Peptide education
Glepaglutide
ZP1848
Glepaglutide is a GLP-2 analog being studied for short bowel syndrome. Researchers are testing whether it can reduce the need for nutrition or fluids given through a vein, called parenteral support. It is investigational and not FDA-approved in the United States.
In the 24-week EASE-1 trial, the twice-weekly group had a greater reduction in parenteral support than the placebo group. The once-weekly group did not significantly differ from placebo on the primary endpoint. FDA called for additional controlled evidence.
Overview
Quick answer
In EASE-1, the twice-weekly group had a larger reduction in support volume than the placebo group. FDA found the submitted evidence insufficient for approval and identified concerns about study conduct and safety. In Europe, the CHMP recommended authorization for a defined adult population; its opinion is not a European Commission marketing authorization.
What is glepaglutide being studied for?
Researchers are studying it in short bowel syndrome with intestinal failure, where patients need parenteral support. It acts on the GLP-2 pathway involved in intestinal adaptation and absorption.
Is it FDA-approved?
No. FDA said the submitted application could not be approved in its present form. The developer describes glepaglutide as investigational and says another controlled phase 3 trial is underway.
What is the EU regulatory position?
The European Medicines Agency's CHMP recommended marketing authorization for Zeydovio in adults with short bowel syndrome who are stable after intestinal adaptation following surgery. This positive opinion is not an authorization; the European Commission decision is pending.
What happened in the main trial?
The twice-weekly group showed a larger average reduction in weekly parenteral support than placebo at 24 weeks. The once-weekly group did not show a statistically significant difference on the primary endpoint. FDA questioned whether the submitted results were sufficiently reliable and persuasive for approval.
What doses were studied?
EASE-1 studied 10 mg injected under the skin either once or twice weekly. Glepaglutide does not have an FDA-approved dose.
What safety questions remain?
FDA described a limited long-term safety database, possible liver injury, cancers and gastric polyps in the submitted data, and adverse events that were not reported at one clinical site. The relationship of these events to treatment requires further study.
Evidence
Evidence snapshot
In 106 randomized participants, the reported model-adjusted mean weekly support change at 24 weeks was minus 5.13 L with twice-weekly glepaglutide versus minus 2.85 L with placebo. FDA identified limitations in interpreting these data.
The once-weekly arm did not show a statistically significant difference from placebo on the primary endpoint.
Ten participants received once-weekly treatment. The primary wet-weight absorption endpoint did not reach statistical significance, although the study reported an increase in a secondary energy-absorption measure.
FDA raised concerns about support-adjustment data, safety follow-up, and unreported adverse events. It recommended another controlled trial with a longer treatment period.
The CHMP recommended authorization for a defined adult short bowel syndrome population. The European Commission decision is pending.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Glepaglutide reduced parenteral support in a controlled trial. | The published twice-weekly arm had a larger average reduction than placebo at 24 weeks. The once-weekly arm was not statistically significant on the primary endpoint. | GLP-2 signaling is involved in intestinal adaptation and absorption, but mechanism alone cannot establish a treatment effect. | The published finding is specific to one schedule and study. FDA raised concerns about the reliability and sufficiency of the submitted evidence. |
| The small absorption study confirmed the main trial. | The open-label study enrolled 10 people and used once-weekly dosing. Its primary change in wet-weight absorption did not reach statistical significance; an energy-absorption measure was secondary. | No. FDA said the small, uncontrolled study did not provide adequate confirmation for the proposed twice-weekly regimen. | |
| A GLP-2 analog has the same approval or safety record as Gattex. | The developer describes glepaglutide as investigational, and FDA declined to approve its submitted application. Its evidence and risks need their own assessment. | No. Sharing a drug class does not give an investigational compound another product's approval or label. |
Bottom line
Main takeaway
A trial found a promising reduction in intravenous support at one schedule, but glepaglutide is still investigational in the United States.
FDA questioned data reliability and said the submitted safety database was too limited for the proposed long-term treatment.
Separate the controlled twice-weekly result, the non-significant once-weekly comparison, and the small uncontrolled absorption study. FDA's complete response letter explains its concerns about the evidence.
Identity
What it is
Glepaglutide is a long-acting GLP-2 analog developed for short bowel syndrome. The clinical program studies people whose remaining intestinal function does not meet their fluid or nutritional needs without support.
In the main phase 3 trial, researchers assigned 106 adults to two active schedules or placebo. FDA found the submitted evidence insufficient to establish efficacy and safety for approval.
Use context
Routes, doses, and cycle patterns
EASE-1 compared two subcutaneous schedules with placebo for 24 weeks. EASE-4 studied once-weekly dosing and intestinal absorption in an open-label study.
Human studies and product labels
EASE-1 twice-weekly arm
- Purpose
- Reduction in parenteral support
- Context
- Randomized, placebo-controlled phase 3 study in adults
- Route
- Subcutaneous injection
- Amount
- 10 mg
- Frequency
- Twice weekly
- Duration
- 24 weeks
The trial reported a significant difference in support-volume change versus placebo. FDA raised concerns about the study data.
EASE-1 once-weekly arm
- Purpose
- Reduction in parenteral support
- Context
- Randomized, placebo-controlled phase 3 study in adults
- Route
- Subcutaneous injection
- Amount
- 10 mg
- Frequency
- Once weekly
- Duration
- 24 weeks
This group did not significantly differ from placebo on the primary endpoint.
EASE-4 absorption study
- Purpose
- Measure intestinal absorption and support use
- Context
- Single-center, open-label study in 10 adults
- Route
- Subcutaneous injection
- Amount
- 10 mg
- Frequency
- Once weekly
- Duration
- 52 weeks, with the primary absorption assessment at week 24
The primary wet-weight absorption endpoint did not reach statistical significance. The study had no concurrent control group.
What varies
- Status: the compound is investigational and has no FDA-approved dose.
- Schedule: the once-weekly and twice-weekly trial arms had different results.
- Evidence: FDA identified concerns about support adjustments, documentation, and safety reporting.
Research
Research evidence
EASE-1 reported a 24-week reduction in parenteral support with twice-weekly treatment versus placebo, while the once-weekly arm was not significant on the main endpoint. A separate 10-person, uncontrolled study reported a secondary energy-absorption finding but did not meet its primary wet-weight endpoint. FDA judged the submitted program insufficient for approval and recommended another controlled trial to address efficacy and safety gaps.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| EASE-1 | 106 adults with short bowel syndrome and intestinal failure receiving support at least three days per week | Randomized, double-blind, placebo-controlled phase 3 study | 10 mg subcutaneously once or twice weekly, compared with placebo | The published model-adjusted mean weekly support change at 24 weeks was minus 5.13 L for the twice-weekly group and minus 2.85 L for placebo. The once-weekly group did not significantly differ from placebo on the primary endpoint. | FDA identified deviations in support adjustments, missing documentation, and concerns about whether the effect and long-term safety were adequately established. The trial publication has a linked corrigendum; the corrected trial registry reports the primary comparisons. | Controlled human trial with regulatory limitations |
| EASE-4 | 10 adults with short bowel syndrome, eight with intestinal failure | Single-center, open-label metabolic balance study | 10 mg subcutaneously once weekly | The primary wet-weight absorption change at week 24 was 398 g/day with p=0.0585. The study reported increased energy absorption as a secondary outcome. | Small, uncontrolled, and studied at a different schedule from the proposed twice-weekly regimen. FDA did not regard it as confirmatory. | Limited human data |
| FDA application review | Submitted glepaglutide clinical program | Regulatory review of the application | Proposed treatment for adult short bowel syndrome | FDA found the evidence insufficient for approval and recommended a second controlled trial with at least 52 weeks of treatment. | The letter assesses the submitted application and does not predict the outcome of later trials or reviews. | Direct regulatory assessment |
Use context
Reported use context
EASE-1 compared 10 mg once or twice weekly with placebo. EASE-4 studied 10 mg once weekly in 10 adults.
Study and label context
10 mg once or twice weekly for 24 weeks, with placebo comparison.
10 mg once weekly in a small open-label study.
Cautions
Safety and unknowns
- FDA said the submitted database was too limited to adequately characterize long-term safety for the proposed schedule. It recommended longer placebo-controlled follow-up.
- FDA identified potential drug-induced liver injury, cancers and gastric polyps in the submitted safety database. Their relationship to treatment requires further evaluation.
- An FDA inspection identified adverse events that had not been reported at one clinical site, including serious events. This raised concern about the reliability of the safety information.
- The trial results register reports serious adverse events in each study group. An event occurring during a trial does not by itself establish that treatment caused it.
Product quality
Product identity and quality
Trial material is supplied and monitored within a research protocol. An independently sourced product is not established as the same formulation or quality merely because its label uses the same name.
Investigational status
Glepaglutide remains investigational and does not have an FDA-approved formulation or dose.
Identity and concentration
The study describes a specific investigational injection. A separate supplier's labeling does not verify identity, concentration, or sterility.
Mechanism
How it is proposed to work
Glepaglutide is designed to act like GLP-2, a gut hormone involved in intestinal adaptation and absorption. Researchers are studying whether that activity can reduce the need for intravenous fluids and nutrition.
The development program investigates whether GLP-2 activity improves absorption enough to reduce intravenous support in short bowel syndrome.
The small absorption study measured wet-weight and energy absorption, but the primary wet-weight endpoint did not reach statistical significance and the study lacked a control group.
FAQ
Common questions
Is glepaglutide FDA-approved?
No. FDA did not approve the submitted application, and the developer describes the compound as investigational.
What is the EU regulatory position?
EMA's CHMP recommended authorization for Zeydovio in adults with short bowel syndrome who are stable after intestinal adaptation following surgery. The opinion is not marketing authorization; the European Commission decision is pending.
Did both schedules succeed in the phase 3 trial?
No. The published trial reported a significant primary outcome for twice-weekly dosing, but not once-weekly dosing. FDA also raised concerns about the reliability and sufficiency of the submitted evidence.
Details
Technical details
Sources
References
- 1.
FDA. FDA complete response letter for glepaglutide application NDA 218828
FDA assessment of efficacy, safety, trial conduct, and the need for an additional controlled trial.
- 2.
FDA. FDA orphan-drug designation and approval status for glepaglutide
FDA lists the short bowel syndrome orphan designation as not FDA-approved for the designated indication.
- 3.
European Medicines Agency. Zeydovio: CHMP positive opinion
CHMP recommended marketing authorization for a defined adult short bowel syndrome population; the opinion itself is not authorization.
- 4.
European Medicines Agency. CHMP meeting highlights: Zeydovio
EMA lists the CHMP recommendation as pending a European Commission decision.
- 5.
doi:10.1053/j.gastro.2024.11.023 PMID:39708985 NCT03690206
EASE-1 randomized trial; PubMed lists a linked corrigendum.
- 6.
EU Clinical Trials Register. EASE-1 clinical trial results, EudraCT 2017-004394-14
Trial-arm details and corrected adverse-event reporting.
- 7.
Research institution publication record. Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome
doi:10.1016/j.clnesp.2025.08.006 PMID:40774623 NCT04991311
Investigator institution's abstract of the single-center, open-label EASE-4 study.
- 8.
Zealand Pharma. Glepaglutide development status
Developer-reported current U.S. investigational status and ongoing phase 3 program.