Tarius SAC Tracker®


Background Analysis: US FDA Advisory Committee to Review Shire’s Prucalopride for the Treatment of Chronic Idiopathic Constipation – OCT 18, 2018 (GIDAC)


The US FDA has scheduled a meeting of the Gastrointestinal Drugs Advisory Committee (GIDAC) for Thursday, October 18, 2018. The committee will discuss a new drug application for prucalopride tablets for oral administration, submitted by Shire Development, LLC (Shire), proposed for the treatment of chronic idiopathic constipation in adults.

Indication Background

Description of Indication

Chronic idiopathic constipation is a commonly-occurring condition that affects nearly one in eight people in the US. The condition affects far more women than men. People with chronic idiopathic constipation experience symptoms of constipation, but no cause can be identified through standard diagnostic testing. Stool can remain in the bowel for more than a week and the buildup within the colon causes pelvic and abdominal pressure and pain, making it difficult to bend, sit down, and even walk. Other symptoms include poor appetite, back pain, and general malaise. The usual methods to relieve occasional constipation (e.g., high-fiber diets, laxatives, enemas) generally do not work for these patients.

Product Background

Description of Product

Prucalopride is a 5-HT4 agonist. It is a gastrointestinal prokinetic agent that stimulates colonic peristalsis. It activates the 5-HT4 receptors for the neurotransmitter serotonin. This activation is thought to increase the motility of the intestinal system by increasing peristalsis, or the muscle movements of the intestines that propel stool out of the body, making stools easier to pass and resulting in more frequent bowel movements.

Other FDA-Approved Products for the Indication

In addition to drugs that treat the individual symptoms of constipation, the following drugs are US FDA-approved for chronic idiopathic constipation:

·       Amitiza (lubiprostone) is a chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation.

·       Linzess (linoclotide) is a guanylate cyclase-C (GCC) agonist. Linaclotide binds to GCC and acts locally on the luminal surface of the intestinal epithelium, resulting in increases in cyclic guanosine monophosphate (cGMP), secretion of chloride and bicarbonate into the intestinal lumen, and increased intestinal fluid and accelerated transit through the intestine.

Clinical Trials of Proposed Indication

The NDA submission includes data from five phase 3 and one phase 4 double-blind, placebo-controlled trials, according to a Shire press release. The  integrated efficacy analysis from these trials (n = 2,484) showed that significantly more patients achieved an average of three or more complete spontaneous bowel movements per week over 12 weeks of treatment vs. placebo (27.8% vs. 13.2%; P < .001). An integrated safety analysis (n = 2,552) showed the most frequent treatment-emergent adverse events, occurring in at least 5% of the treatment group, included GI disorders (nausea, diarrhea, and abdominal pain) and headache, and comparable proportions of the treatment and placebo groups experienced adverse cardiovascular events (2% vs. 1.8%). Serious treatment-emergent adverse events occurred in 1.6% of the treatment group vs 2.4% of the placebo group, and no treatment-emergent adverse events resulted in death.

Shire also included results from a real-world observational safety study in the NDA to estimate the risk for major adverse cardiovascular events associated with prucalopride vs. polyethylene glycol, as “drugs similar to prucalopride have been associated with adverse cardiovascular events in the past,” according to the press release.

Comprehensive data from the NDA, including detailed analyses by the company and by the FDA, as well as specific FDA questions for the Committee, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

December 21, 2018 – PDUFA date

March 5, 2018 – Shire announced the FDA’s acceptance of the NDA (NDA 210166) for prucalopride for chronic idiopathic constipation.

Ex-US Regulatory Background

Prucalopride is currently approved for chronic constipation in the European Union and other countries outside of Europe, but it remains an investigational compound in the US. Examples include:

October 15, 2009 – European Commission approved prucalopride (trade name Resolor) for the treatment of constipation.

December 7, 2011 - Health Canada approved prucalopride (trade name Resotran, by Janssen) for the treatment of chronic idiopathic constipation in adult female patients in whom laxatives failed to provide adequate relief. There were an insufficient number of male patients in the clinical trials to demonstrate efficacy.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Shire Development, LLC Drug Name: prucalopride Drug Class: serotonin type 4 (5-HT4) receptor agonist Indication: chronic idiopathic constipation.

For more information about SAC Tracker reports and other benefits for our subscribers, click here.

DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.