Plecanatide

A synthetic 16-amino-acid analog of human uroguanylin, FDA approved since 2017 as a once-daily oral tablet for chronic idiopathic constipation and IBS-C, that activates intestinal guanylate cyclase-C in a pH-dependent manner to increase luminal fluid secretion.

Also referenced as: Trulance, SP-304, SP304, Plectide

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What is Plecanatide?

Plecanatide is a synthetic 16-amino-acid peptide (sequence NDECELCVNVACTGCL, two disulfide bonds linking Cys4–Cys12 and Cys7–Cys15, molecular formula C65H104N18O26S4, molecular weight 1682 Da) that is a structural analog of human uroguanylin, an endogenous hormone the small intestine secretes after meals to regulate fluid and electrolyte movement. It differs from native uroguanylin by a single conservative substitution, glutamic acid for aspartic acid at position 3, and was developed by Synergy Pharmaceuticals under the code SP-304. Marketed in the U.S. as Trulance, it was approved on January 19, 2017 for chronic idiopathic constipation (CIC) and on January 24, 2018 for irritable bowel syndrome with constipation (IBS-C), both in adults.

Where it appears in reagent catalogs, it does so as one of a small group of orally active, gut-restricted peptide drugs with a complete regulatory record. Interest comes from people reading about guanylate cyclase-C (GC-C) agonists and intestinal cGMP signaling, and from its close relationship to linaclotide, the other approved GC-C agonist, rather than from any laboratory-reagent role.

How it works

Plecanatide binds and activates guanylate cyclase-C, a transmembrane receptor on the luminal surface of intestinal epithelial cells. The approved labeling and the primary literature describe the chain of events as follows:

• GC-C activation raises intestinal cGMP — receptor activation increases intracellular and extracellular cyclic guanosine monophosphate, which stimulates chloride and bicarbonate secretion into the lumen, mainly through the CFTR channel; the added fluid softens stool and accelerates transit. Plecanatide acts locally with no measurable systemic absorption, which was first shown in a single-dose Phase 1 study of 72 healthy volunteers using a plasma assay sensitive to 1 ng/mL (Shailubhai et al., Digestive Diseases and Sciences, 2013, 58(9):2580–2586)
• pH-dependent activity inherited from uroguanylin — like its parent hormone, plecanatide retains the two acid-sensing N-terminal residues (Asp2 and Glu3) that make uroguanylin most active in the mildly acidic environment of the proximal small intestine. Molecular dynamics simulations found plecanatide’s most active conformers at pH 5.0, with activity falling at the more neutral pH of the distal gut; the same work contrasted this with linaclotide and bacterial heat-stable enterotoxin, which lack those residues and activate GC-C in a pH-independent manner (Brancale et al., Pharmacology Research & Perspectives, 2017, 5(2):e00295)
• The single-residue change is a potency change, not a mechanism change — the Glu3 substitution preserves uroguanylin’s receptor target and pH profile while improving GC-C agonist potency. Plecanatide and the related analog dolcanatide produced potent cGMP responses in human T84 intestinal cells and reduced inflammation in chemically induced and spontaneous murine colitis models, the latter remaining a preclinical observation only (Shailubhai et al., World Journal of Gastrointestinal Pharmacology and Therapeutics, 2015, 6(4):213–222)
• The clinical readout is bowel-movement frequency — in the pivotal Phase 3 CIC program, weekly complete spontaneous bowel movements rose by about 2.5 per week versus 1.2 on placebo, with effects evident in the first week and sustained through 12 weeks (Miner et al., American Journal of Gastroenterology, 2017, 112(4):613–621)

Research status

Plecanatide has a complete adult Phase 3 program, two U.S. approvals, and an ongoing pediatric program; its commercial history includes the bankruptcy of its original sponsor.

Chronic idiopathic constipation — two Phase 3 trials. CIC3 (NCT01982240) randomized 1,394 adults to two once-daily dose levels of plecanatide or placebo for 12 weeks. The durable overall CSBM responder rate was 21.0% at the lower dose and 19.5% at the higher dose versus 10.2% on placebo (P < 0.001 for both); diarrhea was the most common adverse event at 5.9% and 5.7% versus 1.3% (Miner et al., American Journal of Gastroenterology, 2017, 112(4):613–621). The National CIC3 study (NCT02122471), of near-identical design in 1,337 analyzed patients, found responder rates of 20.1% and 20.0% versus 12.8% (P = 0.004 for each dose), with diarrhea at 3.2% and 4.5% versus 1.3% (DeMicco et al., Therapeutic Advances in Gastroenterology, 2017, 10(11):837–851). The approved label reports these as 21% vs 10% and 21% vs 13%. Only the lower dose was approved; the higher dose offered no added efficacy.

IBS-C — two Phase 3 trials. NCT02387359 (n = 1,054) and NCT02493452 (n = 1,135) randomized adults meeting Rome III criteria to the same two dose levels or placebo for 12 weeks. Overall responder rates (at least a 30% reduction in worst abdominal pain plus an increase of at least one CSBM in the same week, for 6 of 12 weeks) were 30.2% and 29.5% versus 17.8% in Study 1 and 21.5% and 24.0% versus 14.2% in Study 2; diarrhea occurred in 4.3%, 4.0%, and 1.0%, and discontinuation for diarrhea was infrequent (Brenner et al., American Journal of Gastroenterology, 2018, 113(5):735–745). The IBS-C supplement was approved on January 24, 2018. An open-label long-term safety study in IBS-C (NCT02706483) enrolled 2,272 patients, completed in June 2017, and has results posted.

Pediatrics — restricted, with trials still running. The U.S. label carries a boxed warning on the risk of serious dehydration in pediatric patients, with a contraindication under 6 years of age (single oral doses caused deaths from dehydration in young juvenile mice, at ages the label equates to roughly 1 month to under 2 years in humans) and advice to avoid use between 6 and under 18 years. Two Phase 2 pediatric studies have completed with results posted: a 4-week dose-ranging study in 124 adolescents aged 12 to under 18 with CIC (NCT03120520, completed September 2018) and a dose-ranging study in 218 children aged 6 to under 18 with IBS-C (NCT03596905, completed November 25, 2024, results posted December 2025). No peer-reviewed efficacy publication from either has been located. A new Phase 2b placebo-controlled study of two weight-based dose groups in an estimated 180 children aged 6 to under 18 with functional constipation (NCT07723924) began on August 18, 2026, is listed as active but not recruiting, and has primary completion estimated for October 2027. No pediatric indication exists as of November 2026; the related GC-C agonist linaclotide holds a pediatric functional-constipation indication, plecanatide does not.

Regulatory and commercial record. NDA 208745 was approved as a new molecular entity on January 19, 2017. Drugs@FDA lists labeling supplements through April 13, 2021, and the DailyMed label is dated 03/2024; no new indication, formulation, or safety-labeling action was recorded in 2025 or 2026. Synergy Pharmaceuticals filed for Chapter 11 on December 12, 2018 after sales fell short of debt covenants; Bausch Health acquired Trulance, dolcanatide, and related intellectual property through a court-approved sale (approved March 1, 2019, closed March 6, 2019), and the product is now sold by Salix, a Bausch Health division. In Canada, Health Canada issued a Notice of Compliance for IBS-C on October 10, 2019 to Cipher Pharmaceuticals, which had licensed the Canadian rights; Bausch terminated that license in January 2020 and an arbitration award later ordered the product transferred to Bausch Health Canada, which obtained the CIC indication on December 24, 2024. The molecule is also marketed in India, where MSN Laboratories sells it as Plectide and other local brands exist. There is no EU marketing authorization. Patent suits against two generic applicants over the 3 mg tablet were settled on confidential terms, with Mylan in May 2025 and with MSN Laboratories in April 2026; no U.S. generic has been approved as of November 2026.

Beyond constipation. Preclinical colitis data (Shailubhai et al., 2015) were followed by the sponsor’s development of a separate, more protease-resistant analog, dolcanatide, for inflammatory bowel disease, not by human plecanatide trials in that setting. No registered human program exists for plecanatide outside constipation disorders.

Common dosage forms

• Oral immediate-release tablet (approved product) — the only approved format, supplied as white to off-white round tablets debossed “SP” on one side, in bottles with a desiccant, stored at room temperature.
• No injectable or capsule product exists — plecanatide is not systemically absorbed and is designed to act in the gut lumen; there is no approved or investigational parenteral form.
• Research supply — where it appears in reagent catalogs, it is as lyophilized peptide powder in vials. Any such material is uncharacterized relative to the approved tablet, whose clinical data depend on a specific oral formulation.

Key considerations

• Approval is real and the status is unambiguous. An FDA-approved drug product containing plecanatide exists for two adult indications, CIC and IBS-C; the “FDA Approved” status reflects that. The compound acts only on the gut.
• The pediatric boxed warning is current and the pediatric program is unfinished. Contraindicated under 6 years, avoid use between 6 and under 18 years; this is based on juvenile-mouse dehydration deaths rather than human events. Two Phase 2 pediatric studies are complete with posted but unpublished results, and a Phase 2b functional-constipation study started in 2026. Nothing in the record supports pediatric use today.
• Diarrhea is the characteristic safety signal. Across the four Phase 3 trials, diarrhea occurred in roughly 3% to 6% of plecanatide-treated adults versus about 1% on placebo, and the label advises stopping and rehydrating if severe diarrhea occurs. Mechanical gastrointestinal obstruction is a contraindication. Because the drug is not absorbed, systemic adverse effects are not expected and were not seen.
• Plecanatide and linaclotide are related but not interchangeable. Both are GC-C agonists, but plecanatide is a uroguanylin analog whose activity is pH-dependent and favors the proximal small intestine, whereas linaclotide is modeled on bacterial heat-stable enterotoxin and activates GC-C regardless of pH. Plecanatide is a single-strength tablet; linaclotide is a multi-strength capsule. Whether the pH difference translates into a clinically meaningful difference in diarrhea rates has not been tested head to head, and claims that it does rest on cross-trial comparison and modeling.
• The commercial failure of the original sponsor is not an efficacy failure. Synergy’s 2018 bankruptcy followed slow uptake in a market already occupied by linaclotide and lubiprostone, not a safety or regulatory action; the trial data and approvals were unaffected and the product remains marketed under new ownership. The brand names Trulance (U.S., Canada) and Plectide (India) and the development code SP-304 all refer to the same molecule.