Apraglutide

A synthetic, long-acting glucagon-like peptide-2 analog from Ironwood Pharmaceuticals, dosed once weekly, that reduced parenteral-support volume in the phase 3 STARS trial in short bowel syndrome but must repeat the result in the confirmatory STARS-2 trial, which began enrolling in June 2026, before Ironwood files.

Also referenced as: FE 203799, FE203799

Also appears in: Metabolic

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What is Apraglutide?

Apraglutide (development code FE 203799) is a synthetic 33-amino-acid analog of human glucagon-like peptide-2 (GLP-2), the intestinotrophic hormone that intestinal L-cells cut from the same proglucagon precursor that yields glucagon and GLP-1. It was engineered at Ferring’s research institute with four substitutions relative to native GLP-2 (glycine at position 2, the same change that defines teduglutide, plus norleucine at position 10, D-phenylalanine at position 11, and leucine at position 16) and a C-terminal amide, a combination that produces very low clearance and high plasma protein binding and allows once-weekly rather than once-daily injection. The program originated at Ferring and is now developed by Ironwood Pharmaceuticals; VectivBio AG, an Ironwood subsidiary, remains the sponsor of record on the trial registrations.

Apraglutide is in clinical development for short bowel syndrome with intestinal failure (SBS-IF), the same indication teduglutide is approved for, and was explored in steroid-refractory gastrointestinal acute graft-versus-host disease before that program was wound down. It holds FDA orphan drug designation for short bowel syndrome (granted December 20, 2018) and for prevention of acute graft-versus-host disease (May 25, 2021), and a European orphan designation for short bowel syndrome (EU/3/18/2102, November 19, 2018). It has essentially no presence on the research-peptide market.

How it works

• Selective GLP-2 receptor agonism. Apraglutide activates the GLP-2 receptor with potency and selectivity comparable to native human GLP-2, whereas the competing long-acting analog glepaglutide was less potent and less selective in the same assays (Hargrove et al., Journal of Pharmacology and Experimental Therapeutics, 2020;373(2):193–203). The receptor sits on enteroendocrine cells, subepithelial myofibroblasts, and enteric neurons rather than on absorptive enterocytes, so the growth signal to the mucosa is indirect, mediated by local release of factors such as IGF-1 and keratinocyte growth factor.
• Pharmacokinetics built for weekly dosing. In rat intravenous studies, apraglutide’s clearance was 0.27 mL/kg/min against 9.9 for teduglutide and 25 for native GLP-2, with an elimination half-life of 159 minutes against 19 and 6.4 minutes, respectively; the profile was confirmed in monkey and minipig, and in rats the long half-life translated into greater small-intestinal growth at less frequent dosing intervals (Hargrove et al., Journal of Pharmacology and Experimental Therapeutics, 2020). In healthy adults given six weekly subcutaneous doses, estimated clearance was 16.5–20.7 L/day and the rise in plasma citrulline, a marker of enterocyte mass, persisted 10–17 days after the final dose (Bolognani et al., Journal of Pharmacology and Experimental Therapeutics, 2023;386(2):129–137).
• Mucosal expansion and absorption. In nine adults with SBS-IF and colon-in-continuity treated for 52 weeks, MRI-measured small bowel length increased from 29.7 to 40.7 cm, duodenal wall thickness increased by 0.8 mm, proximal colonic motility slowed, and wet-weight and energy absorption rose by 316 g/day and 1,134 kJ/day at week 48 (Verbiest et al., Clinical Nutrition, 2024;43(12):158–166). In an earlier metabolic balance study, four weeks of weekly dosing raised wet-weight absorption by 741 g/day and energy absorption by 1,095 kJ/day (Eliasson et al., JPEN Journal of Parenteral and Enteral Nutrition, 2022;46(7):1639–1649).
• Fluid retention as the pharmacodynamic readout. Because the remnant intestine absorbs more, urine output rises: in a placebo-controlled crossover trial, weekly apraglutide increased urine volume by an adjusted 714–795 mL/day over placebo, with no significant difference between the two doses tested (Eliasson et al., JPEN Journal of Parenteral and Enteral Nutrition, 2022;46(4):896–904).

Research status

Apraglutide has a completed pivotal phase 3 trial, a published positive primary endpoint, and no approval anywhere. The regulatory path reset in 2025 and now runs through a second phase 3 trial that began enrolling in June 2026.

Phase 2 (Copenhagen). Two small investigator-led trials established the human pharmacology. A placebo-controlled, double-blind, randomized crossover trial in eight adults with SBS-IF compared weekly 5 mg and 10 mg apraglutide with placebo over four-week periods; safety was the primary endpoint, treatment-related adverse events were mild to moderate (polyuria, decreased stoma output, stoma complications, decreased thirst, edema), no serious adverse event was judged drug-related, and urine output rose significantly on both doses (Eliasson et al., JPEN Journal of Parenteral and Enteral Nutrition, 2022;46(4):896–904). An open-label phase 1/2 metabolic balance trial in eight patients, four with SBS intestinal insufficiency and four with intestinal failure, confirmed increased wet-weight, energy, sodium, and potassium absorption after four weekly 5 mg doses; the one treatment-related serious adverse event was abdominal pain (Eliasson et al., JPEN Journal of Parenteral and Enteral Nutrition, 2022;46(7):1639–1649).

STARS Nutrition (NCT04964986). A multicenter, open-label, 52-week phase 2 metabolic balance study that enrolled ten and treated nine adults with SBS-IF and colon-in-continuity, completed June 6, 2023. Parenteral-support volume fell by 4,702 mL/week (52%, p < 0.001) at week 52, seven of nine patients gained at least one day per week off parenteral support, and MRI and absorption changes were recorded; 127 adverse events were logged, mostly mild to moderate (Verbiest et al., Clinical Nutrition, 2024;43(12):158–166). Open-label and uncontrolled, it is supportive rather than confirmatory.

STARS (NCT04627025), the pivotal trial. A global, double-blind, placebo-controlled phase 3 trial that randomized adults with parenteral-support-dependent SBS-IF 2:1 to once-weekly subcutaneous apraglutide or placebo, stratified by remnant anatomy (stoma versus colon-in-continuity); it ran from January 26, 2021 to February 22, 2024, and Ironwood announced topline results on February 29, 2024. Of 164 enrolled, 163 were randomized and dosed (80 stoma, 83 colon-in-continuity). The primary endpoint was met: mean relative change in weekly parenteral-support volume at week 24 was −25.5% on apraglutide versus −12.5% on placebo (p = 0.001), and the stoma subgroup showed −25.6% versus −7.8% (p < 0.001). The proportion achieving at least one day per week off parenteral support at week 24 was 43.0% versus 27.5% (p = 0.040). The colon-in-continuity key secondary endpoints at week 48 did not separate from placebo: at least one day off per week in 51.8% versus 44.4% (p = 0.348) and enteral autonomy in 12.5% (7 of 56) versus 7.4% (2 of 27) (nominal p = 0.387) (Joly et al., Clinical Gastroenterology and Hepatology, published online September 3, 2026). The effect was therefore clearest in patients with a stoma, and the week-48 colon-in-continuity outcomes were not statistically demonstrated. No results have been posted to the registry entry.

STARS Extend (NCT05018286). An open-label extension enrolling 158 patients from the STARS program, tracking safety out to 208 weeks or until commercial availability, with completion estimated for October 30, 2027. On January 29, 2025 and again on April 14, 2025, Ironwood reported that 27 apraglutide-treated patients who had been parenteral-support-dependent reached enteral autonomy in the extension, without stating a denominator. In May 2026 the company presented pooled safety data from STARS Nutrition, STARS, and STARS Extend at Digestive Disease Week, describing a long-term safety profile consistent with earlier studies and no new safety observations. These are sponsor disclosures and congress abstracts, not peer-reviewed results.

The 2025 regulatory reset. On January 29, 2025, Ironwood announced it had initiated a rolling New Drug Application for apraglutide in parenteral-support-dependent short bowel syndrome, with completion expected in the third quarter of 2025. On April 14, 2025, the company disclosed that pharmacokinetic analysis performed in preparation for that submission found that the exposure and dose actually delivered in STARS were lower than planned, attributed to dose preparation and administration, and that following dialogue with the FDA a confirmatory phase 3 trial would be needed to seek approval; the rolling submission was never completed, and the company’s annual report for 2025 describes the NDA only as something a confirmatory trial is needed to support. Ironwood met with the FDA in the fourth quarter of 2025 and reported alignment on key design elements of that trial.

STARS-2 (NCT07742735). On July 14, 2026, Ironwood announced that STARS-2 had been initiated in June 2026 and was actively recruiting. The trial was first posted on ClinicalTrials.gov on August 3, 2026, is listed as recruiting with a planned enrollment of 124 adults with SBS-IF, randomized 1:1 and double-blind to weekly subcutaneous apraglutide or placebo for 24 weeks, stratified by anatomy and baseline parenteral-support volume, with the same primary endpoint as STARS (relative change in weekly parenteral-support volume at week 24) and an estimated primary completion date of October 2028. Ironwood’s August 6, 2026 quarterly release repeated that the trial was enrolling and gave no timeline for topline data or an NDA; as of November 3, 2026 the company has disclosed no NDA under FDA review and no filing date.

Acute graft-versus-host disease. The FDA granted orphan drug designation for apraglutide in prevention of acute GVHD on May 25, 2021. STARGAZE (NCT05415410), a randomized, single-blind phase 2 proof-of-concept trial in 31 adults with grade II–IV steroid-refractory gastrointestinal acute GVHD on best available therapy, ran from May 25, 2022 to December 17, 2024 with safety as the primary endpoint; patients were assigned to a weight-based low-dose arm (15), a weight-based high-dose arm (15), or a fixed-dose arm for lower body weight (1). Interim data presented at the American Society of Hematology meeting in December 2024 reported a day-28 all-organ overall response rate of 58.1% and a complete response rate of 25.8%, with 11 fatal events assessed as unrelated to the drug (Zeiser et al., Blood, 2024;144(Suppl 1):100). A follow-up analysis comparing the trial’s apraglutide-plus-ruxolitinib patients with a MAGIC control cohort was presented in February 2025 (Zeiser et al., Transplantation and Cellular Therapy, 2025;31(2 Suppl):S278–S279). Ironwood announced on January 29, 2025 that it was winding down STARGAZE to concentrate on short bowel syndrome; the registry entry lists the trial as terminated by company decision, with results posted October 20, 2025 that record 10 deaths and note that administered doses were lower than protocol-specified because of dilution and injection-related volume loss. A 2018 phase 1b/2a lymphoma study of FE 203799 (NCT03417765) was withdrawn before enrolling anyone.

Common dosage forms

• Investigational subcutaneous injection. Supplied only to clinical-trial sites under the sponsor’s protocols. The pivotal trial used a vial presentation; a relative-bioavailability study in healthy volunteers (NCT06002555, completed September 22, 2023) compared a dual-chamber syringe presentation against that reference vial.
• Analytical reference material. Apraglutide acetate listed by laboratory-reagent suppliers for in vitro use.
• No approved presentation. No approved pharmaceutical presentation exists in any country.

Key considerations

• Regulatory status. The Investigational status reflects a completed phase 3 trial (STARS) with no marketing application under FDA review. The FDA asked for a confirmatory trial, STARS-2 (NCT07742735), which began enrolling in June 2026, and the rolling NDA opened in January 2025 was never completed.
• Dose-delivery caveat. Ironwood itself reported that the dose actually delivered in STARS was lower than intended because of how the drug was prepared and administered, and the posted STARGAZE results record the same problem. The −25.5% versus −12.5% result is real, but it is uncertain which exposure produced it, which is part of why a second trial was required.
• Efficacy was anatomy-dependent. The reduction in parenteral support was driven by patients with a stoma; in the colon-in-continuity subgroup, the week-48 secondary endpoints for days off support and enteral autonomy did not reach significance. The uncontrolled STARS Nutrition data in colon-in-continuity patients look stronger than the randomized comparison, which is the usual direction of open-label bias.
• Class safety signals. Fluid retention, edema, polyuria, and stoma complications recur across the apraglutide trials, and the approved comparator teduglutide carries label requirements for endoscopic surveillance because GLP-2 agonism can accelerate growth of existing gastrointestinal neoplasia. Apraglutide’s longer exposure per dose does not remove that mechanism, and its long-term safety is still being collected in STARS Extend. No controlled trial in people with an anatomically normal gut, no pediatric efficacy trial and no peer-reviewed publication of the GVHD results exist.
• Naming and class confusion. The “-glutide” suffix is shared with GLP-1 drugs such as semaglutide and liraglutide, but apraglutide acts on the GLP-2 receptor and has no weight-loss, appetite, or glycemic evidence. The development code FE 203799 reflects its Ferring origin.