Glepaglutide: one trial, two regulators, two answers
The same phase 3 trial was judged differently in Washington and Amsterdam. The FDA asked for another study. The EMA committee recommended approval.
Glepaglutide is a long-acting GLP-2 analogue developed by Zealand Pharma in Copenhagen for short bowel syndrome. It is given as a 10 mg injection under the skin, and the goal is to replace the daily injection of teduglutide with a twice weekly one. In Europe it will be sold as Zeydovio if the European Commission confirms the EMA's recommendation. In the United States it is not approved.
The pivotal trial: EASE-1
EASE SBS 1 was an international, double-blind, placebo-controlled phase 3 trial. It enrolled adults with short bowel syndrome and intestinal failure who needed parenteral support at least three days a week, and randomised them 1:1:1 to glepaglutide 10 mg twice weekly, glepaglutide 10 mg once weekly, or placebo for 24 weeks. As in other trials in this field, intravenous support was reduced whenever 48-hour urine volume rose more than 10% above baseline. The results were published in Gastroenterology in April 2025.
| Trial | Year, journal | n | Duration | Drug and dose | Primary result vs comparator |
|---|---|---|---|---|---|
| EASE-1, twice weekly arm | 2025, Gastroenterology | 106 across 3 arms | 24 weeks | Glepaglutide 10 mg twice weekly vs placebo | PS volume: down 5.13 vs 2.85 L/week (P = .0039) |
| Same trial, responders | Weeks 20 and 24 | Twice weekly vs placebo | 20% or more PS cut: 65.7% vs 38.9% (P = .0243) | ||
| Same trial, days off | Week 24 | Twice weekly vs placebo | At least 1 fewer PS day a week: 51.4% vs 19.4% (P = .0043) | ||
| Same trial, weaning | Week 24 | Twice weekly vs placebo | Off PS entirely: 5 patients (14%) vs 0 | ||
| EASE-1, once weekly arm | 24 weeks | Glepaglutide 10 mg once weekly vs placebo | No statistically significant difference on primary or key secondary endpoints |
Two things stand out. The twice weekly dose worked on every main measure. The once weekly dose did not separate from placebo. That split is what the US decision turned on.
The rest of the EASE programme
EASE-1 did not stand alone. Zealand ran a phase 2 study and three further phase 3 studies, listed here with the numbers from their ClinicalTrials.gov records.
| Study | Type | n | Duration | Primary outcome |
|---|---|---|---|---|
| Phase 2 (ZP1848) | Phase 2 | 18 | 3 week treatment periods | Change in wet weight of stoma output or diarrhoea |
| EASE SBS 1 | Phase 3, placebo-controlled | 106 | 24 weeks | Change in weekly PS volume |
| EASE SBS 2 | Phase 3 extension | 150 | 2 years | Adverse events |
| EASE SBS 3 | Phase 3 extension | 84 | 108 weeks | Adverse events |
| EASE SBS 4 | Phase 3 mechanistic | 12 | 24 weeks | Change in absorption of wet weight and fluids |
| EASE SBS 5 | Phase 3, placebo-controlled, confirmatory | 90 planned | 24 week primary, then open-label | Change in weekly PS volume |
The extension and mechanistic studies are open-label or small. They inform long-term safety and how the drug works, not whether it beats placebo.
The FDA: a complete response letter
On 19 December 2024 Zealand announced that the FDA had issued a complete response letter, its formal way of declining to approve an application as submitted. The FDA said the application did not provide substantial evidence of efficacy and safety for the to-be-marketed dose, and recommended an additional clinical trial to confirm it. The application rested on a single pivotal trial in which only one of two dosing arms succeeded.
The answer: EASE-5
EASE SBS 5 is the confirmatory trial. According to its ClinicalTrials.gov record, it is a phase 3, double-blind, placebo-controlled trial of glepaglutide 10 mg twice weekly in about 90 adults with short bowel syndrome and intestinal failure, followed by a long-term open-label safety period. Its primary endpoint is the change in weekly parenteral support volume from baseline to week 24. The record lists a start in February 2026, status recruiting, and an estimated primary completion in October 2028. A US resubmission would follow results.
The EMA: a positive opinion
Zealand submitted a marketing authorisation application to the EMA in June 2025, based on EASE-1 plus interim data from the EASE-2 and EASE-3 extension trials and the EASE-4 mechanistic trial. On 17 September 2026 the EMA's human medicines committee (CHMP) adopted a positive opinion recommending authorisation of Zeydovio as a 10 mg solution in a pre-filled pen. The recommended indication is adults with short bowel syndrome who are stable after a period of intestinal adaptation following surgery. EMA's summary describes the evidence as a larger reduction in weekly parenteral support volume with twice weekly glepaglutide than placebo over 24 weeks.
A CHMP opinion is a recommendation. The legal authorisation comes from the European Commission, usually within about two months. At the time of writing, EMA's page still says the product information will be published once the Commission grants authorisation.
Side effects
EMA lists the most common side effects as injection site reactions, stoma complications in people with a stoma, abdominal pain, abdominal distension, nausea, fluid retention or overload, and vomiting. That profile overlaps closely with teduglutide's, which is expected from a drug acting on the same receptor. The full EU label with any monitoring requirements, such as colonoscopy timing, will be in the summary of product characteristics once it is published.
How it compares
| Drug | Injection | Status (October 2026) | Pivotal headline |
|---|---|---|---|
| Teduglutide (Gattex, Revestive) | Once daily | Approved US and EU since 2012 | STEPS: 63% vs 30% responders |
| Glepaglutide (Zeydovio) | Twice weekly | EU: CHMP positive opinion Sept 2026. US: not approved, confirmatory trial running | EASE-1: 65.7% vs 38.9% responders |
| Apraglutide | Once weekly | Not approved; confirmatory STARS-2 trial running | STARS: PS volume down 25.5% vs 12.5% |
The responder rates look similar across teduglutide and glepaglutide, but the placebo groups differed (30% vs 38.9%) and so did the patients and weaning rules. Only a head-to-head trial could rank them, and none exists. The apraglutide page covers the once weekly competitor.
What to log
A twice weekly injection is easier to miss than a daily one. Peptide AI's dose log and protocol planner track scheduled days, with site rotation and bloodwork on the same timeline for clinic reviews.
Questions people ask
Is glepaglutide approved?
Not yet anywhere. The FDA issued a complete response letter in December 2024. In the EU, the EMA committee recommended approval of Zeydovio on 17 September 2026; the European Commission makes the final decision.
How well did glepaglutide work in EASE-1?
At 10 mg twice weekly, weekly parenteral support fell 5.13 litres vs 2.85 litres on placebo over 24 weeks, and 65.7% vs 38.9% were responders. Once weekly dosing did not beat placebo.
Why did the FDA reject glepaglutide?
The FDA said the application lacked substantial evidence of efficacy and safety for the to-be-marketed dose and asked for another trial. The application relied on one phase 3 trial where only the twice weekly arm succeeded.
What is EASE-5?
The confirmatory phase 3 trial of glepaglutide 10 mg twice weekly vs placebo in about 90 adults, with a 24 week primary endpoint. It started in February 2026 with primary completion estimated in October 2028.
How is glepaglutide different from teduglutide?
Both act on the GLP-2 receptor. Teduglutide is injected daily; glepaglutide is long-acting and injected twice weekly at a fixed 10 mg dose. There is no head-to-head trial.
Sources
- Glepaglutide, a long-acting glucagon-like peptide-2 analogue, reduces parenteral support in patients with short bowel syndrome: a phase 3 randomized controlled trial (EASE-1), Gastroenterology, 2025
- EASE SBS 1 trial record (NCT03690206), ClinicalTrials.gov
- FDA issues CRL for glepaglutide in short bowel syndrome, cites insufficient evidence, HCPLive, December 2024
- EASE SBS 5 trial record (NCT07197944), ClinicalTrials.gov
- Zealand Pharma submits marketing authorization application to the European Medicines Agency for glepaglutide in short bowel syndrome, Zealand Pharma via BioSpace, June 2025
- Zeydovio (glepaglutide): pending EC decision, European Medicines Agency, CHMP opinion 17 September 2026
- Phase 2 trial of ZP1848 (glepaglutide) in short bowel syndrome (NCT02690025), ClinicalTrials.gov
- EASE SBS 2 trial record (NCT03905707), ClinicalTrials.gov
- EASE SBS 3 trial record (NCT04881825), ClinicalTrials.gov
- EASE SBS 4 trial record (NCT04991311), ClinicalTrials.gov
