Linaclotide

A synthetic 14-amino-acid guanylate cyclase-C agonist taken orally and minimally absorbed, FDA approved since 2012 as Linzess for constipation-predominant irritable bowel syndrome and chronic idiopathic constipation, with pediatric constipation indications added in 2023 through 2026.

Also referenced as: Linzess, Constella, MD-1100, ASP0456, Linaclotide acetate

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What is Linaclotide?

Linaclotide is a synthetic 14-amino-acid peptide (Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr, molecular formula C59H79N15O21S6, molecular weight 1526.8) held in a compact fold by three disulfide bonds (Cys1–Cys6, Cys2–Cys10, Cys5–Cys13). It is a structural relative of the bacterial heat-stable enterotoxins and of the endogenous intestinal peptides guanylin and uroguanylin, all of which activate guanylate cyclase-C (GC-C) on the luminal surface of the gut lining. Developed by Ironwood (originally Microbia) under the code MD-1100 and marketed in the U.S. as Linzess, it was approved by the FDA on August 30, 2012 for adults with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC); it is sold in Europe as Constella and in Japan, where Astellas developed it as ASP0456, as Linzess tablets.

It is unusual among approved peptides in being taken by mouth and in working without entering the bloodstream: the approved labeling describes plasma concentrations of linaclotide and its active metabolite below the limit of quantitation after therapeutic doses, with activity confined to the intestinal lumen. Where it appears in reagent catalogs, it is as a lyophilized reference compound from laboratory-reagent suppliers rather than the injectable-peptide catalogs, and it attracts attention from people reading about gut motility and visceral pain rather than from any performance or longevity framing.

How it works

Linaclotide binds and activates GC-C receptors on the apical membrane of intestinal epithelial cells. The downstream signal is cyclic GMP, which acts both inside the cell and, after export, on nearby nerve endings:

• Selective GC-C agonism with local action — linaclotide binds GC-C with low-nanomolar, pH-independent affinity, raises cGMP in intestinal cells, resists gastric acid and pepsin, and increases fluid secretion and transit in rats despite an oral bioavailability of about 0.1%, which is the basis for describing the drug as acting locally in the gut (Busby et al., European Journal of Pharmacology, 2010, 649(1-3):328–335). Loss of the C-terminal tyrosine in the gut yields an active 13-residue metabolite, MM-419447, that also activates GC-C and contributes to the effect (Busby et al., Journal of Pharmacology and Experimental Therapeutics, 2013, 344(1):196–206)
• Chloride and bicarbonate secretion through CFTR — intracellular cGMP activates protein kinase G II, which phosphorylates and opens the cystic fibrosis transmembrane conductance regulator (CFTR) channel; chloride and bicarbonate move into the lumen, water follows, stool softens, and transit accelerates. The approved labeling summarizes this sequence as the mechanism for the bowel-symptom effects (FDA label, Linzess, 2026)
• Extracellular cGMP inhibits colonic nociceptors — in mice, intra-colonic linaclotide reduced firing of colonic sensory afferents and spinal signaling of noxious colorectal distention, with a larger effect during chronic visceral hypersensitivity. GC-C was expressed in mucosa but not in neurons, the effect was lost in Gucy2c-knockout animals and blocked by inhibiting cGMP transporters or removing the mucosa, supporting a model in which cGMP released from epithelium dampens pain-sensing nerves (Castro et al., Gastroenterology, 2013, 145(6):1334–1346.e1–11)
• Pain relief in the clinic tracks the mechanism — in the same report’s post-hoc analysis of the 26-week Phase 3 trial (804 patients on 290 mcg or placebo), 70% of linaclotide-treated IBS-C patients had at least a 30% reduction in abdominal pain versus 50% on placebo, a result consistent with the preclinical analgesic pathway rather than a secondary effect of easier bowel movements alone (Castro et al., Gastroenterology, 2013)

Research status

Linaclotide has a complete adult Phase 3 program, a pediatric program that produced three successive label expansions, multiple regulatory approvals, and one clearly failed follow-on formulation.

Chronic constipation (NCT00765882, NCT00730015). Two 12-week, dual-dose Phase 3 trials (Trials 303 and 01) randomized 1,276 adults to placebo or linaclotide 145 or 290 mcg once daily. The primary endpoint, at least three complete spontaneous bowel movements (CSBMs) per week with an increase of at least one from baseline during 9 of 12 weeks, was met by 21.2% and 16.0% of patients on 145 mcg and 19.4% and 21.3% on 290 mcg, versus 3.3% and 6.0% on placebo (P < 0.01 for all comparisons). Diarrhea led to discontinuation in 4.2% of linaclotide patients (Lembo et al., New England Journal of Medicine, 2011, 365(6):527–536).

IBS-C (NCT00938717, NCT00948818). A 26-week Phase 3 trial (NCT00938717) in 804 patients found 33.7% of linaclotide 290 mcg patients met the FDA composite responder endpoint (at least 30% improvement in worst abdominal pain plus at least one additional CSBM in the same week for 6 of 12 weeks) versus 13.9% on placebo (P < 0.0001; number needed to treat 5.1); diarrhea caused discontinuation in 4.5% versus 0.2% (Chey et al., American Journal of Gastroenterology, 2012, 107(11):1702–1712). A parallel 12-week trial with a 4-week randomized withdrawal period (NCT00948818) in 800 patients found 33.6% versus 21.0% on the same endpoint (P < 0.0001; number needed to treat 8.0); patients re-randomized to placebo saw symptoms return without rebound below baseline, and 5.7% versus 0.3% discontinued for diarrhea (Rao et al., American Journal of Gastroenterology, 2012, 107(11):1714–1724).

Low-dose CIC. A 12-week Phase 3 trial in 1,223 adults with CIC compared 72 mcg and 145 mcg with placebo. The 72 mcg dose met the CSBM overall-responder endpoint in 13.4% of patients versus 4.7% on placebo (P < 0.0001; 12.4% on 145 mcg), with discontinuation for diarrhea in 2.4% versus 3.2% on 145 mcg and 0% on placebo (Schoenfeld et al., American Journal of Gastroenterology, 2018, 113(1):105–114). The FDA approved the 72 mcg dosing regimen for CIC on January 25, 2017.

Pediatric program (NCT04026113 and related studies). The Phase 3 study NCT04026113 enrolled 438 children aged 6–17 with either functional constipation or IBS-C. Its functional-constipation arm, run at 64 sites in seven countries, randomized 330 children to linaclotide 72 mcg or placebo for 12 weeks. Spontaneous bowel movement frequency rose by a least-squares mean of 2.22 per week on linaclotide versus 1.05 on placebo (difference 1.17; 95% CI 0.65–1.69; P < 0.0001), and stool consistency also improved. Diarrhea was reported in 4% versus 2%; one 17-year-old was hospitalized for severe diarrhea with dehydration and recovered with intravenous fluids (Di Lorenzo et al., Lancet Gastroenterology & Hepatology, 2024, 9(3):238–250). The IBS-C arm (children 7–17, 145 mcg or a higher dose) has been reported only in the FDA label: of 108 randomized, 30% of the 53 evaluated on 145 mcg met a combined pain-and-stool responder definition (95% CI 18–44%), and the higher dose added no benefit. The supporting Phase 2 work was published as three 2024 papers in the Journal of Pediatric Gastroenterology and Nutrition: a 4-week dose-ranging study in 101 children aged 7–17 with IBS-C (NCT02559817, listed as terminated on the registry; 78(3):539–547), a dose-ranging study in 173 children aged 6–17 with functional constipation (78(5):1059–1068), and a 4-week study in 35 children aged 2–5 with functional constipation (NCT04110145; 79(3):510–518). A Phase 3 study in children aged 2–5 with functional constipation (NCT05652205, 123 participants, primary completion September 2025; 62 on 72 mcg versus 61 on placebo, SBM change 2.1 versus 1.4 per week, 95% CI for the difference 0.03–1.31 in the label’s account) supported the youngest indication.

Regulatory record (Drugs@FDA, NDA 202811). Original approval August 30, 2012 (adult IBS-C and CIC); 72 mcg CIC dosing regimen January 25, 2017; pediatric functional constipation ages 6–17 on June 12, 2023 (priority review); pediatric IBS-C ages 7 and older on November 4, 2025, which the FDA described as the first approved treatment for pediatric IBS-C, with the functional-constipation upper age limit removed in the same revision (the November 2025 label reads “6 years of age and older”); functional constipation extended down to age 2 on May 21, 2026, under priority review. The current label is revised 10/2026 and lists three indications: IBS-C in adults and pediatric patients 7 years and older, CIC in adults, and functional constipation in pediatric patients 2 years and older. In the European Union, Constella received marketing authorization on November 26, 2012 for moderate to severe IBS-C in adults, as a 290 mcg capsule. In Japan, Linzess Tablets 0.25 mg (Astellas) were approved on December 19, 2016 for IBS-C and on August 21, 2018 for chronic constipation.

MD-7246 — a failure. A delayed-release linaclotide formulation designed to deliver the peptide to the colon as a non-opioid visceral analgesic without a laxative effect was tested in 515 adults with diarrhea-predominant IBS (NCT03931785; 300, 600, or 1,200 mcg once daily for 12 weeks, or placebo). In May 2020 the sponsors reported that the Phase 2 trial missed its primary and key secondary abdominal-pain endpoints, and Ironwood’s second-quarter 2020 report confirmed that Ironwood and AbbVie were discontinuing development. The posted results show why: 6-of-12-week pain responders were 55.7% on placebo versus 56.7%, 44.3%, and 48.5% on the three doses, with every confidence interval spanning zero. The analgesic mechanism did not translate to a population without constipation.

Active work. ClinicalTrials.gov currently lists investigator-initiated studies of linaclotide as a single-agent colonoscopy bowel preparation (NCT06692673, Phase 1/2, recruiting), in type 2 diabetics with chronic constipation (NCT03119584, Phase 4, 23 enrolled, active but not recruiting), as a chemoprevention candidate in stage 0–III colorectal cancer (NCT03796884, Phase 2, 150 enrolled, active but not recruiting), and an early-phase proof-of-principle study in cystic fibrosis (NCT07569419, recruiting). None of these has reported efficacy results, and no new molecular indication is pending at the FDA.

Common dosage forms

• Oral capsules (approved product) — hard gelatin capsules in three strengths: 72 mcg, 145 mcg, and 290 mcg, each containing linaclotide-coated beads; the label describes an alternative for patients who cannot swallow capsules. The 72 mcg strength is the one used for pediatric functional constipation and low-dose adult CIC; 145 mcg for adult CIC and pediatric IBS-C; 290 mcg for adult IBS-C.
• Oral tablets abroad — in Japan, linaclotide is supplied as a 0.25 mg tablet; the EU product is a 290 mcg capsule.
• Delayed-release formulation — MD-7246 reached Phase 2 and was discontinued; it is not a marketed format.
• Research supply — where it appears in reagent catalogs, it is as lyophilized linaclotide (CAS 851199-59-2 for the peptide; suppliers often list it as the acetate salt) in milligram vials for in vitro and animal work. Approved products are dosed in micrograms orally; a milligram vial holds a quantity of a different order than any single approved dose and is not formulated for oral delivery.

Key considerations

• The boxed warning was narrowed, not removed. It is sometimes described as having been removed; the labeling record says otherwise. At launch the box applied to all patients under 18 and the contraindication to those under 6, and the April 2021 label still read that way. On August 24, 2021, the FDA approved a revised label that narrowed both to patients under 2 years of age, and the current label (revised 10/2026) still carries a boxed warning titled “Risk of serious dehydration in pediatric patients less than 2 years of age,” grounded in neonatal mouse studies in which a single clinically relevant adult dose caused deaths from dehydration. Linaclotide is also contraindicated in known or suspected mechanical gastrointestinal obstruction.
• Diarrhea is the characteristic adverse effect, and it is dose-related. Across the Phase 3 program, diarrhea was the most common adverse event and the main reason for discontinuation (roughly 4–6% on 290 mcg in IBS-C, 2.4% on 72 mcg in CIC). Severe diarrhea with dehydration requiring hospitalization has occurred in both adult and pediatric trials and in post-marketing reports; the label directs stopping the drug and rehydrating if severe diarrhea develops. The label’s GC-C ontogeny data show no age-dependent trend in intestinal GC-C expression from age 2 to under 18, but insufficient data below age 2, which is the basis for the current contraindication.
• The approval is real and current, and the molecule is a peptide. Linaclotide’s FDA Approved status reflects three approved indications under NDA 202811, the most recent in May 2026. It is a genuine 14-residue peptide, but its oral route and minimal absorption set it apart from the injectable peptides it is sometimes grouped with; it is not a systemic hormone analog and has no studied role outside the gastrointestinal tract.
• Evidence gaps. Long-term controlled data beyond 26 weeks are limited to open-label safety extensions (a pediatric long-term safety study, NCT04166058, enrolled 381 children and reached primary completion in June 2025; no peer-reviewed publication had appeared as of November 2026, and the Phase 3 pediatric IBS-C arm is likewise described only in the label). Responder rates in the pivotal trials were modest in absolute terms (roughly 16–21% versus 3–6% for CIC; 34% versus 14–21% for IBS-C), and the visceral-analgesic mechanism did not produce pain relief in IBS-D when the laxative effect was engineered away.
• Naming confusions. Linaclotide is distinct from plecanatide (Trulance), a uroguanylin analog that activates the same GC-C receptor and is often described as a class sibling, and from lubiprostone, a chloride-channel activator with a different target. The brand names Linzess (U.S., Japan) and Constella (EU, Canada) refer to the same molecule; the development codes MD-1100 (Ironwood) and ASP0456 (Astellas) also do, while MM-419447 is the active metabolite, not the parent drug. MD-7246 was a different formulation of the same peptide and is discontinued.