Plecanatide
Plecanatide (Trulance), uroguanylin analogue and guanylate cyclase-C agonist
Written by Aaron CuhaReviewed Sep 2026
Also known as: Trulance, SP-304
An oral 16-amino-acid uroguanylin analogue approved in 2017 for chronic idiopathic constipation and irritable bowel syndrome with constipation. In its pivotal phase 3, 20.1 percent of patients on 3 mg were durable responders versus 12.8 percent on placebo, a 7.3 point absolute difference. Its claimed tolerability advantage over linaclotide has never been tested head to head.
Overview
Plecanatide is a 16-amino-acid peptide that differs from human uroguanylin, the body's own guanylate cyclase-C ligand, by a single amino acid. The FDA approved it on 19 January 2017 under NDA 208745 for chronic idiopathic constipation in adults, and later for irritable bowel syndrome with constipation. It is taken orally, 3 mg once daily, and it acts almost entirely in the gut lumen rather than systemically.
The design argument is about pH. Uroguanylin is pH-sensitive and most active in the slightly acidic proximal small intestine, so the claim for plecanatide is that its secretory effect is segment-selective and more physiological than linaclotide, which derives from a bacterial heat-stable enterotoxin peptide and is pH-independent. That is a coherent mechanistic story. It has never been tested against linaclotide in a randomised head-to-head trial, so whether it produces a real tolerability advantage in patients remains an argument rather than a result.
The efficacy numbers are worth stating plainly because responder-rate endpoints in constipation trials look larger in a press release than they are. In the pivotal 12-week phase 3, durable overall complete spontaneous bowel movement responders were 20.1 percent on 3 mg and 20.0 percent on 6 mg against 12.8 percent on placebo. The drug works, the effect is statistically clear, and roughly one patient in fourteen benefits over placebo on that definition. The 6 mg dose added nothing, which is why 3 mg is the approved dose.
Diarrhoea is the dose-limiting adverse effect, at 5 percent versus 1 percent on placebo in the pooled chronic idiopathic constipation trials, usually in the first three days. Like linaclotide, it carries a contraindication in children under six because of a risk of serious dehydration seen in juvenile animals.
Mechanism of action
Agonism at guanylate cyclase-C on the luminal surface of intestinal epithelial cells. Receptor activation raises intracellular cyclic GMP, which activates the cystic fibrosis transmembrane conductance regulator and drives chloride and bicarbonate into the gut lumen, pulling water with them. The result is softer stool and faster transit. Cyclic GMP also crosses to the basolateral side, where it is thought to reduce afferent nociceptor firing, which is the proposed basis for the abdominal pain benefit in irritable bowel syndrome. Because plecanatide is derived from uroguanylin, its activity is greater at the slightly acidic pH of the proximal small intestine, which is the claimed point of difference from linaclotide.
Human evidence
A completed phase 3 programme in chronic idiopathic constipation and irritable bowel syndrome with constipation, with statistically clear but modest responder-rate separation from placebo, conducted and largely authored by the sponsor.
- Pivotal phase 3, 1337 adults: durable responders 20.1 percent on 3 mg versus 12.8 percent on placebo, an absolute difference of 7.3 percentage points.
- The 6 mg dose gave 20.0 percent, no better than 3 mg, which is why the approved dose is 3 mg.
- Stool consistency and stool frequency improved significantly from week 1 and were maintained through week 12.
- Pooled chronic idiopathic constipation safety data, 863 on 3 mg versus 870 on placebo: diarrhoea 5 percent versus 1 percent, severe diarrhoea 0.6 percent versus 0.3 percent, discontinuation for adverse events 4 percent versus 2 percent.
- No randomised head-to-head against linaclotide has been conducted.
What this does not tell you: The responder definition is a composite of bowel movement counts over 12 weeks, not a measure of how a patient feels overall, and a 7 point absolute separation means most people who take it will not meet the responder definition. The pivotal trial was sponsor-run with sponsor-employed authors, disclosed in the paper. Trials ran 12 weeks, so nothing here speaks to years of use. The pH-selectivity claim that distinguishes it from linaclotide has never been tested in patients.
Reading the research record
Plecanatide is a useful case of a mechanistic differentiator that was never converted into clinical evidence.
The uroguanylin derivation and the pH sensitivity are real molecular facts, and the argument that they should produce a gentler, more proximal secretory effect than linaclotide is plausible. Marketing has leaned on it for years. What would settle it is a randomised trial of plecanatide against linaclotide with diarrhoea and discontinuation as endpoints, and that trial does not exist. Comparing the diarrhoea rates from separate placebo-controlled programmes is not a substitute, because the populations, definitions and eras differ.
The second thing to flag is the gap between the approved use and the way guanylate cyclase-C agonists are sometimes discussed in gut health content. This drug was approved to increase bowel movement frequency in people who meet formal criteria for chronic constipation. It was not studied for gut barrier function, for leaky gut, for microbiome effects, or for general digestive wellbeing, and it has a hard contraindication in young children.
The evidence, charted
Fig. 1 · evidence composition
2of 3 citations (67%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 3 distinct years, 2017 to 2023, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Approved
UK
Not approved
AU
Not approved
CA
Not approved
Approved in 1 of 4, prescription route in 0, not approved in 3. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2017
Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation
Double-blind placebo-controlled phase 3, 1337 adults meeting modified Rome III criteria randomised to plecanatide 3 mg (n equal to 443), 6 mg (n equal to 449) or placebo (n equal to 445). Durable overall complete spontaneous bowel movement responders: 20.1 percent on 3 mg, 20.0 percent on 6 mg, 12.8 percent on placebo, P equal to 0.004 for each dose. Diarrhoea 3.2 percent, 4.5 percent and 1.3 percent respectively. Four of the five authors were employees and stockholders of the sponsor, Synergy Pharmaceuticals, which the paper discloses.
Therapeutic Advances in Gastroenterology - Human2023
Influence of Demographic Factors on Clinical Outcomes in Adults With Chronic Idiopathic Constipation Treated With Plecanatide
A phase 3 randomised analysis examining whether age, sex, race and other demographic factors change the treatment response in chronic idiopathic constipation. This is the genuine randomised evidence in this compound's later literature, and it is an analysis of who responds rather than a new efficacy trial.
Clinical and Translational Gastroenterology - Review2018
Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation
A narrative review of the compound and its place in therapy. Listed here explicitly as a review, because it is sometimes catalogued as human randomised evidence, which it is not. It is useful for context on the uroguanylin rationale and useless as a source of trial results.
Therapeutic Advances in Gastroenterology
Frequently asked questions
What is plecanatide approved for?
Chronic idiopathic constipation and irritable bowel syndrome with constipation, in adults, at 3 mg once daily. It is contraindicated in children under six because of a risk of serious dehydration, and its use is avoided in children aged six to under 18.
Is plecanatide better tolerated than linaclotide?
That is the claim and it has never been tested. The two have not been compared head to head in a randomised trial. The pH-sensitivity argument is mechanistic. Comparing diarrhoea rates across separate placebo-controlled programmes does not answer the question.
How well does it work?
In the pivotal phase 3, 20.1 percent of patients on 3 mg met the durable responder definition versus 12.8 percent on placebo. That is a clear statistical result and a modest absolute one, roughly one additional responder for every fourteen people treated.
Will it help leaky gut or general digestive health?
There is no evidence for that. The trials measured complete spontaneous bowel movements, stool consistency and abdominal symptoms in people meeting formal constipation criteria. Intestinal permeability was not an endpoint in the approval programme.
Does it get absorbed into the bloodstream?
Minimally. Systemic absorption is low enough that the label states a half-life could not be calculated. It acts on receptors facing into the gut lumen, which is also why its adverse effects are almost entirely gastrointestinal.