Glepaglutide
A GLP-2 analogue with a six-lysine tail that made it stable enough to sell as a ready-to-use liquid autoinjector. Its phase 3 trial worked twice weekly and failed once weekly — the FDA asked for another trial, and Europe's regulator recommended approval in September 2026.
Glepaglutide is an experimental injection for short bowel syndrome, a condition where people have lost so much intestine that they need intravenous feeding. It copies a gut hormone that makes the remaining bowel absorb more. In its main trial, injecting twice a week worked and injecting once a week did not. The US regulator asked for another trial; Europe's expert committee recommended approving it in September 2026. The side effects are substantial — most patients in the earlier trial had stoma problems, injection-site reactions or fluid swelling.
What is Glepaglutide?
Glepaglutide is a long-acting analogue of glucagon-like peptide-2, the hormone that tells the intestine to grow and absorb more after a meal. It is being developed for short bowel syndrome with intestinal failure, where enough bowel has been surgically removed that patients cannot absorb sufficient fluid and nutrition by mouth and depend on intravenous parenteral support, often for twelve hours a night. Chemically it is the native 33-amino-acid GLP-2 sequence with nine substitutions, plus something no other peptide in this class carries: a tail of six lysine residues attached to the C-terminus. That tail — the developers call it a Structure Inducing Probe — improved both synthesis yield and physical stability enough that glepaglutide became the first GLP-2 analogue stable in liquid, and therefore the first that can be supplied in a ready-to-use autoinjector rather than a vial of powder. It is not approved in the United States, where the FDA issued a complete response letter in December 2024, but the European Medicines Agency's CHMP adopted a positive opinion on 17 September 2026 under the name Zeydovio, with a European Commission decision pending.
What Glepaglutide Is Investigated For
Glepaglutide's evidence has an unusually clear shape, and it is about dose frequency rather than about whether the drug works. The phase 3 EASE-1 trial randomised 106 patients three ways — 10 mg twice weekly, 10 mg once weekly, or placebo. The twice-weekly arm met the primary endpoint, cutting weekly parenteral support volume by 5.13 litres against 2.85 on placebo, and beat placebo on clinical response and on days off support as well. The once-weekly arm did not separate from placebo on the primary endpoint or on any key secondary. A separate open-label study of once-weekly 10 mg in ten patients then missed its own primary endpoint on wet weight absorption at a P value of 0.0585, though energy absorption and parenteral volume did improve. Converging on the same conclusion from two directions: the weekly schedule that would have been the headline convenience feature is not enough drug. The FDA's complete response letter in December 2024 asked for an additional trial to confirm efficacy and safety at the to-be-marketed dose, which is the regulator making the same point. Europe's filing is for twice weekly, and that is the dose its CHMP opinion covers.
History & Discovery
Zealand Pharma came to GLP-2 from the same place it came to glucagon: a view that the limiting problem with peptide hormones is usually chemistry rather than biology. Native GLP-2 is a 33-amino-acid peptide that is both rapidly degraded and physically unstable, which is why the first analogue, teduglutide, needed only a single substitution to be useful as a drug but still had to be shipped as a freeze-dried powder for reconstitution. Zealand's programme set out to produce something that could be put in a liquid autoinjector. The chemistry paper, published in 2025 but describing work done much earlier, sets out how. Nine substitutions on the GLP-2 backbone improved stability and receptor properties, and a tail of six lysine residues attached to the C-terminus — Structure Inducing Probe technology — markedly improved synthesis yields and gave the molecule the physicochemical stability needed for a ready-to-use formulation. The resulting peptide, ZP1848, became glepaglutide, and the paper is explicit that it is the only hGLP-2 analogue in clinical testing dosed from a ready-to-use injection. The phase 2 trial, published in Lancet Gastroenterology and Hepatology in 2019, was a single-centre crossover in 18 patients using daily injections of 0.1, 1 or 10 mg with metabolic balance studies as the endpoint. It produced a clean dose-response — faecal output down 592 g/day at 1 mg and 833 g/day at 10 mg, nothing at 0.1 mg — and a long and honest list of adverse events, with stoma complications in nearly three-quarters of patients. Phase 3 was where the drug's defining ambiguity appeared. EASE-1 randomised 106 patients to 10 mg twice weekly, 10 mg once weekly or placebo. The twice-weekly arm met the primary endpoint and the key secondaries; the once-weekly arm met nothing. The result put the programme in an awkward position, since the long dosing interval was the point of designing a long-acting analogue in the first place. In December 2024 the FDA issued a complete response letter asking for an additional clinical trial to confirm efficacy and safety at the dose intended for marketing, and Zealand planned a further study, EASE-5, to support US resubmission. A separate open-label phase 3b study of once-weekly dosing then missed its own primary endpoint on wet weight absorption. Europe went a different way. Zealand submitted a marketing authorisation application for the twice-weekly regimen in June 2025, and on 17 September 2026 the CHMP adopted a positive opinion recommending authorisation of Zeydovio for the treatment of adults with short bowel syndrome, with a European Commission decision expected within roughly 67 days. Coverage noted it as the first new treatment recommendation for this indication in Europe in more than a decade — teduglutide having been approved in 2012. Three correspondence pieces questioning aspects of EASE-1 appeared in Gastroenterology in October 2025, and an erratum to the trial paper was published the same month. A drug can be rejected on one side of the Atlantic and recommended on the other on the same dataset, and glepaglutide is a clean example of why: the difference is which dose each application asked for.
How It Works
GLP-2 is the hormone the gut releases after eating to tell its own lining to grow taller, slow down and absorb more. In short bowel syndrome, where much of the intestine has been removed, that signal is both weaker and more needed. Glepaglutide is a longer-lasting copy of the hormone, so an injection keeps the signal going for days. The remaining bowel thickens, transit slows, and more fluid and energy get absorbed — which is what allows the intravenous feeding volume to come down. The practical wrinkle is that it takes two injections a week to do it: once a week was tested in the same trial and did not work.
Glepaglutide is published as [Gly2 Glu3 Thr5 Ser8 Leu10 Ala11,16,24,28]hGLP-2[1-33]-NH-[Lys]6-NH2: the native 33-amino-acid human GLP-2 sequence carrying nine substitutions, extended by a C-terminal tail of six lysine residues. The substitution at position 2, glycine for alanine, blocks cleavage by dipeptidyl peptidase-4 — the same trick teduglutide uses — while the remaining changes improve chemical stability and receptor pharmacology. The hexalysine tail is the distinctive element: added as a Structure Inducing Probe, it substantially improved synthesis yields and conferred enough physicochemical stability for liquid formulation, making glepaglutide the only GLP-2 analogue deliverable from a ready-to-use autoinjector. Pharmacologically it is a GLP-2 receptor agonist. The receptor is a class B G-protein-coupled receptor expressed not on enterocytes but on subepithelial myofibroblasts and enteric neurons, so the trophic effect is indirect, mediated through IGF-1, keratinocyte growth factor, VEGF and nitric oxide, and produces crypt cell proliferation, reduced enterocyte apoptosis, taller villi, increased mucosal blood flow, slower gastric emptying and reduced gastric acid secretion. In patients, phase 2 metabolic balance studies showed daily glepaglutide reducing faecal wet weight output by 592 g/day at 1 mg and 833 g/day at 10 mg, with no effect at 0.1 mg. Mechanistic substudies in the same programme documented changes in intestinal morphology and mucosal perfusion, slower gastrointestinal transit and altered motility, shifts in the bile acid-farnesoid X receptor-FGF19 axis, and effects on markers of liver status — the latter relevant because intestinal failure-associated liver disease is a major competing cause of death in this population. Pharmacokinetics have been characterised in healthy subjects and in renal impairment, and comparative preclinical work placed glepaglutide's rat intravenous clearance at 2.8 mL/kg/min with an elimination half-life of 16 minutes, between teduglutide and apraglutide; the same paper, authored by apraglutide's developers, reported glepaglutide as less potent and less selective at the receptor, a characterisation Zealand Pharma's scientists formally disputed in print.
Evidence Snapshot
Human Clinical Evidence
Moderate but small. One phase 3 randomised controlled trial of 106 patients in which the twice-weekly arm met its primary endpoint and the once-weekly arm did not, one 18-patient randomised crossover phase 2 trial, one 10-patient open-label phase 3b study whose primary endpoint missed significance, plus pharmacokinetic studies in healthy subjects and renal impairment and several mechanistic substudies on morphology, transit, bile acids and liver markers. The FDA issued a complete response letter in December 2024; the CHMP adopted a positive opinion in September 2026. Three correspondence pieces questioning the pivotal trial, and an erratum, are part of the record.
Animal / Preclinical
Adequate and partly exploratory. Comparative pharmacokinetics across species established the clearance profile, work on short- and long-term intestinotrophic effects examined species and sex differences, and separate studies in an experimental inflammatory bowel disease model showed anti-inflammatory and mucosal regenerative effects, extended by a topical glepaglutide-loaded foam formulation.
Mechanistic Rationale
Strong for the target and specific to this molecule for the formulation. GLP-2 receptor biology is well validated by teduglutide's approval since 2012, the dose-response in the phase 2 metabolic balance study was clean, and the chemistry paper documents exactly what the hexalysine tail was for. The weak point is the dose interval: the design intent was a long-acting analogue, and the pivotal trial showed that intent only half-realised.
Research Gaps & Open Questions
What the current literature has not yet settled about Glepaglutide:
- 01Whether twice weekly is the right interval or simply the one that happened to work. The pivotal trial tested exactly two frequencies and one dose; nobody has explored whether three times weekly, a higher twice-weekly dose, or individualised dosing would do better, which is the question the correspondence on personalised dosing raised.
- 02Why once-weekly dosing failed. The molecule was designed as a long-acting analogue and its pharmacokinetics support a long interval, so the gap between predicted and observed performance at seven days is unexplained and has implications for the whole long-acting GLP-2 strategy.
- 03Whether reducing parenteral support changes outcomes that matter. No GLP-2 trial has been powered for catheter-related bloodstream infection, intestinal failure-associated liver disease, transplantation or survival, so even an authorised product would be approved on a surrogate.
- 04How glepaglutide compares with teduglutide and apraglutide in patients. Only indirect network meta-analysis exists, and the one published head-to-head receptor pharmacology comparison was generated by a competitor and disputed by the sponsor.
- 05Long-term safety and neoplasia risk under years of intestinal growth factor exposure, unquantified for the class and only answerable from registries.
- 06Whether the European and American regulators will converge. The same dataset produced a complete response letter and a positive opinion, and how EASE-5 reads out will determine whether that divergence closes.
- 07Whether GLP-2 agonism has a role in inflammatory bowel disease. Anti-inflammatory and mucosal regenerative effects in an experimental colitis model, and a topical foam formulation, are interesting and entirely preclinical.
Forms & Administration
Subcutaneous injection from a ready-to-use liquid autoinjector — the formulation advantage that distinguishes glepaglutide from every other GLP-2 analogue, none of which is stable enough in solution to be supplied that way. The regimen taken into the European application is 10 mg twice weekly. The phase 3 trial also tested 10 mg once weekly, which failed to separate from placebo, and the original phase 2 trial used daily injections at 0.1, 1 and 10 mg. No product is yet authorised, so there is no approved presentation, device description or handling instruction in the public domain; the summary of product characteristics will only be published if and when the European Commission grants the marketing authorisation. In practice, administration is inseparable from a protocol-driven reduction of parenteral support: in EASE-1, support volume was reduced when mean urine volume over a 48-hour balance period exceeded baseline by more than 10%, an algorithm that is itself part of what the trial measured.
Dosing & Protocols
The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.
Typical Range
10 mg twice weekly is the regimen that met the phase 3 primary endpoint and the one submitted for European authorisation. 10 mg once weekly was tested in the same trial and did not separate from placebo on the primary endpoint or on any key secondary. The phase 2 trial used daily injections at 0.1, 1 and 10 mg, with no effect at 0.1 mg.
Frequency
Twice weekly by subcutaneous injection from a ready-to-use autoinjector.
Timing Considerations
Time of day
Any consistent time on the chosen days
Relative to meals
No relationship to food established
Relative to exercise
Not tied to exercise timing.
Twice-weekly dosing is typically spaced across the week; the trial protocol rather than patient preference determined the interval, and no study has compared different spacings of the two weekly doses.
Cycle Length
Indefinite. Short bowel syndrome is a permanent anatomical loss and GLP-2 analogues maintain an adapted mucosa only while they are given, so treatment is continuous.
Protocol Notes
There is no approved dosing guidance to follow, because no regulator has yet authorised the product — the European summary of product characteristics will be published only if the Commission grants the authorisation. What the trial record establishes is narrower and more useful than a dose: frequency is not a convenience variable for this molecule. The same 10 mg dose worked at twice weekly and failed at once weekly within a single randomised trial, and an open-label study of once-weekly dosing subsequently missed its primary endpoint on absorption. Anyone encountering a once-weekly glepaglutide protocol should know it is the regimen the evidence does not support. The second thing worth understanding is that dosing in this condition is only half the intervention. Parenteral support has to be reduced as absorption improves, and in EASE-1 that reduction was triggered by an objective rule — mean urine volume over a 48-hour balance period exceeding baseline by more than 10%. Without that structured weaning, improved absorption simply becomes fluid overload, which is the most likely explanation for peripheral oedema appearing in over half of phase 2 patients.
Glepaglutide is an investigational drug. It received a complete response letter from the FDA in December 2024 and a positive CHMP opinion in September 2026, and is not yet authorised in any jurisdiction. It is not available by prescription, from compounding pharmacies or from peptide suppliers. Short bowel syndrome with intestinal failure is a life-threatening condition requiring management in a specialist intestinal rehabilitation centre.
Timeline of Effects
Onset
Absorptive changes are measurable within weeks. The phase 2 crossover used only three weeks per treatment period and detected faecal output reductions of 592 to 833 g/day over that interval, which makes it the fastest clean signal in the GLP-2 literature. Clinical benefit — litres of intravenous support avoided — arrives more slowly because it is gated by how quickly the weaning protocol permits support to be reduced, and the phase 3 primary endpoint was measured at 24 weeks.
Peak Effect
Still accruing at the end of the trials. The phase 3 trial's clinical response endpoint was assessed at weeks 20 and 24 and the open-label study reported its largest parenteral reductions at week 52, suggesting the plateau lies beyond six months. Whether that reflects continuing mucosal adaptation or continuing weaning is not separable from the available data.
After Discontinuation
Regression toward the untreated state. GLP-2 analogues sustain an adapted mucosa rather than permanently remodelling it, and preclinical work on this class found that linear small-intestinal growth is not fully durable after treatment stops. Parenteral support requirements would be expected to rise again, over weeks rather than days given the long dosing interval. No formal withdrawal study in patients has been published.
Monitoring & Measurement
Bloodwork & Labs
- •Serum electrolytes, urea, creatinine and magnesium, measured repeatedly through parenteral support weaning, where dehydration and overload are both live risks
- •48-hour fluid balance studies with urine volume — the objective trigger used in the phase 3 trial, where a mean urine volume more than 10% above baseline prompted a reduction in support
- •Liver function tests and bilirubin, because intestinal failure-associated liver disease competes with everything else as a threat in this population, and a phase 2 substudy specifically examined glepaglutide's effect on liver markers
- •Plasma citrulline as a marker of enterocyte mass, used across the GLP-2 class
- •Fat-soluble vitamins, trace elements and B12, which remain deficient regardless of treatment
Functional & Performance Tests
- •Stoma or faecal output volume, measured daily during initiation and weaning — the phase 2 primary endpoint and the earliest sign the drug is working
- •Body weight, clinical volume status and peripheral oedema, which together detect the shift from under- to over-replacement sooner than any laboratory value
- •Colonoscopy before starting and periodically afterwards, the class-standard surveillance for an intestinal growth factor
- •Days per week free of parenteral support, the outcome patients consistently identify in exit interviews as the one that changes their life
- •Stoma appliance fit, since mucosal thickening can alter it and stoma obstruction appeared among the serious adverse events
When to Test
In the trial protocols, baseline metabolic balance before the first dose, 48-hour fluid balance studies at intervals to drive support reduction, and formal assessment at 20 and 24 weeks, with the open-label work continuing to 52. Colonoscopy before initiation and at intervals thereafter. Outside a trial there is no schedule, because the drug is not yet authorised anywhere.
Interpretation & Notes
Two things are worth holding onto when reading glepaglutide's numbers. The first is that the endpoint and the intervention are entangled: parenteral support only falls because clinicians deliberately reduce it, and in EASE-1 that reduction was driven by an objective urine-volume rule rather than clinical judgement. Placebo patients on the same rule reduced their weekly volume by 2.85 litres. Any account of what this drug does has to subtract that. The second is that absorption improves before support is reduced, and the interval between the two is where peripheral oedema comes from — more than half of phase 2 patients experienced it, which in a population carrying a central line and often borderline cardiac and renal reserve is not a cosmetic problem. Weight and volume status checked frequently in the early weeks catch it earlier than electrolytes do. The exit-interview study is the one piece of this literature that explains why patients and clinicians persist with a treatment whose adverse event list runs this long: a single day a week disconnected from the pump reads very differently from the inside than a 5.13-litre reduction does on paper.
Common Questions
Why does the dosing frequency matter so much?
Because it is the one thing the trials disagreed about. EASE-1 tested 10 mg twice weekly and 10 mg once weekly against placebo in the same study, and the two arms produced opposite results: twice weekly reduced weekly parenteral support volume by 5.13 litres versus 2.85 on placebo and was superior on clinical response and days off support, while once weekly showed no statistically significant difference on the primary endpoint or on any key secondary. A separate open-label phase 3b study of once-weekly 10 mg in ten patients missed its primary endpoint on wet weight absorption at P = 0.0585. The FDA's complete response letter then asked specifically for confirmation of efficacy and safety at the to-be-marketed dose. Read together, these are three independent signals that weekly dosing underpowers the drug, and the European application accordingly covers the twice-weekly regimen.
What is the six-lysine tail for?
Manufacturing and stability, not pharmacology. Native GLP-2 is chemically and physically unstable as well as short-lived, which is why the first analogue, teduglutide, is supplied as a lyophilised powder requiring reconstitution. Zealand's chemists found that adding a hexalysine tail to the C-terminus — their Structure Inducing Probe approach — substantially improved synthesis yields and gave the finished peptide enough physicochemical stability to survive in liquid formulation. The published structure is the 33-residue hGLP-2 backbone with nine amino acid substitutions and that NH-(Lys)6-NH2 tail. The practical result is the only GLP-2 analogue that can be dosed subcutaneously from a ready-to-use autoinjector, which for someone already managing nightly infusions and a central line is a meaningful reduction in daily handling.
How does it compare with teduglutide and apraglutide?
No head-to-head trial has ever been run, so comparisons are indirect and partly contested. The one published direct comparison of receptor pharmacology came from apraglutide's developers, who reported that apraglutide and teduglutide retain potency and selectivity comparable to native human GLP-2 while glepaglutide was less potent and less selective, with a rat intravenous clearance of 2.8 mL/kg/min against apraglutide's 0.27 and teduglutide's 9.9. Four scientists from Zealand Pharma, glepaglutide's developer, published a formal comment in the same journal disputing that characterisation, and a correction was issued alongside. A network meta-analysis attempting an indirect ranking exists but is limited by differing endpoints and weaning algorithms across the three programmes. What can be said without controversy: teduglutide is daily and approved, apraglutide is weekly and requires a second phase 3 trial, and glepaglutide is twice weekly with a positive European opinion and a US complete response letter.
What are the side effects actually like?
Substantial, and the phase 2 trial reported them more plainly than most. Among 18 patients receiving daily glepaglutide, treatment-related adverse events included stoma complications in 72%, injection-site reactions in 61%, peripheral oedema in 56%, nausea and abdominal pain in 44% each, polyuria and fatigue in 33% each, abdominal distension, vomiting and dizziness in 28% each, and cough and decreased appetite in 22% each. Four patients had related or possibly related serious adverse events, including abdominal pain, stoma obstruction, catheter-related sepsis and infection of unknown origin. The paper's conclusion describes the drug as well tolerated, which is accurate in the regulatory sense that nothing required stopping development, and worth reading alongside the numbers. Most of these are class effects of driving intestinal growth and absorption in a bowel that has been surgically shortened, and peripheral oedema in particular reflects improving absorption while intravenous support is still being tapered.
Can I get glepaglutide?
Not yet, anywhere. The FDA issued a complete response letter in December 2024 requesting an additional trial, and a study named EASE-5 is planned to support resubmission in the United States. In Europe, a marketing authorisation application for the twice-weekly regimen was submitted in June 2025 and the CHMP adopted a positive opinion on 17 September 2026 for Zeydovio, for the treatment of adults with short bowel syndrome; the European Commission decision was expected within roughly 67 days of that opinion, which points to late in 2026. Until the Commission grants the authorisation, the summary of product characteristics is not even published. Access in the meantime is through clinical trials at specialist intestinal rehabilitation centres. Teduglutide remains the approved GLP-2 analogue.
Who Glepaglutide Is NOT For
- •Active gastrointestinal malignancy, or malignancy elsewhere in the gastrointestinal tract, because GLP-2 analogues are intestinal growth factors — a class consideration carried from the approved agents rather than an observed glepaglutide finding.
- •Known or suspected intestinal obstruction. Stoma obstruction was among the serious adverse events in the phase 2 trial, and increasing mucosal bulk in an already narrowed segment is the mechanism.
- •Active biliary or pancreatic disease, monitored across the class because GLP-2 affects biliary flow and pancreatic secretion.
- •Known hypersensitivity to glepaglutide or its excipients.
- •Pregnancy and breastfeeding — no data.
- •Children — the programme has been conducted entirely in adults.
- •Any use outside a clinical trial while the drug remains unauthorised, and in particular any use of the once-weekly regimen, which failed to separate from placebo in the pivotal trial.
Drug & Supplement Interactions
No dedicated drug interaction programme has been published, and no authorised label exists to consult. Two considerations dominate in practice. The first is pharmacodynamic and unavoidable: glepaglutide increases enteral absorption, so intravenous fluid and nutrition must come down as it works, and failing to taper produces fluid overload — peripheral oedema was reported in 56% of phase 2 patients and is best understood as an interaction with the patient's parenteral prescription rather than as a side effect of the drug alone. The second is a class effect on oral drug absorption. By increasing absorptive surface and slowing gastric emptying and intestinal transit, GLP-2 analogues can increase the absorption of co-administered oral medicines, which matters most for narrow-therapeutic-index drugs and for sedatives and opioids that are commonly used in this population; the approved agents in the class carry exactly this caution, and patients with short bowel syndrome frequently have unpredictable oral absorption to begin with. Pharmacokinetically, glepaglutide is a peptide cleared by proteolysis rather than by cytochrome P450 enzymes, so metabolic interactions are not anticipated; dedicated studies in healthy subjects and in renal impairment have been published. Mechanistic substudies also documented shifts in the bile acid-FXR-FGF19 axis, which is worth bearing in mind in patients taking bile acid sequestrants, though no interaction has been formally demonstrated.
Safety Profile
Common Side Effects
Cautions
- • Fluid overload is the characteristic hazard of effective GLP-2 therapy. As enteral absorption improves, unchanged intravenous volume becomes excess volume, and peripheral oedema was reported in more than half of phase 2 patients. Parenteral support must be reduced on a measured schedule.
- • Stoma complications are frequent and include obstruction, not merely increased output; patients with an ostomy need close review in the first weeks.
- • GLP-2 analogues are intestinal growth factors, and the class carries a theoretical neoplasia risk that is managed with colonoscopy before starting and periodic surveillance thereafter.
- • Serious adverse events in the phase 2 trial included catheter-related sepsis — a constant hazard in this population that is not caused by the drug but is not removed by it either.
- • Biliary and pancreatic function are monitored across the class, since GLP-2 influences biliary flow and pancreatic secretion.
- • Once-weekly dosing should not be assumed to be a lower-risk version of the same treatment; in the phase 3 trial it was simply ineffective, and an ineffective dose carries adverse effects without benefit.
- • No data exist in pregnancy, lactation or children, and the entire randomised dataset comprises roughly 130 patients.
What We Don't Know
For a drug on the edge of European authorisation, the evidence base is strikingly small — 106 randomised patients in the pivotal trial, 18 in phase 2, 10 in the open-label phase 3b study. Three separate groups published correspondence in Gastroenterology questioning aspects of the pivotal trial, with titles that between them ask whether the results generalise and whether dosing should be individualised rather than fixed, and an erratum to the paper was published in October 2025. The specific open questions are about dose and duration: whether twice weekly is optimal or merely sufficient, whether individual patients need more or less, and what happens over years rather than the 24 weeks the trial ran. Beyond that, the field-wide gaps apply. No GLP-2 trial has been powered for catheter infections, liver disease, transplantation or survival, so approval rests on a surrogate endpoint. Long-term neoplasia risk under sustained intestinal growth factor exposure is unquantified. And the inflammatory bowel disease work — anti-inflammatory and mucosal regenerative effects in an experimental colitis model, and a glepaglutide-loaded foam for topical delivery — is entirely preclinical.
Legal Status
United States
Investigational. The FDA issued a complete response letter in December 2024 for the glepaglutide new drug application in short bowel syndrome, requesting an additional clinical trial to provide further evidence confirming efficacy and safety at the to-be-marketed dose. A phase 3 study, EASE-5, is planned to support resubmission. Glepaglutide has no US brand name, is not a controlled substance, and is not legally available outside a clinical trial or from any compounding pharmacy.
International
Closest to authorisation in Europe. A marketing authorisation application for the twice-weekly regimen was submitted to the EMA in June 2025, and on 17 September 2026 the CHMP adopted a positive opinion recommending authorisation of Zeydovio (glepaglutide acetate), with the indication wording covering the treatment of adults with short bowel syndrome. The European Commission decision was outstanding as of late October 2026 and had been expected within roughly 67 days of the opinion; an authorisation would extend to the EU member states plus Iceland, Liechtenstein and Norway. The product information, including the summary of product characteristics, is published only after the Commission grants the authorisation, so the final indication and dosing text are not yet public.
Sports & Competition
Not prohibited. GLP-2 and its analogues appear nowhere on the WADA Prohibited List, and the growth factor catch-all in class S2.3 is written around factors affecting muscle, tendon, ligament, vascularisation, energy utilisation, regenerative capacity or fibre type switching — not a trophic hormone restricted to the intestinal mucosa. The separate prohibition on substances with no current approval for human therapeutic use would nonetheless apply while glepaglutide remains unauthorised, so an athlete could not use it outside a trial regardless.
Regulatory status changes over time. Verify current local rules with a qualified professional.
Myths & Misconceptions
Myth
Glepaglutide is a once-weekly GLP-2 analogue.
Reality
It was designed to be and it is not. The phase 3 trial randomised patients to 10 mg twice weekly, 10 mg once weekly and placebo; twice weekly met the primary endpoint and every key secondary, and once weekly met none of them. A separate open-label study of once-weekly dosing then missed its own primary endpoint on wet weight absorption at P = 0.0585. The European application is for twice weekly, and the FDA's complete response letter asked specifically for confirmation at the to-be-marketed dose.
Myth
The FDA rejected it because the drug does not work.
Reality
The complete response letter asked for an additional trial to confirm efficacy and safety at the dose intended for marketing — a dose question, not a verdict on the mechanism. The same dataset supported a positive CHMP opinion in Europe in September 2026 for the twice-weekly regimen. Two regulators reading one trial differently usually reflects what each application asked them to approve.
Myth
It is well tolerated.
Reality
That phrase appears in the phase 2 publication and means something specific: nothing required halting development. The numbers from the same paper are stoma complications in 72% of patients, injection-site reactions in 61%, peripheral oedema in 56%, nausea and abdominal pain in 44% each, and four of 18 patients with related or possibly related serious adverse events including stoma obstruction and catheter-related sepsis. These are mostly consequences of making a surgically shortened bowel grow and absorb more, and they are not trivial.
Myth
The six-lysine tail makes it more potent.
Reality
It makes it manufacturable and stable. The design paper describes the hexalysine tail as Structure Inducing Probe technology that markedly improved synthesis yields and gave the peptide enough physicochemical stability for a liquid formulation — which is why it is the only GLP-2 analogue in a ready-to-use autoinjector. On potency, the one published direct comparison, from a competitor, reported glepaglutide as less potent and less selective at the receptor than apraglutide or teduglutide, and the sponsor disputed it.
Myth
It will cure short bowel syndrome.
Reality
Five patients in the entire 106-patient pivotal trial achieved full enteral autonomy. For the rest, the realistic outcome is fewer litres and fewer nights on intravenous support — in the twice-weekly arm, 51.4% achieved at least one day a week off, against 19.4% on placebo. That is a meaningful change to a life organised around an infusion pump, and it is not independence from one. GLP-2 analogues maintain an adapted mucosa while they are given; the anatomy does not come back.
Published Research
27 studiesBeyond intestinal failure: Expanding therapeutic frontiers of glucagon-like peptide-2 in gastrointestinal disease
Glucagon-like peptide agonists and use in short bowel syndrome - what about the side effects?
Exploring the disease burden and quality of life in patients with short bowel syndrome with intestinal failure: Insights from exit interviews in the glepaglutide phase 3 trial
Exit interviews with EASE-1 participants, and a useful corrective to reading this field purely in litres of parenteral support. What patients describe — hours tethered to a pump, interrupted sleep, catheter anxiety, restricted travel and work — explains why a day a week off support registers as a large change even when the volume reduction looks modest on paper.
Investigation of the stool microbiome of short bowel syndrome patients before and after a 24-week treatment with the glucagon-like peptide 2 analog glepaglutide
Positive clinical outcomes associated with use of glucagon-like peptide-2 (GLP-2) analogues in patients with intestinal failure: A systematic review and meta-analysis
Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome
Ten patients, open-label, 10 mg once weekly, with gold-standard metabolic balance measurement. The primary endpoint — absolute change in intestinal wet weight absorption at 24 weeks — missed significance at P = 0.0585, while energy absorption rose by 1,038 kJ/day (P = 0.0215) and parenteral support volume fell by 800 mL/day at week 52 (P = 0.0106). A second independent indication that the once-weekly interval sits at the edge of what this molecule can deliver.
Potential and Challenges of Glepaglutide for SBS-IF
Glepaglutide in Short Bowel Syndrome: Promising, But Questions Remain
One of three independent correspondence pieces published in Gastroenterology in October 2025 responding to EASE-1, alongside letters on personalised dosing and on the drug's potential and challenges. Three separate author groups publishing on a single 106-patient trial is itself a signal of how much interpretive weight a small pivotal study in a rare disease has to carry.
Personalized Dosing Strategies: The Missing Link in Glepaglutide Therapy for Short Bowel Syndrome
Glepaglutide-Loaded Foam for the Induction of Mucosal Healing in the Treatment of Inflammatory Bowel Disease
Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection
The design paper, and the source of the published structure: [Gly2Glu3Thr5Ser8Leu10Ala11,16,24,28]hGLP-2[1-33]-NH-[Lys]6-NH2. It explains what the six-lysine tail is for — Structure Inducing Probe technology that markedly improved synthesis yields and physicochemical stability, enough to make glepaglutide the only GLP-2 analogue dosed subcutaneously from a ready-to-use liquid formulation in an autoinjector.
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, the pivotal trial, and the clearest dose-frequency result in the GLP-2 literature. 106 patients randomised 1:1:1 to glepaglutide 10 mg twice weekly, 10 mg once weekly or placebo for 24 weeks. Twice weekly met the primary endpoint, reducing weekly parenteral support volume by 5.13 litres against 2.85 on placebo (P = .0039), with clinical response in 65.7% versus 38.9% and at least one day a week off support in 51.4% versus 19.4%. Once weekly showed no significant difference from placebo on the primary endpoint or any key secondary. Five patients across the trial achieved full enteral autonomy. An erratum was published in October 2025.
Use of glucagon-like polypeptide 2 analogs for intestinal failure
Intestinal adaptation and rehabilitation in adults with short bowel syndrome
Emerging drugs for the treatment of short bowel syndrome
Efficacy and safety of glucagon-like peptide 2 in patients with short bowel syndrome: a systematic review and network meta-analysis
Glepaglutide, a novel glucagon-like peptide-2 agonist, has anti-inflammatory and mucosal regenerative effects in an experimental model of inflammatory bowel disease
Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment
Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects
Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial
Short- versus long-term, gender and species differences in the intestinotrophic effects of long-acting glucagon-like peptide 2 analog
Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial
Comments on 'Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome'
Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome
The comparative study that placed glepaglutide's rat intravenous clearance at 2.8 mL/kg/min and half-life at 16 minutes, between teduglutide and apraglutide — and also reported glepaglutide as less potent and less selective at the GLP-2 receptor than either. It was written by apraglutide's developers, four Zealand Pharma scientists published a formal comment disputing it, and a correction followed. Cited here because it is the only direct comparison that exists, and because knowing who generated it is part of reading it.
Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome
Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial
Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial
Eighteen patients, daily dosing at 0.1, 1 and 10 mg in a crossover design with metabolic balance studies. Faecal wet weight output fell by 592 g/day at 1 mg and 833 g/day at 10 mg, with no effect at 0.1 mg. The adverse event list is the most candid in the programme: stoma complications 72%, injection-site reactions 61%, peripheral oedema 56%, nausea and abdominal pain 44% each, and four patients with related serious events including stoma obstruction and catheter-related sepsis. Funded by Zealand Pharma.
Quick Facts
- Class
- GLP-2 Analogue
- Tier
- C
- Evidence
- Moderate
- Safety
- Moderate Data
- Updated
- Oct 2026
- Citations
- 27PubMed
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Clinical Trials
View Clinical TrialsLinks to ClinicalTrials.gov for reference. Listing does not imply endorsement.