PST045216. 2017.

¹⁰ 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.

¹¹ Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393–407.

¹² Ford AC, Moayyedi P, Lacy BE, et. al. American College of Gastroenterology Monograph on the
  Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation. Am J Gastroenterol
  2014;109:S2 – S26.

¹³ Resolor^® (prucalopride), EU Summary of Product Characteristics, December 2015.