Glepaglutide

Zeydovio (EU brand, following positive CHMP opinion), ZP1848

Recovery, repair & tissue

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Summary

Class: Synthetic GLP-2 analogue, 39 amino acids, with substitutions and a C-terminal lysine extension that give protease resistance and self-association into a depot at the injection site
Mechanism: Activates the intestinal GLP-2 receptor to expand absorptive mucosal surface, reducing the intravenous nutrition and fluid people with short bowel syndrome need
Routes studied: Subcutaneous, twice weekly (and once weekly in earlier arms), via ready-to-use autoinjector
Half-life: Extended relative to native GLP-2 by self-association at the injection site rather than albumin binding; reported effective duration supports twice-weekly dosing †
Storage: Liquid, ready-to-use single-dose autoinjector; refrigerated storage with a defined room-temperature period †
Regulatory status: CHMP positive opinion September 2026 for adults with short bowel syndrome (EU); not approved in the US, where an additional Phase 3 trial (EASE-5) is being run to support a submission

Doses are as reported in studies or by the community — never recommendations.

1What it is

Glepaglutide is a second GLP-2 analogue developed for short bowel syndrome (SBS), the condition in which surgical loss of intestine leaves too little absorptive surface and people depend on intravenous nutrition and fluid. Like apraglutide (#243) it is engineered to resist the DPP-4 enzyme that destroys natural GLP-2 within minutes, but it achieves its long action differently: the molecule self-associates into a depot after injection and is released slowly from there. It is formulated as a liquid in a ready-to-use single-dose autoinjector, which matters for a patient group that already manages complex home infusions.

Its regulatory history has diverged by region. The EU committee (CHMP) recommended marketing authorisation in September 2026 under the brand name Zeydovio, for adults with SBS. In the US it holds orphan drug designation but is not approved, and a further Phase 3 trial (EASE-5) is being run to support a US submission. Readers comparing the two GLP-2 analogues in development should note that both ran into regulatory friction after positive Phase 3 results, for different reasons.

2How it's thought to work

GLP-2 receptor activation. in subepithelial cells of the intestine releases IGF-1, KGF and nitric oxide, which drive crypt cell proliferation and villus growth.

Mucosal expansion. villus height and crypt depth increase, enlarging absorptive surface. Gastric emptying and intestinal transit slow, and splanchnic blood flow rises.

Clinical consequence. more fluid and nutrient absorption enterally, so prescribed parenteral support volume can be reduced, and in some patients stopped.

Depot pharmacology. the C-terminal extension promotes self-assembly at the injection site, which flattens and lengthens exposure without albumin binding or a fatty-acid chain. This is a different extension strategy from apraglutide's and from the one used in insulin icodec (#241).

A GLP-2 analogue designed to self-assemble into a depot under the skin, giving twice-weekly dosing.Schematic — not to scale

3What the research shows

Short bowel syndrome, Phase 3

EASE-1 was a randomised, double-blind, placebo-controlled Phase 3 trial of glepaglutide 10 mg once weekly or twice weekly in adults with SBS dependent on parenteral support. The twice-weekly arm reduced weekly parenteral support volume significantly versus placebo; the once-weekly arm did not reach statistical significance on the primary endpoint (sponsor reports 2023; peer-reviewed publication to be confirmed before citing exact volumes). This split result is the reason the twice-weekly regimen is the one taken forward.

Earlier clinical work

A Phase 2 crossover trial in SBS reported increased intestinal wet weight absorption and reduced faecal output with glepaglutide versus placebo, with dose-dependent rises in plasma citrulline (Hvistendahl 2020, JPEN / Clin Nutr †). [1]

Long-term extension

Open-label extension data have been reported for continued parenteral support reduction and enteral autonomy in a subset of patients. Uncontrolled; treat as supportive only.

Not graded

US regulatory position

The FDA has not approved glepaglutide. The sponsor is running EASE-5, a further Phase 3 trial, to support a US submission. Reports of the exact nature of earlier FDA feedback vary across secondary sources; treat the specific reasons as unconfirmed †. Community use: essentially none documented. This is a hospital-prescribed drug for a rare condition with no self-directed use.

4Reported side effects and interactions

Literature-reported

the GLP-2 class profile — gastrointestinal: abdominal pain, distension, nausea, vomiting; peripheral oedema and fluid overload if parenteral volume is not reduced in step; stoma complications (stomal swelling or obstruction) in patients with a stoma; injection-site reactions. Rates reported in EASE-1 should be read from the final publication or label rather than from press summaries.

Community-reported

none; no community use exists.

Theoretical / class-level. the mucosal-trophic mechanism carries a theoretical risk of promoting existing intestinal neoplasia. Pre-treatment colonoscopy and periodic surveillance are the established class precaution, set by the teduglutide label. Biliary tract and pancreatic events are monitored with GLP-2 analogues.

Interactions. improved enteral absorption can raise exposure to oral medicines, including narrow-margin drugs. Parenteral nutrition and fluid prescriptions must be actively reduced as absorption improves — in practice the most important interaction is with the patient's own infusion regimen.

Markers researchers commonly monitor

From the GLP-2 class and SBS trial protocols:

Marker	Why it's watched
Weekly parenteral support volume	the endpoint that defines benefit in this condition.
Plasma citrulline	enterocyte mass marker; the pharmacodynamic readout that the drug is engaging its target.
Faecal/stomal output and oral fluid intake	the day-to-day measures patients and teams actually track.
Body weight and fluid balance	to detect fluid overload during the transition off intravenous volume.
Electrolytes, magnesium, creatinine, eGFR	routinely fragile in intestinal failure.
Liver enzymes and bilirubin	intestinal-failure-associated liver disease; also class biliary concern.
Lipase and amylase	pancreatic events are a class concern.
Colonoscopy before and during treatment	the standard GLP-2 precaution given the trophic mechanism.

Free for everyone. Safety information is never behind a paywall.

5Formulation and administration context

Supplied as a liquid in a ready-to-use, single-dose autoinjector, given twice weekly. No is involved and there is no self-preparation route; the autoinjector exists specifically so that patients do not handle vials. Storage follows the approved label, typically refrigerated with a defined in-use period at room temperature †. Doses and the matching reduction in intravenous support are set and adjusted by the treating intestinal-failure team.

6Commonly studied alongside

Teduglutide (#164) as the approved comparator, apraglutide (#243) as the other late-stage GLP-2 analogue, and parenteral nutrition management. No combination with other peptides is studied or sensible here.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not approved. Orphan drug designation for SBS; Phase 3 EASE-5 ongoing to support a planned submission †
European Union	CHMP positive opinion September 2026 recommending authorisation as Zeydovio for adults with short bowel syndrome; European Commission decision and launch status †
United Kingdom	Not licensed †
Australia	Not approved †
South Africa	Not registered †
Sport	Not specifically listed by WADA; a non-approved substance would fall under S0. Check the current list

8Open questions

Why the once-weekly arm failed and the twice-weekly arm succeeded in EASE-1, and what that says about required exposure duration.
How glepaglutide compares with daily teduglutide or weekly apraglutide — no head-to-head trials exist.
Long-term neoplasia surveillance findings with sustained GLP-2 receptor agonism.
Whether the US and EU assessments will converge once EASE-5 reports.

9References

1Hvistendahl MK et al. (2020). Effect of glepaglutide, a long-acting GLP-2 analogue, on intestinal absorption in patients with short bowel syndrome. Clin Nutr / JPEN [verify journal]. PubMed
2Jeppesen PB et al. (2023–2025). EASE-1: Phase 3 trial of glepaglutide in short bowel syndrome. [Publication to be confirmed before citing figures.] PubMed
3Naimi RM et al. (2019). Glepaglutide, a novel long-acting GLP-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterol Hepatol. PubMed · DOI
4EMA / CHMP (2026). Summary of opinion: Zeydovio (glepaglutide). PubMed
5Drucker DJ, Yusta B (2014). Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol. PubMed · DOI

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

31 Oct 2026Profile published — awaiting medical review

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