Glepaglutide
Medium EvidenceA long-acting glucagon-like peptide-2 (GLP-2) analog given by once- or twice-weekly subcutaneous injection that helps the gut absorb more nutrients in short bowel syndrome, reducing dependence on IV (parenteral) nutrition.
What It Is
Glepaglutide (ZP1848), developed by Zealand Pharma, is a long-acting analog of glucagon-like peptide-2 (GLP-2), a hormone the intestine releases after eating that promotes growth and absorptive capacity of the gut lining. Unlike the GLP-1 and GIP peptides that dominate the obesity and diabetes conversation, glepaglutide is an intestinotrophic (gut-growing) peptide developed for short bowel syndrome with intestinal failure (SBS-IF) — a rare, serious condition in which people who have lost much of their small intestine cannot absorb enough nutrition and depend on parenteral support (intravenous nutrition and fluids). Glepaglutide is engineered for stability in a ready-to-use aqueous (liquid) formulation delivered by autoinjector, with a long effective half-life of roughly 88 hours that allows once- or twice-weekly dosing rather than the daily injection required by the first approved GLP-2 analog, teduglutide (Gattex/Revestive). It works as a GLP-2 receptor agonist: by activating GLP-2 receptors in the gut it increases intestinal mucosal mass, villus height and blood flow, improving the remaining bowel's ability to absorb fluid and nutrients. In the pivotal Phase 3 EASE-SBS 1 trial (106 patients), 10 mg twice weekly significantly reduced weekly parenteral support volume versus placebo (mean change −5.13 vs −2.85 L/week; P=0.0039), about two-thirds of twice-weekly patients achieved a clinically meaningful (>20%) reduction in IV support, and nine glepaglutide-treated patients were fully weaned off parenteral support versus none on placebo. In December 2024 the U.S. FDA issued a Complete Response Letter requesting an additional trial; Zealand Pharma submitted a European Marketing Authorization Application to the EMA in June 2025 (supported by EASE-1 and the EASE-2/EASE-3 long-term extensions) and planned a new confirmatory Phase 3 for U.S. approval. Glepaglutide is an investigational prescription peptide for a specific disease — not an approved or self-administered wellness 'research peptide.'
Regulatory Status
Glepaglutide (ZP1848, Zealand Pharma) is an investigational long-acting GLP-2 analog for short bowel syndrome with intestinal failure. The U.S. FDA issued a Complete Response Letter on December 19, 2024, concluding the application did not provide substantial evidence of efficacy/safety for the proposed dose and requesting an additional clinical trial. Zealand Pharma submitted a Marketing Authorization Application to the European Medicines Agency (EMA) in June 2025 based on the Phase 3 EASE-SBS 1 trial and the EASE-2/EASE-3 extensions, and planned a further Phase 3 trial to support U.S. approval. It is not approved or marketed and is administered by prescription under specialist care.
Effective: June 2026
View FDA SourceWhy Researchers Study It
Glepaglutide is studied because short bowel syndrome with intestinal failure is a rare but devastating condition in which patients depend on lengthy daily IV nutrition, with major impacts on quality of life and risk of line infections and liver complications. GLP-2 directly drives growth and absorptive capacity of the remaining intestine, so a long-acting GLP-2 analog that can be dosed once or twice weekly — rather than the daily subcutaneous injection of teduglutide — could meaningfully reduce treatment burden while cutting or eliminating parenteral support. Researchers are interested in glepaglutide's ready-to-use liquid autoinjector formulation, its ~88-hour effective half-life, its ability to wean some patients off IV nutrition entirely, and how it compares with other GLP-2 analogs (teduglutide and the once-weekly apraglutide) in the emerging class of intestinotrophic peptides.
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, supporting nutrient and fluid uptake
- Slows gastric emptying and reduces intestinal secretion, improving the time and capacity for absorption
- Improves fluid and energy absorption, lowering the volume of parenteral (IV) nutrition and fluids patients require
- Engineered for a long effective half-life (~88 hours) in a stable aqueous formulation, enabling once- or twice-weekly subcutaneous dosing
Evidence Snapshot
| Study Type | Model | Outcome | Link |
|---|---|---|---|
| Clinical (Phase 3, EASE-SBS 1) | 106 adults with short bowel syndrome and intestinal failure dependent on parenteral support, randomized to glepaglutide 10 mg once weekly, twice weekly, or placebo for 24 weeks | Positive (twice weekly): significant reduction in weekly parenteral support volume vs placebo (mean change −5.13 vs −2.85 L/week; P=0.0039); ~66% achieved >20% reduction and 9 patients weaned off parenteral support. Once-weekly dosing showed a numeric but non-significant reduction. | Source |
| Clinical (Phase 3 long-term extensions, EASE-2 / EASE-3) | Ongoing open-label long-term safety and durability extensions of EASE-SBS 1 | Supportive: interim results used alongside EASE-1 to support the EU Marketing Authorization Application (submitted June 2025) | Source |
| Regulatory (U.S. FDA) | New Drug Application review for SBS with intestinal failure | Complete Response Letter (Dec 19, 2024): FDA found insufficient substantial evidence for the to-be-marketed dose and requested an additional clinical trial | Source |
| Clinical pharmacology (Phase 1) | Pharmacokinetics characterizing the long ~88-hour effective half-life supporting weekly dosing | Supportive: long-acting PK profile consistent with once-/twice-weekly subcutaneous administration | Source |
Commonly Discussed Benefits
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Safety & Cautions
- An investigational, unapproved peptide — the U.S. FDA has not approved it and requested an additional trial; it is not available outside clinical development and the EU review is ongoing
- 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 GLP-2 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
- Dosing, long-term safety and the to-be-marketed regimen are still being confirmed in additional trials
- Any antimicrobial or '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] U.S. FDA issues Complete Response Letter for the glepaglutide NDA for short bowel syndrome — Zealand Pharma (Dec 19, 2024) PubMed
- [2] Glepaglutide, a Long-Acting GLP-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 RCT (EASE-SBS 1) — Gastroenterology PubMed
- [3] Zealand Pharma submits Marketing Authorization Application to the EMA for glepaglutide in short bowel syndrome (June 2025) PubMed
- [4] Apraglutide / GLP-2 analog once-weekly metabolic balance trial in SBS — PMC (class context) PubMed
- [5] FDA Issues Complete Response Letter for Much-Anticipated GLP-2 Analog — Pharmacy Times PubMed
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