What Is Apraglutide?

1. What is apraglutide, and how was it designed?

GLP-2 is a 33-amino-acid hormone released by the gut after eating. It promotes growth of the intestinal lining and improves absorption by acting on the GLP-2 receptor, which sits mostly in the gut. Natural GLP-2 lasts only minutes in the blood, which makes it useless as a medicine. The teduglutide page explains the hormone and how it relates to GLP-1.

Apraglutide came out of a medicinal chemistry program described by Wiśniewski and colleagues in 2016. The team made a series of GLP-2 analogs with a glycine at position 2, the same change that protects teduglutide from breakdown, plus a norleucine at position 10 and other substitutions at positions 11 and 16. The goal was a molecule that was:

• more potent at the human GLP-2 receptor than the natural hormone;
• selective, with little action at the GLP-1 and glucagon receptors;
• cleared very slowly from the body.

The compound selected for development was FE 203799, later named apraglutide. According to Bolognani and colleagues, compared with natural GLP-2 it is absorbed more slowly, cleared less and bound more to blood proteins, which allows weekly dosing.

2. What do the early studies show?

In healthy volunteers

In a study of 24 healthy adults given six weekly injections of 1, 5 or 10 mg or placebo, blood citrulline rose with dose. Citrulline is an amino acid made by intestinal lining cells and is used as a marker of how much working gut a person has. Modeling suggested that 5 mg weekly produced the maximal citrulline response, and citrulline stayed raised for 10 to 17 days after the last dose.

In kidney and liver impairment

Kidney and liver problems are common in intestinal failure. In single-dose studies, people with severe kidney impairment and those with moderate liver impairment did not have higher exposure than healthy controls, and the authors concluded no dose change would be needed. That differs from teduglutide, whose label halves the dose when kidney function is reduced (Gattex label).

In a phase 2 absorption study

Verbiest and colleagues treated 9 adults with short bowel syndrome and the colon still connected for 52 weeks, measuring everything that went in and came out in metabolic balance studies.

The study had no control group and only nine patients. Its main outcome was safety; 127 adverse events were recorded, mostly mild to moderate. In a neonatal piglet model, the compound also lengthened the intestine, which the authors said they had not seen with native GLP-2 in the same model.

3. What did the STARS phase 3 trial find?

STARS was a global, double-blind, placebo-controlled trial published by Joly and colleagues in Clinical Gastroenterology and Hepatology in 2026 (registry entry NCT04627025, completed February 2024). It randomized 163 adults with short bowel syndrome and intestinal failure two to one to weekly apraglutide or placebo, split by bowel anatomy: 80 with a stoma and 83 with the colon in continuity. According to AGA’s summary of the paper, patients had less than 200 cm of small bowel, needed IV support at least 3 days a week, started at about 13 L a week, and were treated at 68 centers. Stoma patients were treated for 24 weeks and colon-in-continuity patients for 48.

In absolute terms, AGA’s summary puts the week 24 reduction at about 2.9 L a week on apraglutide and 1.5 L on placebo, with separation from placebo as early as week 8. Seven people on apraglutide and none on placebo had come off IV support entirely by week 24, which was not significant in the prespecified analysis.

Why the colon matters

People whose colon is still connected absorb some fluid and energy through the colon and tend to adapt better on their own. That raises the placebo response and makes a drug effect harder to show, which is one plausible reason the colon-in-continuity results were not significant. It also matters for any future label, since roughly half of the trial population had this anatomy.

4. What went wrong with dosing, and what is STARS-2?

On April 14, 2025, Ironwood announced that a pharmacokinetic analysis done while preparing its US application had found that drug exposure and delivered dose in STARS were lower than planned, which it attributed to “dose preparation and administration.” After discussing this with the FDA, it said a confirmatory phase 3 trial would be needed.

The published paper spells out the gap. Patients weighing 50 kg or more received about 3.5 mg instead of the protocol’s 5 mg, and those under 50 kg about 1.4 mg instead of 2.5 mg, because of dilution and volume loss when doses were made up (AGA summary). In other words, STARS was positive even though patients received less drug than the protocol called for.

Ironwood says it aligned with the FDA on the design in late 2025 (full-year 2025 results).

In its November 5, 2026 results, Ironwood said STARS-2 was “ongoing,” that it was still adding US sites, that all planned international clinical trial applications had been submitted and were under review or approved, and that, subject to the results, it “plans to file for regulatory approval in 2029.” That puts any approval several years away.

The long-term extension, STARS Extend, enrolled 158 patients and is listed as active but not recruiting, with completion estimated for October 2027. Ironwood’s April 2025 release said 27 patients in the extension had reached enteral autonomy; that figure has not been published in a journal.

5. Who owns apraglutide?

Apraglutide was developed by VectivBio, a Swiss company. Ironwood, best known for the constipation drug Linzess, bought VectivBio in 2023 through a tender offer and completed the squeeze-out of remaining shares on December 12, 2023 (Ironwood).

6. What are the side effects?

STARS reported safety in broad terms (AGA summary):

The most common events were nausea, headache and central venous catheter infection. Catheter infections reflect the IV lines patients rely on rather than a direct drug effect. One patient on apraglutide with pre-existing heart disease died suddenly, and investigators judged the death unrelated to treatment.

Because apraglutide was under-dosed in STARS, its safety at the intended dose is still being tested in STARS-2. The class-wide concerns seen with teduglutide also apply: growth of the gut lining raises questions about polyps and tumors, and better absorption means IV volumes must be lowered to avoid fluid overload. The teduglutide label requires colonoscopies and gallbladder and pancreas monitoring for those reasons (Gattex label). Any apraglutide label would set its own rules.

7. Was apraglutide tested in other diseases?

GLP-2 protects the cells lining the gut, including the stem cells that renew it, which made it a candidate for graft-versus-host disease of the gut, a serious complication of bone marrow transplants (Zeiser et al., 2023). A phase 2 trial enrolled 31 people with steroid-refractory gastrointestinal acute graft-versus-host disease and tested weekly doses from 1.4 to 7.6 mg alongside best available therapy. ClinicalTrials.gov lists it as terminated in December 2024, with “company decision” as the reason. We found no published efficacy results.

8. How does apraglutide compare with other GLP-2 drugs?

No head-to-head trials exist, so this compares programs, not results.

The pivotal trials measured response differently, in percent, liters or responder rates, and enrolled different populations, so the numbers cannot be lined up directly.

9. Is apraglutide relevant to people on GLP-1 drugs?

Only indirectly. Apraglutide’s parent compound was selected for selectivity over the GLP-1 receptor (Wiśniewski et al.), so it is not expected to reduce appetite, lower blood sugar or cause weight loss like semaglutide or tirzepatide. Its purpose is the opposite: helping a short gut absorb more of what a person eats.

Some practical points:

• Overlapping symptoms. Nausea was among the most common side effects in STARS, and nausea is the best-known side effect of GLP-1 drugs.
• Opposing aims. Reduced food intake on a GLP-1 drug could undercut efforts to wean someone off IV nutrition.
• No combination data. No published trial has paired apraglutide with a GLP-1 drug. Zealand’s dapiglutide, a single molecule aimed at both receptors, was paused in November 2025.

10. What questions are still open?

STARS answered whether weekly GLP-2 dosing can work. Several questions remain for STARS-2 and the extension studies to settle:

• The right dose. STARS patients got roughly 70% of the planned 5 mg dose, or about 56% of 2.5 mg in lighter patients. Whether the intended dose gives a larger effect, more side effects, or both, is not yet known.
• Colon-in-continuity patients. This group made up about half of STARS and did not show a significant benefit at the dose delivered. A future label could depend on whether STARS-2 changes that.
• Long-term safety. STARS Extend is designed to follow patients for up to 208 weeks, and its results are not yet published in full. Colon polyp and tumor monitoring data will matter for any approval, as they did for teduglutide.
• Real-world fit. Weekly dosing could reduce the burden of daily injections. Whether that improves adherence or outcomes in routine care has not been studied.
• Comparisons. No trial has compared apraglutide with teduglutide or glepaglutide, and none is listed in the registry records we checked.

Until those answers arrive, apraglutide remains an experimental drug with one positive but complicated phase 3 trial behind it.

11. What can be tracked in an apraglutide trial?

Trial participants and their teams follow the same measures the trials used:

• IV support. Weekly volume and number of infusion days, with each change dated.
• Fluid balance. Urine output, stoma or stool output, weight and swelling.
• Dose log. The weekly injection day and site, and any missed or late doses. In a weekly schedule, one late dose shifts the whole week, and STARS showed how much delivered dose can matter.
• Labs. Citrulline if measured, electrolytes, kidney and liver tests.
• Symptoms. Nausea, abdominal pain, line problems and fevers.

A peptide tracker or spreadsheet can hold that record. It does not replace the specialist team’s judgment on when IV support can safely be reduced. Apraglutide is available only through clinical trials.

12. Apraglutide FAQ

• Is apraglutide FDA approved?

  No. It is investigational. In April 2025 Ironwood said the FDA had indicated a confirmatory phase 3 trial was needed. That trial, STARS-2, is recruiting, and in November 2026 Ironwood said it plans to file for approval in 2029, subject to the results.

• What did the STARS trial show?

  Across 163 adults with short bowel syndrome and intestinal failure, once-weekly apraglutide reduced weekly IV support by 25.5% from baseline at 24 weeks, against 12.5% on placebo. In people with a stoma the reduction was 25.6% against 7.8%. In people with the colon still connected, the differences were not statistically significant.

• Why does apraglutide need another trial?

  While preparing its application, Ironwood found that drug exposure in STARS was lower than planned because of how doses were prepared and administered. Doses were reduced by dilution and volume loss when the injections were made up. After discussions with the FDA, the company said a confirmatory phase 3 trial was needed.

• How is apraglutide different from teduglutide?

  Both are GLP-2 analogs. Teduglutide clears in about 2 hours and is injected daily. Apraglutide was designed with slower absorption, lower clearance and higher protein binding so it can be given once a week. No head-to-head trial has compared them.

• What are the side effects of apraglutide?

  In STARS, 89% of people on both apraglutide and placebo had an adverse event. Serious events occurred in 36% on apraglutide and 32% on placebo. Nausea, headache and central line infections were among the most common. One sudden death in a patient with existing heart disease was judged unrelated to treatment.

• Is apraglutide a GLP-1 drug?

  No. Its parent compound was built to activate the GLP-2 receptor with high selectivity over the GLP-1 and glucagon receptors. GLP-2 helps the gut absorb more; it does not reduce appetite or body weight the way GLP-1 drugs do.

• Was apraglutide tested for anything besides short bowel syndrome?

  Yes. A phase 2 trial tested it in steroid-refractory gastrointestinal graft-versus-host disease, a transplant complication. ClinicalTrials.gov lists that trial as terminated in December 2024 for a company decision. Short bowel syndrome is the program Ironwood is pursuing.

13. Sources