FDA Approves Motegrity (prucalopride) for Adults with Chronic Idiopathic Constipation (CIC)

Shire plc (LSE: SHP, NASDAQ: SHPG) has announced that the U.S. Food and Drug Administration (FDA) has approved Motegrity™ (prucalopride), a once-daily, oral treatment option for adults with Chronic Idiopathic Constipation (CIC).

Motegrity, a selective serotonin-4 (5-HT4) receptor agonist, provides a different class of treatment for CIC that works by enhancing colonic peristalsis to increase bowel motility.1-3Motegrity is expected to launch in 2019 in the United States, where an estimated 35 million adults are living with CIC.4,5*While not all patients may be right for treatment, Motegrity represents an important new option.

"The approval of Motegrity marks a new day in the treatment of CIC," said Howard Mayer, M.D., Senior Vice President and Chief Medical Officer, Shire. "This significant milestone reinforces our continued commitment to the GI community and advances our goal of addressing the unmet need of patients suffering from rare, specialized and common GI conditions."

The efficacy of once-daily treatment with Motegrity was evaluated in six double-blind, placebo-controlled, randomized, multicenter clinical studies lasting 12 weeks (studies 1-5) or 24 weeks (study 6).1 Of the 2,484 patients, most were female (76%) and Caucasian (76%), with an average age of 47 (+/- 16 years).1

"As a gastroenterologist, it’s important for me to help patients with CIC find a treatment that works well for them," said Brooks Cash, M.D., Chief of the Division of Gastroenterology, Hepatology, and Nutrition at the University of Texas Health Science Center at Houston. "It’s exciting to be able to now offer my patients a new treatment option that addresses colonic peristalsis."

During studies, significantly more patients taking Motegrity achieved the primary endpoint (an average of ≥3 complete spontaneous bowel movements [CSBMs] per week over 12 weeks, considered normalization of BM frequency) than those in the placebo group (19-38% Motegrity ≤2 mg vs. 10-20% placebo) across five of six trials. A rapid response was seen with Motegrity as early as week 1, with improvements maintained throughout 12 weeks of treatment.1 The FDA has requested that Shire conduct five post-marketing studies evaluating the pharmacokinetics, efficacy, and safety of Motegrity in pediatric patients with CIC (6 months old to less than 18 years of age) and pregnant and lactating women with CIC treated with Motegrity.6

Motegrity is contraindicated in patients with a history of hypersensitivity to Motegrity. Reactions include dyspnea, rash, pruritus, urticaria, and facial edema have been observed. Motegrity is also contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, and toxic megacolon/megarectum.1

In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. A causal association between treatment with Motegrity and an increased risk of suicidal ideation and behavior has not been established. Monitor all patients treated with Motegrity for persistent worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider. Instruct patients to discontinue Motegrity immediately and contact their healthcare provider if they experience any of these symptoms.1

Most common adverse reactions (≥2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence and fatigue.1 Overall, discontinuation due to adverse events was low (5% Motegrity 2 mg once daily; 3% placebo). If reported, adverse events of diarrhea or headache typically resolved within a few days.1 In addition, cardiovascular safety was evaluated in a MACE† (major adverse cardiovascular events) analysis of the double-blind, placebo-controlled and open-label studies. It was also assessed in a retrospective observational study, which demonstrated no increase in the risk of MACE† with Motegrity relative to polyethylene glycol (PEG).1

CIC is a common condition affecting roughly 14% of the adult population.4,5 Symptoms can range from straining and bloating, to infrequent, or incomplete bowel movements.7 While "idiopathic" by definition (meaning the exact cause is not known), it is believed that CIC may be caused by insufficient movement of the colon muscle.7

Important Safety Information

Contraindications

• Motegrity is contraindicated in patients with:
• A history of hypersensitivity to Motegrity. Reactions include dyspnea, rash, pruritus, urticaria, and facial edema have been observed.

Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, and toxic megacolon/megarectum

Warnings and Precautions
In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. A causal association between treatment with Motegrity and an increased risk of suicidal ideation and behavior has not been established.

Monitor all patients treated with Motegrity for persistent worsening of depression or the emergence of suicidal thoughts and behaviors. Counsel patients, their caregivers, and family members of patients to be aware of any unusual changes in mood or behavior and alert the healthcare provider. Instruct patients to discontinue Motegrity immediately and contact their healthcare provider if they experience any of these symptoms.

Adverse Reactions
Most common adverse reactions (≥2%) are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence and fatigue.1 Overall, discontinuation due to adverse events was low (5% Motegrity 2 mg once daily; 3% placebo). If reported, adverse events of diarrhea or headache typically resolved within a few days.1 In addition, cardiovascular safety was evaluated in a MACE† (major adverse cardiovascular events) analysis of the double-blind, placebo-controlled and open-label studies. It was also assessed in a retrospective observational study, which demonstrated no increase in the risk of MACE† with Motegrity relative to polyethylene glycol (PEG).1

Use in Specific Populations

• Lactation: Motegrity is present in breast milk. Consider risks and benefits of breastfeeding.
• Pediatric: Safety and effectiveness in pediatric patients have not been established.
• Renal Impairment: A decreased dosage is recommended in patients with severe renal impairment. Avoid Motegrity in patients with end stage renal disease requiring dialysis.

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.

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.4

†Major adverse cardiovascular events (MACE) is defined as cardiovascular death; nonfatal myocardial infarction; and nonfatal stroke.

References
1. Motegrity™ (prucalopride) Prescribing Information. Lexington, MA; Shire LLC; 2018.
2. Camilleri M, Ford AC, Mawe GM, et al. Nat Rev Dis Primers.2017;3:17095.
3. Tack J, Camilleri M, Chang L, et al. Aliment Pharmacol Ther. 2012:35(7):745-767.
4. U.S. Census Bureau. Quick Facts (2017). https://www.census.gov/quickfacts/fact/table/US/PST045216.
5. Suares NC, Ford AC. Am J Gastroenterol. 2011;106(9):1582-1591.
6. Motegrity (prucalopride) FDA NDA Approval Letter, December 2018
7. Lacy BE, Mearin F, Chang L, et al. Gastroenterology 2016;150:1393–1407.

Source: Shire plc

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