Healthcare Industry News: U.S. Food and Drug Administration
News Release - March 5, 2018
U.S. FDA Accepts New Drug Application for Prucalopride (SHP555) for Chronic Idiopathic ConstipationNDA acceptance of prucalopride reinforces Shire's long-standing heritage in gastrointestinal (GI) conditions and deep in-house capabilities in the category
If approved, prucalopride will be the only readily available 5-HT4 agonist in the U.S. for chronic idiopathic constipation in adults
Chronic idiopathic constipation affects an estimated 35 million people in the U.S., [*]
Submission includes real-world evidence from an observational, pharmacoepidemiology cardiovascular safety study
Cambridge, Mass. - March 5, 2018 -- (Healthcare Sales & Marketing Network) -- Shire plc (LSE: SHP, NASDAQ: SHPG) announces that the U.S. Food and Drug Administration (FDA) has accepted the submission of a New Drug Application (NDA) for prucalopride (also known as SHP555). Prucalopride is being evaluated as a potential once-daily treatment option for chronic idiopathic constipation (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 with FDA noting that timelines are flexible and subject to change based on workload and identification of potential review issues.
"Today's acceptance of the NDA reinforces the breadth and depth of Shire's capabilities in gastrointestinal conditions and commitment to providing new treatment options for patients living with hard-to-treat conditions," said Andreas Busch, Ph.D., Head of Research and Development at Shire. "If approved by the FDA, prucalopride will be the only readily available 5-HT4 agonist1 in the United States for chronic idiopathic constipation in adults. We look forward to working with the FDA as the agency reviews our application."
There is an estimated 35 million people in the United States with chronic idiopathic constipation.2,3 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. 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.
"Chronic idiopathic constipation is a commonly-occurring condition that affects nearly one in eight people in the United States,"2,3 said William D. Chey, M.D., Professor of Gastroenterology & Nutrition Sciences, and Director of the GI Nutrition & Behavioral Wellness Program at the University of Michigan Health System, Ann Arbor. "Many patients use over-the-counter and prescription medicines, including laxatives, but continue to have constipation symptoms."
For more than 10 years, Shire has demonstrated its commitment to the GI community and cultivated deep in-house capabilities and expertise in the category. Through a diversified portfolio and growing pipeline, Shire aims to extend its GI footprint to new indications and therapeutic areas to meet the needs of patients living with rare and specialized GI conditions.
Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, is a gastrointestinal prokinetic agent that stimulates colonic peristalsis, increasing bowel motility., 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 that informed the NDA submission.
An integrated analysis of the 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 is less than or equal to 2 mg/day or placebo. 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 gastrointestinal disorders (nausea, diarrhea, and abdominal pain) and headache. 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 vs 2.4% of patients who received placebo. No fatal TEAEs occurred.
Shire conducted an observational, pharmacoepidemiology safety study to estimate, in real-world settings, the risk of major adverse cardiovascular events (MACE) in patients treated with prucalopride compared to patients treated with polyethylene glycol (PEG). Drugs similar to prucalopride have been associated with adverse cardiovascular events in the past. Study results are included in the NDA to provide the FDA additional understanding of the CV safety profile of prucalopride.
The FDA's acceptance of the prucalopride NDA reinforces Shire's breadth and depth of its therapeutic areas expertise in bringing possible treatment options to patients. In 2017 alone, Shire received either Breakthrough Therapy, Orphan Drug, Priority Review or Fast Track designations by the FDA for five of its therapies and anticipates continued progress of key regulatory milestones for late-stage programs.
Prucalopride is an investigational compound, and has not been approved for use by the U.S. Food and Drug Administration.
Prucalopride currently is 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. It is also available in several other countries outside of Europe.
About Shire GI
Shire has a long-standing heritage in gastrointestinal (GI) conditions. With a rich and diversified portfolio, we seek to transform the outlook of patients living with rare and hard to treat GI conditions by helping to address unmet needs. For more than 10 years, we have made a continued commitment to the GI community, and to cultivating a deep in-house expertise in the category. Through a growing pipeline, Shire aims to extend its GI portfolio to new indications and therapeutic areas to meet the needs of adult and pediatric patients living with rare and specialized GI conditions.
NOTES TO EDITORS
Shire is the global leader in serving patients with rare diseases. We strive to develop best-in-class therapies across a core of rare disease areas including hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology. Our diversified capabilities enable us to reach patients in more than 100 countries who are struggling to live their lives to the fullest.
We feel a strong sense of urgency to address unmet medical needs and work tirelessly to improve people's lives with medicines that have a meaningful impact on patients and all who support them on their journey.
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; and
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.
 Briejer MR et al. Eur J Pharmacol 2001;423:71-83.
 US 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)
 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.
 Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393-407.
 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.
 Johanson, J. F. and Kralstein, J. (2007), Chronic constipation: a survey of the patient perspective. Alimentary Pharmacology & Therapeutics, 25: 599-608. doi:10.1111/j.1365-2036.2006.03238.
 Camilleri, M, et al. 2008 A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation. N Engl J Med. 2008;358:2344-2354.
 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.
 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.
 European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. Cohort Study of the Relative Incidence of Major Cardiovascular Events Among Patients Initiating Prucalopride Versus a Matched Comparator Cohort..Available at: http://www.encepp.eu/encepp/viewResource.htm?id=22643. Accessed March 5, 2018.
 Resolor® (prucalopride), EU Summary of Product Characteristics, December 2015.
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