Glepaglutide

Origin and structure

GLP-2 (glucagon-like peptide-2) is a 33-amino-acid hormone that the L cells of the gut lining release after a meal. It is cut from the same precursor, proglucagon, as GLP-1, but it acts on a receptor of its own and makes the lining of the bowel grow. Natural GLP-2 has a short half-life and is chemically and physically unstable, which makes it unsuitable as a medicine.

Zealand Pharma in Denmark designed glepaglutide (development code ZP1848) to get around that. Nine of the 33 amino acids of human GLP-2 are replaced, among them the alanine at position 2, which becomes glycine as in teduglutide, and a tail of six lysines is attached at the end. According to its developers the tail raised the yield of the synthesis, and the result was the first long-acting GLP-2 analogue stable enough to be supplied as a ready-to-use solution. The EU recommendation covers a 10 mg pre-filled pen.

After an injection under the skin, glepaglutide stays in a depot from which its two main breakdown products, both active, are slowly released. In healthy volunteers given 5 or 10 mg once a week for six weeks, those two products made up more than 98% of the exposure at steady state, and the original molecule less than 1%. The effective half-life was 88 hours at 10 mg and 124 hours at 5 mg, long enough for one or two injections a week.

How it works

Short bowel syndrome is what remains when so much of the small intestine has been removed, or works so poorly, that the rest cannot absorb enough water and nutrients. Many patients then depend on parenteral support: nutrition and fluids infused straight into a vein through a catheter, often on several days a week. Infections of that catheter are a constant risk, and in the main glepaglutide trial they were among the most frequent serious adverse events, on placebo too.

Glepaglutide binds the GLP-2 receptor. According to the EMA it increases blood flow to the intestine and through the portal vein, reduces stomach acid secretion and slows the movement of the gut, and it makes the mucosa grow, with a thicker lining, taller epithelial cells and deeper crypts. The aim is that the remaining bowel absorbs more, so that less has to be given by vein.

In the phase 3 trial, intravenous support was lowered by a fixed rule: when a patient's urine volume over 48 hours was more than 10% above the starting value, a sign that the gut was taking up more fluid, the infused volume was reduced. The FDA later questioned how consistently that rule had been applied.

Is glepaglutide approved?

Not yet, anywhere. In the EU a positive recommendation is waiting for the European Commission's decision; in the US the application was turned down and a new trial is under way.

In the Netherlands, patients have received glepaglutide in clinical trials. Radboud university medical center in Nijmegen took part in EASE SBS 1, which included four Dutch participants, and is recruiting for EASE SBS 5. Once the European Commission grants the licence, Zeydovio will be authorised in every EU country, the Netherlands included; whether basic health insurance will pay for it is a separate Dutch decision that has not been taken.

Any glepaglutide sold as a research chemical is not this medicine. It has no marketing authorisation, is not made under a medicines licence and may not be used in people.

• EU: on 2 June 2025 Zealand Pharma announced its application to the EMA, based on EASE SBS 1, interim results of the EASE SBS 2 and 3 extensions and the mechanistic study EASE SBS 4. On 17 September 2026 the CHMP recommended a marketing authorisation for Zeydovio, a 10 mg pre-filled pen, for adults with short bowel syndrome who are stable after a period of intestinal adaptation following surgery, with treatment started under the supervision of a doctor experienced in the condition. The European Commission normally decides within 67 days of the opinion and had not yet done so on 28 October 2026.
• US: Zealand submitted a new drug application (NDA 218828) in December 2023. On 19 December 2024 the FDA issued a complete response letter: it could not conclude that there was substantial evidence of effectiveness, nor that the benefits outweighed the risks, and recommended a second double-blind, placebo-controlled trial with at least 52 weeks of treatment. Since October 2017 glepaglutide has had orphan drug designation from the FDA for short bowel syndrome. EASE SBS 5, meant to support a new application, started in February 2026.

What the research shows

The evidence comes from studies funded by Zealand Pharma: one small phase 2 trial, one completed placebo-controlled phase 3 trial, its long-term extensions without a placebo group and a small mechanistic study without a control group. The main results:

• Phase 2 (Lancet Gastroenterol Hepatol 2019): 18 adults in Copenhagen with a stool or stoma output of at least 1,500 g a day received two of three doses (0.1, 1 or 10 mg daily) for three weeks each, double-blind and in random order. Output fell by 592 g a day on 1 mg and by 833 g a day on 10 mg; 0.1 mg had no effect.
• EASE SBS 1 (Gastroenterology 2025): 106 adults from nine countries who needed parenteral support on at least three days a week were randomised to 10 mg twice weekly, 10 mg once weekly or placebo for 24 weeks. On the twice-weekly dose the weekly volume fell by 5.13 litres against 2.85 on placebo (difference 2.28 litres, 95% CI 0.73 to 3.83, P = 0.0039). A response, at least 20% less volume, was reached by 65.7% against 38.9%, at least one day a week less support by 51.4% against 19.4%, and 5 of 35 (14%) came off parenteral support completely, against none on placebo. The once-weekly dose did not differ significantly from placebo on the primary or key secondary endpoints.
• EASE SBS 4 (Clin Nutr ESPEN 2025): 10 adults received 10 mg once weekly, without a control group. After 24 weeks, the primary endpoint, absorption of fluid measured as wet weight, had risen by 398 g a day, short of statistical significance (P = 0.06), while energy absorption rose by 1,038 kJ a day. By week 52 parenteral support had fallen by 800 ml a day, and body weight and composition stayed stable.
• Extensions: EASE SBS 2 (two years, once or twice weekly) and EASE SBS 3 (about two more years, once weekly) ended in April 2026; Zealand expects to present the full results in 2027. In its letter, the FDA wrote that these extensions were not designed as independent evidence of effectiveness, and that people who started treatment in EASE SBS 2 showed no clear dose-response.
• EASE SBS 5 (recruiting): about 90 adults with short bowel syndrome and intestinal failure get 10 mg twice weekly or placebo, double-blind, with the primary endpoint at week 24 and secondary endpoints up to week 52, followed by open-label treatment. The data for the primary endpoint are expected to be complete in October 2028.
• Outside short bowel syndrome, signs of benefit come from animals only. In rats with drug-induced inflammation of the small bowel, glepaglutide lowered inflammation markers and increased bowel mass (BMC Gastroenterol 2023, by Zealand scientists). The one registered human study in inflammatory bowel disease was a phase 1 safety trial in 2009 and 2010 that gave repeated doses to people with Crohn's disease in remission; no results were posted and no efficacy trial followed.

Side effects and the FDA's concerns

In EASE SBS 1 the most frequently reported adverse events were injection-site reactions and stomach and bowel complaints. The term 'injection site reaction' alone was reported by 9 of 35 people on twice-weekly dosing, 15 of 35 on once-weekly dosing and 1 of 36 on placebo; nausea by 7, 3 and 1, abdominal pain by 5, 6 and 2, and vomiting by 3, 6 and 0. Among people with a stoma, stoma swelling occurred in 4 of 17 on twice-weekly dosing and in none of 21 on placebo. Serious adverse events affected 9, 10 and 7 people in the three groups, and nobody died. The EMA names injection-site reactions, stoma complications, abdominal pain and distension, nausea, fluid retention or overload and vomiting as the most common side effects.

The FDA's complete response letter was more critical. It called the safety database too small for a medicine meant for long-term use, as the agency generally wants about 100 people treated with the intended dose for at least a year. Within that database it noted possible drug-induced liver injury, cancers (a gastric neuroendocrine carcinoma and basal-cell and basosquamous carcinomas of the skin) and gastric polyps, several of which had not been reported with teduglutide. Up to 23% of the twice-weekly group lost more than 10% of their body weight during EASE SBS 1 and 2, and without them two key secondary results were no longer significant. Nearly half the participants in each group had at least one adjustment of their parenteral support that departed from the protocol rule, and an inspection of one trial site found unreported adverse events in 6 of its 9 participants.

Because GLP-2 makes gut tissue grow, teduglutide, the one approved GLP-2 medicine, comes with regular bowel checks and warnings about polyps and tumour growth. How these points are handled for glepaglutide will become clear when its EU product information is published, together with the EMA's assessment report.

Glepaglutide versus teduglutide

Teduglutide (Revestive in the EU, Gattex in the US) has been the only approved GLP-2 analogue since 2012. It is cleared within hours, so it is injected once a day at a dose based on body weight, from a powder dissolved before use, and it is also licensed for children. Glepaglutide lasts days, comes as a fixed 10 mg dose in a ready-to-use pen and was given twice a week in its main trial, in adults only.

Their main placebo-controlled trials used similar designs and definitions of response, but they were run years apart in different patients, and no trial has compared the two directly. Another long-acting analogue, apraglutide from Ironwood Pharmaceuticals, is injected once a week and is in a second phase 3 trial.

Frequently asked questions

Is glepaglutide (Zeydovio) approved in Europe?

Not yet. On 17 September 2026 the EMA's medicines committee, the CHMP, recommended authorising it as Zeydovio for adults with short bowel syndrome. The European Commission takes the final decision, normally within 67 days of the opinion, and had not done so by 28 October 2026. A licence would apply in every EU country, the Netherlands included, and in Iceland, Liechtenstein and Norway.

Why did the FDA reject glepaglutide?

In its complete response letter of 19 December 2024, the FDA said a single phase 3 trial was not persuasive enough. It pointed to departures from the protocol when intravenous support was adjusted, missing urine records, key results that depended on people who lost more than 10% of their weight, no clear dose-response in the extension, and a safety database that was too small. It asked for a second placebo-controlled trial of at least 52 weeks, and Zealand started EASE SBS 5 in February 2026.

What is the difference between glepaglutide and teduglutide (Revestive)?

Both act on the GLP-2 receptor. Teduglutide has been approved since 2012, is injected once a day at a dose based on body weight and is also licensed for children. Glepaglutide lasts days instead of hours, comes as a fixed 10 mg dose in a ready-to-use pen and was given twice a week in its main trial, in adults only. No trial has compared the two directly.

Is glepaglutide a GLP-1 drug like Ozempic?

No. GLP-1 and GLP-2 come from the same precursor in the gut but act on different receptors. GLP-1 drugs such as semaglutide lower blood sugar and appetite. Glepaglutide acts on the GLP-2 receptor, which makes the bowel lining grow and absorb more. It has not been studied for weight loss, and the FDA even raised concerns about trial participants who lost more than 10% of their body weight.

Is glepaglutide legal in the Netherlands?

It is not yet a registered medicine in the Netherlands or anywhere else, so it may not be sold, advertised or supplied for use in people. Dutch patients have received it in clinical trials, and EASE SBS 5 is recruiting at Radboud university medical center in Nijmegen. If the European Commission grants the licence, Zeydovio can be prescribed, with treatment started under the supervision of a doctor experienced in short bowel syndrome. DutchPeptides does not sell glepaglutide.

Is glepaglutide banned in sport?

It is not named on the WADA Prohibited List, but as a substance without approval anywhere it falls under class S0, non-approved substances, which is banned at all times. Once it is licensed, S0 no longer applies, and GLP-2 analogues are not named in any other class. In the Netherlands the Dopingautoriteit applies the same list.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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