Apraglutide

Origin and structure

Apraglutide is a synthetic analogue of GLP-2 (glucagon-like peptide-2), a hormone that L-cells in the gut lining release after a meal and that helps the intestine grow and absorb. The natural hormone is broken down within minutes, about 7 in people, largely by the enzyme DPP-4. Apraglutide has the same length of 33 amino acids but differs at four positions: glycine replaces alanine at position 2, as in the approved analogue teduglutide, to resist DPP-4, and norleucine, D-phenylalanine and leucine replace the amino acids at positions 10, 11 and 16. The chain also ends in an amide. According to the developer, these changes make it bind more strongly to blood proteins and leave the injection site more slowly, so that it is cleared very slowly. In rats given an intravenous dose its half-life was 159 minutes, against 19 for teduglutide and 6.4 for natural GLP-2.

Ferring Pharmaceuticals designed the peptide under the code FE 203799, and Ferring's research institute in San Diego published its pharmacology. Ferring licensed it to GlyPharma Therapeutic, which started the first trials in patients and which the rare-disease company Therachon bought in September 2018. When Pfizer bought Therachon in 2019, the apraglutide programme was split off on 1 July 2019 into a new company in Basel, VectivBio, which ran the later trials, STARS included, and licensed the Japanese rights to Asahi Kasei Pharma in March 2022. Ironwood Pharmaceuticals, the Boston company behind the constipation drug linaclotide (Linzess), acquired VectivBio in June 2023. Apraglutide is made synthetically; in the trials so far it was supplied as a freeze-dried powder that had to be dissolved before injection.

How it works

Apraglutide activates the GLP-2 receptor, with a potency and selectivity in cell tests comparable to those of the natural hormone. GLP-2 signalling makes the intestinal lining grow, with taller villi and deeper crypts, increases blood flow to the gut, slows the passage of food and reduces acid secretion in the stomach. Together these give the remaining bowel more surface and more time to absorb fluid and nutrients. GLP-2 comes from the same precursor protein as GLP-1 but acts on a different receptor: apraglutide is not a diabetes or weight-loss drug like semaglutide.

The condition it is developed for is short bowel syndrome. After surgery for Crohn's disease, a blocked blood supply to the bowel, trauma or cancer, too little small intestine may be left to absorb enough food and fluid. People with intestinal failure depend on parenteral support, nutrition and fluids given by drip into a central vein; the trials required it on at least three days a week. Long-term parenteral support carries risks such as line infections and liver and kidney damage. When apraglutide received its EU orphan designation in 2018, short bowel syndrome affected about 0.6 in 10,000 people in the EU. Trials split patients into two groups: those with a stoma, whose remaining small bowel ends at the skin, and those with a colon in continuity, whose small bowel is still joined to the large bowel.

In healthy volunteers apraglutide raised plasma citrulline, an amino acid made by the cells of the intestinal lining and used as a marker of their mass. A weekly dose of 5 mg gave the largest response, and citrulline stayed raised for 10 to 17 days after the last injection.

Is apraglutide approved?

No. Apraglutide is not authorised as a medicine anywhere. In the EU it was designated an orphan medicine for short bowel syndrome on 19 November 2018 (EU/3/18/2102), and Ironwood reports orphan drug designation in the US as well. An orphan designation brings incentives for development but is not a marketing authorisation, and Ironwood has not announced an application to the EMA.

In the Netherlands it is not a registered medicine and can only be given within a clinical trial. STARS had no Dutch sites; the STARS-2 record on ClinicalTrials.gov lists Radboudumc in Nijmegen among its planned sites. DutchPeptides does not sell apraglutide.

• STARS and the US filing: in February 2024 Ironwood announced that STARS had met its primary endpoint, and in January 2025 it began a rolling new drug application to the FDA.
• Less drug than planned: while preparing that application, a pharmacokinetic analysis showed that the exposure and dose patients received in STARS were lower than planned, because of the way doses were prepared and injected. On 14 April 2025 Ironwood announced that, after talks with the FDA, a confirmatory phase 3 trial was needed before approval could be sought. Ironwood has said it expects the STARS data to remain part of an eventual application.
• STARS-2: Ironwood and the FDA agreed on its design in the fourth quarter of 2025, and by August 2026 the trial was recruiting. About 124 adults with short bowel syndrome and intestinal failure, with a stoma or a colon in continuity, are to receive weekly apraglutide or placebo for 24 weeks, with the same primary endpoint as STARS. The record lists 94 sites in 22 countries and expects the main phase to finish in October 2028.
• Japan: Asahi Kasei Pharma holds the rights to apraglutide in Japan, and STARS included Japanese sites.
• Sport: WADA class S0 prohibits at all times any substance that no other section of the list covers and that has no current approval for human therapeutic use, explicitly including drugs still in clinical development. Apraglutide is not named, but falls under this class for as long as it is approved nowhere. In the Netherlands the Dopingautoriteit applies the same list.

What the research shows

All human data come from trials funded by VectivBio or Ironwood: phase 1 studies in healthy volunteers and in people with impaired kidney or liver function, three small phase 2 studies in short bowel syndrome, one randomised phase 3 trial and its open-label extension. Only STARS and one phase 2 study compared apraglutide with placebo. The main results:

• Phase 1 in the Netherlands (Bolognani et al., J Pharmacol Exp Ther 2023): 24 healthy volunteers at the Centre for Human Drug Research in Leiden received 1, 5 or 10 mg or placebo once a week for 6 weeks. Citrulline, the marker of intestinal cell mass, rose with the dose and peaked at 5 mg.
• Phase 2, placebo-controlled crossover (Eliasson et al., JPEN 2022): 8 adults with intestinal failure in Copenhagen received 4 weeks of placebo and 4 weeks each of 5 mg and 10 mg weekly. Urine output, a stand-in for fluid absorbed by the gut, rose by 714 and 795 ml a day more than on placebo, with no difference between the doses.
• Phase 1 and 2 metabolic balance study (Eliasson et al., JPEN 2022): 8 adults in Copenhagen, 4 with intestinal insufficiency and 4 with intestinal failure, received 5 mg weekly for 4 weeks without a placebo group. Measured in hospital, absorption of fluid rose by 741 g a day and of energy by 1,095 kJ a day.
• STARS Nutrition (Verbiest et al., Clin Nutr 2024): 9 adults with intestinal failure and a colon in continuity in Leuven and in Clichy, near Paris, treated for 52 weeks without a control group. Weekly parenteral support fell by 4,702 ml (52%), 7 of the 9 gained at least one day a week without it, energy absorption rose by 1,134 kJ a day, and on MRI the small bowel lengthened from 29.7 to 40.7 cm.
• STARS (Joly et al., Clin Gastroenterol Hepatol 2026): 163 adults with intestinal failure (80 with a stoma, 83 with a colon in continuity) at 68 centres in 18 countries, randomised 2 to 1 to weekly apraglutide or placebo, 2021 to 2024. After 24 weeks weekly parenteral support had fallen by 25.5% against 12.5% on placebo (P = 0.001), and in the stoma group by 25.6% against 7.8%. 43.0% against 27.5% needed it on at least one day a week fewer. In the colon group at 48 weeks, the differences in the share with at least one day a week fewer (51.8% against 44.4%) and in the share fully free of parenteral support (12.5% against 7.4%) were not statistically significant.
• Dose in STARS: the protocol set 5 mg for people of 50 kg or more and 2.5 mg below 50 kg, but because of dilution and volume loss during preparation patients received about 3.5 mg and 1.4 mg. The authors note that the 1.4 mg dose in the lightest group, which included 15 people on apraglutide, may have influenced the results.
• STARS Extend: in the open-label extension, which 158 people entered and which is still running, Ironwood reported in early 2025 that 27 patients on apraglutide no longer needed any parenteral support. Without a control group this figure cannot be credited to the drug alone.
• Other uses: a phase 2 trial in acute graft-versus-host disease of the gut after stem cell transplantation was stopped by company decision in December 2024 after 31 participants. Apraglutide lengthened the remaining bowel in newborn piglets after removal of 75% of the intestine, and protected the gut in mice after chemotherapy and transplantation; these are animal data only.

Side effects and safety

In STARS, adverse events were reported by 89% of participants in both groups, and serious adverse events by 36% on apraglutide against 32% on placebo; nausea, headache and central-line infections were among the most frequent. In Ironwood's analysis, nausea occurred in 13.6% against 11.3%, stoma complications in 7.3% against 3.8% and bowel polyps in 3.6% against 3.8%, all of which could be removed at colonoscopy. There were no cases of complete bowel obstruction and no cancers. One participant on apraglutide died of sudden cardiac death, which was judged unrelated to treatment.

In the small trials, frequent treatment-related events were changes in stoma output and other stoma problems, nausea, flatulence, more urine, less thirst, swelling from fluid retention and abdominal pain. In STARS Nutrition, 3 of the 9 participants had serious adverse events, among them acute pancreatitis and inflammation of the bile ducts; the trial registry does not say whether these were related to apraglutide.

Because GLP-2 makes intestinal tissue grow, the US label of the approved analogue teduglutide warns that it may speed the growth of existing polyps or tumours, and also warns of bowel obstruction, gallbladder, bile-duct and pancreatic disease and fluid overload. STARS-2 therefore requires a colonoscopy or CT or MRI colonography, with removal of any polyps, before entry, and excludes people with cancer in the past five years or hereditary polyposis. Data on longer treatment come only from the uncontrolled extension study, which is still running.

Apraglutide, teduglutide and glepaglutide

Teduglutide is the only GLP-2 analogue authorised in the EU or the US: as Revestive in the EU since 30 August 2012 and as Gattex in the US since December 2012, both now from Takeda, and in the EU since January 2026 also as the generic Teduglutide Viatris. It differs from the natural hormone by one amino acid and is injected once a day, at a dose based on body weight. Apraglutide was built to last long enough for one injection a week. No trial has compared the two directly, so their effects cannot be ranked: the trials differ in design, patients and the way parenteral support was reduced.

Glepaglutide, from Zealand Pharma, is another long-acting GLP-2 analogue, given twice a week in its main trial. Its path resembles apraglutide's: in December 2024 the FDA turned down Zealand's US application and asked for a second placebo-controlled trial, EASE SBS 5, which started in February 2026. In the EU, however, the EMA's medicines committee recommended authorising it as Zeydovio on 17 September 2026; the final decision rests with the European Commission. In a laboratory comparison by apraglutide's developers, apraglutide and teduglutide kept the potency and selectivity of natural GLP-2 at its receptor, while glepaglutide was less potent and less selective; scientists from Zealand responded to that comparison with a published comment.

Frequently asked questions

What is apraglutide used for?

It is being developed for adults with short bowel syndrome and intestinal failure: people who, after losing much of their small intestine, depend on intravenous nutrition and fluids. The aim is to make the remaining bowel absorb more, so that less intravenous support is needed. Outside clinical trials it is not available as a medicine.

Is apraglutide approved, and when could it come on the market?

It is approved nowhere. After STARS, the FDA asked for a confirmatory phase 3 trial, STARS-2, which Ironwood started in 2026; ClinicalTrials.gov expects its main phase to finish in October 2028. An application would follow those results, and Ironwood has not given a date or announced an application in the EU.

Why did the FDA ask for another trial?

While Ironwood was preparing its application, analyses showed that STARS participants had received less apraglutide than planned, because of dilution and volume loss when the injections were prepared: about 3.5 mg instead of 5 mg, and 1.4 mg instead of 2.5 mg in people under 50 kg. After talks with the FDA, Ironwood announced in April 2025 that a confirmatory trial was needed. STARS-2 uses 3.5 mg with revised preparation instructions.

Is apraglutide a GLP-1 drug like Ozempic?

No. The names look alike, but apraglutide mimics GLP-2, a sister hormone of GLP-1 that acts on a different receptor. GLP-2 makes the intestinal lining grow and absorb more. Apraglutide is not a blood-sugar or appetite drug like semaglutide, and it is not being developed for weight loss.

What is the difference between apraglutide and teduglutide (Revestive)?

Both mimic GLP-2. Teduglutide has been an authorised medicine in the EU since 2012 and is injected every day; apraglutide is still experimental and designed for one injection a week. No trial has compared them directly, so it is not known whether either works better.

Is apraglutide legal in the Netherlands, and is it allowed in sport?

It is not a registered medicine in the Netherlands or anywhere else, so it may not be sold, advertised or supplied for use in people; patients can only receive it in a clinical trial. DutchPeptides does not sell it. For athletes under anti-doping rules it is prohibited at all times as a non-approved substance (WADA class S0), which the Dopingautoriteit applies in the Netherlands.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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