Apraglutide
Medium EvidenceA long-acting, once-weekly glucagon-like peptide-2 (GLP-2) analog that boosts intestinal absorption in short bowel syndrome, aiming to reduce dependence on IV (parenteral) nutrition; in Phase 3 development with a confirmatory trial required by the FDA.
What It Is
Apraglutide (FE 203799), developed by Ironwood Pharmaceuticals (originating from VectivBio/Therachon), is a synthetic long-acting analog of glucagon-like peptide-2 (GLP-2), the gut hormone that drives growth and absorptive capacity of the intestinal lining. Like glepaglutide and the approved teduglutide (Gattex/Revestive), it is an intestinotrophic peptide developed for short bowel syndrome with intestinal failure (SBS-IF) — a rare condition in which loss of much of the small intestine forces patients to rely on parenteral support (intravenous nutrition and fluids). Apraglutide is engineered with a four-amino-acid substitution in native GLP-2 that resists DPP-4 degradation and raises plasma protein binding, extending its half-life to roughly 72 hours and enabling once-weekly subcutaneous dosing — versus daily injection for teduglutide. It works as a GLP-2 receptor agonist, increasing intestinal mucosal growth, villus height and blood flow so the remaining bowel absorbs more fluid and nutrients. In the pivotal Phase 3 STARS trial (164 adults randomized 2:1 to once-weekly apraglutide or placebo, stratified by stoma versus colon-in-continuity), apraglutide reduced weekly parenteral support volume by about 25.5% at 24 weeks versus 12.5% for placebo, with particularly strong effects in patients with colon-in-continuity; across long-term extension data, 27 patients achieved enteral autonomy (full independence from parenteral support). In April 2025 the FDA informed Ironwood that a confirmatory Phase 3 trial is required before approval — after concern that drug exposure in STARS was lower than planned due to dose preparation and administration — though STARS data will remain integral to the eventual application. Ironwood expected to begin the confirmatory trial in 2026. Apraglutide is an investigational prescription peptide for a specific disease, not an approved or self-administered wellness 'research peptide.'
Regulatory Status
Apraglutide (FE 203799, Ironwood Pharmaceuticals) is an investigational once-weekly GLP-2 analog for short bowel syndrome with intestinal failure. Its Phase 3 STARS trial met endpoints, but in April 2025 the FDA required a confirmatory Phase 3 trial before it will consider approval (citing lower-than-planned drug exposure in STARS); STARS data are expected to remain part of the eventual NDA. Ironwood planned to initiate the confirmatory trial in 2026. It is not approved or marketed and would be administered by prescription under specialist care.
Effective: June 2026
View FDA SourceWhy Researchers Study It
Apraglutide is studied because short bowel syndrome with intestinal failure leaves patients dependent on burdensome daily IV nutrition, with risks of line infections and liver complications. GLP-2 directly stimulates the remaining intestine to grow and absorb more, and apraglutide's DPP-4-resistant design gives it a long ~72-hour half-life that allows once-weekly dosing — the least frequent of the GLP-2 analogs (vs twice-weekly glepaglutide and daily teduglutide). Researchers are interested in its strong effect in patients with colon-in-continuity, its ability to wean some patients off parenteral support entirely, and whether the FDA-required confirmatory Phase 3 will reproduce the STARS result at the intended exposure.
Proposed Mechanisms
- Acts as a GLP-2 receptor agonist, mimicking the natural intestinal hormone glucagon-like peptide-2 (GLP-2)
- Stimulates growth of the intestinal mucosa — increasing villus height, crypt depth and absorptive surface area of the remaining bowel
- Increases intestinal and mesenteric blood flow to support nutrient and fluid uptake
- Slows gastric emptying and intestinal transit, improving absorption time
- Reduces the volume of parenteral (IV) nutrition and fluids patients require, in some cases enabling full enteral autonomy
- Engineered with a four-amino-acid substitution that resists DPP-4 breakdown and raises protein binding, extending half-life to ~72 hours for once-weekly dosing
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Clinical (Phase 3, STARS) | 164 adults with short bowel syndrome and intestinal failure randomized 2:1 to once-weekly subcutaneous apraglutide or placebo, stratified by stoma vs colon-in-continuity | Positive: ~25.5% reduction in weekly parenteral support volume at 24 weeks vs 12.5% for placebo; especially strong effect in colon-in-continuity patients | Source |
| Clinical (long-term extension) | Open-label extension of STARS in SBS-IF patients dependent on parenteral support | Supportive: 27 apraglutide-treated patients achieved enteral autonomy (full independence from parenteral support) | Source |
| Clinical pharmacology / Phase 2 (metabolic balance) | Open-label Phase 1/2 metabolic balance studies of intestinal fluid and energy absorption; ~72-hour half-life supporting once-weekly dosing | Positive: improved intestinal fluid and energy absorption; DPP-4-resistant long half-life confirmed | Source |
| Regulatory (U.S. FDA) | Rolling NDA review for SBS-IF | Pending: FDA required a confirmatory Phase 3 trial (April 2025) before approval; STARS data to remain part of the eventual NDA | Source |
Commonly Discussed Benefits
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Safety & Cautions
- An investigational, unapproved peptide — the FDA has required an additional confirmatory Phase 3 trial before it will consider approval; it is not available outside clinical development
- Intended only for short bowel syndrome with intestinal failure under specialist (gastroenterology/nutrition) care — not a general wellness or self-experimentation peptide
- GLP-2 analogs are intestinotrophic (they stimulate cell growth), so they require monitoring for intestinal polyps/neoplasia and carry class warnings; colonoscopy and surveillance are part of treatment
- Reported GLP-2-class side effects include gastrointestinal symptoms (abdominal pain, swelling/stoma changes), fluid overload, and potential gallbladder, biliary and pancreatic effects requiring monitoring
- Commercial future is uncertain: an additional trial is required and the developer has discussed strategic alternatives
- Any 'gut-healing' claims sold by unregulated 'research peptide' vendors are unsupported — legitimate use is by prescription within approved indications or clinical trials
Comparisons
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Citations
- [1] Efficacy and Safety of Once-Weekly Apraglutide in SBS-IF: Phase 3 STARS Study — Intestinal Failure journal PubMed
- [2] Ironwood Pharmaceuticals Provides Clinical and Regulatory Update on Apraglutide (FDA requires confirmatory Phase 3) — April 2025 PubMed
- [3] Apraglutide, a novel once-weekly GLP-2 analog, improves intestinal fluid and energy absorption in SBS — Phase 1/2 metabolic balance trial (PMC) PubMed
- [4] Ironwood rethinks options after FDA demands another phase 3 trial for GI drug — Fierce Biotech PubMed
- [5] STARS: Apraglutide Reduces Parenteral Support in Patients with Stoma, Colon-In-Continuity — HCPLive PubMed
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