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MetabolicHuman studies cited: 6

Glepaglutide

Glepaglutide (ZP1848), long-acting GLP-2 receptor agonist

Written by Reviewed Sep 2026

Also known as: ZP1848

A long-acting GLP-2 analogue for short bowel syndrome with intestinal failure. In a 106 person phase 3, 10 mg twice weekly cut weekly parenteral support volume by 5.13 litres against 2.85 on placebo; the once-weekly arm did not separate from placebo. Not approved anywhere as of September 2026, with a further phase 3 recruiting.

Overview

Glepaglutide is a synthetic analogue of glucagon-like peptide 2 (GLP-2), the gut hormone that drives intestinal growth and absorption, engineered by Zealand Pharma for a long enough half-life to be given once or twice a week as a ready-to-use injection. It is a candidate treatment for short bowel syndrome with intestinal failure, in which people who have lost most of their small intestine depend on intravenous parenteral support for fluid and nutrition. The approved drug in this class, teduglutide, is a daily injection.

The pivotal trial is EASE SBS-1 (NCT03690206), an international, randomised, double-blind, placebo-controlled phase 3 published in Gastroenterology in 2025. 106 adults on parenteral support at least 3 days a week were randomised 1:1:1 to glepaglutide 10 mg twice weekly, 10 mg once weekly, or placebo for 24 weeks. Twice-weekly dosing reduced weekly parenteral support volume by 5.13 litres against 2.85 litres on placebo (P equals 0.0039, the primary endpoint). 65.7 percent against 38.9 percent achieved a 20 percent or greater reduction (P equals 0.0243), 51.4 against 19.4 percent dropped at least one day a week of support (P equals 0.0043), and 5 people (14 percent) on twice-weekly dosing came off parenteral support entirely against none on placebo. The once-weekly arm showed no statistically significant difference from placebo on the primary or key secondary endpoints. That is a dose regimen failure inside a positive trial and it shaped what came next. The earlier 18 person phase 2 crossover trial (Lancet Gastroenterology and Hepatology, 2019) had shown reductions in faecal wet weight of 592 g per day at 1 mg and 833 g per day at 10 mg daily, none at 0.1 mg, with stoma complications in 72 percent, injection site reactions in 61 percent and peripheral oedema in 56 percent of participants.

Regulatory position: not approved. No application appears in Drugs@FDA and the European Medicines Agency has no medicine page for glepaglutide as of 11 September 2026. Two long-term extension trials (150 and 84 participants) completed in April 2026 with no results posted. A new phase 3, NCT07197944, began recruiting in February 2026 with an estimated 90 participants and a primary completion date of October 2028; its registered purpose is to confirm the efficacy and safety of 10 mg twice weekly and to generate additional long-term safety data. Three letters in Gastroenterology and one in Clinical Nutrition ESPEN have raised questions about dosing strategy, generalisability and attrition.

Mechanism of action

GLP-2 is released by intestinal L cells after meals and acts on the GLP-2 receptor to increase villus height and crypt depth, slow gastric emptying, raise intestinal blood flow and improve absorption of fluid and nutrients. People who have lost their terminal ileum and colon lose most of their GLP-2 producing cells, which is part of why the remaining bowel adapts poorly. Glepaglutide is a GLP-2 receptor agonist modified for slow release from the injection site and a long circulating half-life, which is what allows twice-weekly dosing where native GLP-2 lasts minutes and teduglutide is dosed daily. In people, the measurable effects are on absorption. The phase 2 trial measured intestinal wet weight and energy absorption by metabolic balance studies and found dose-dependent improvements at 1 and 10 mg. A 10 person open-label study reported a mean increase in wet weight absorption of 398 g per day at 24 weeks that did not reach significance (P equals 0.0585) and an energy absorption gain of 1,038 kJ per day that did (P equals 0.0215). The clinically relevant endpoint in phase 3, reduction in parenteral support volume, is downstream of these absorption changes.

Human evidence

One randomised, double-blind, placebo-controlled phase 3 of 106 people over 24 weeks, one randomised crossover phase 2 of 18, one uncontrolled 10 person absorption study, and two long-term extensions totalling 234 people that completed in 2026 without posted results. All funded by Zealand Pharma.

  • EASE SBS-1: 106 adults, 24 weeks. Twice-weekly 10 mg reduced weekly parenteral support by 5.13 litres against 2.85 on placebo; 14 percent achieved full independence from parenteral support against none on placebo.
  • EASE SBS-1 once-weekly arm: no statistically significant difference from placebo on the primary or key secondary endpoints.
  • Phase 2 crossover, 18 people: faecal output fell 592 g per day at 1 mg and 833 g per day at 10 mg daily; nothing at 0.1 mg. Adverse events were frequent: stoma complications 72 percent, injection site reactions 61 percent, peripheral oedema 56 percent.
  • Open-label 10 person study: energy absorption up 1,038 kJ per day at 24 weeks; wet weight absorption change not significant; parenteral support down 800 mL per day at 52 weeks. No control group.
  • Extensions NCT03905707 (150) and NCT04881825 (84): completed April 2026, no results posted.
  • New phase 3 NCT07197944 (90 estimated) recruiting from February 2026, primary completion October 2028.

What this does not tell you: One positive phase 3 in a rare disease, with one of two active arms failing, is the whole controlled record. The primary endpoint is parenteral support volume, which is protocol-driven (support was reduced when urine output rose) rather than a hard clinical outcome. Nobody has compared glepaglutide with teduglutide, the approved GLP-2 analogue, in a randomised trial, so nothing here says whether twice-weekly dosing is better, worse or the same as daily teduglutide. Long-term safety data exist in two completed extensions but have not been published or posted. GLP-2 analogues promote intestinal growth, and the class carries a theoretical concern about accelerating polyp or neoplasm growth that 24 week trials cannot address.

Reading the research record

Glepaglutide's record is the record of a single sponsor developing a drug for a very small population. Short bowel syndrome with intestinal failure affects a few thousand people in each large country, so trials are small by necessity: 106 people is a large phase 3 in this field. The phase 3 met its primary endpoint for one of its two dose regimens and missed for the other, and the once-weekly failure is the fact most worth carrying forward, because it shows that the dose interval matters and that a long-acting peptide is not automatically long-acting enough.

What happened after the phase 3 is visible only in the registry. The research document this profile was built from stated that all registered phase 3 trials were complete. That was true when it was written and is no longer true: a new confirmatory phase 3 (NCT07197944) started in February 2026 with an estimated 90 participants and a primary completion date in late 2028, described by the sponsor as confirming the efficacy and safety of the twice-weekly regimen and generating additional long-term safety data. No regulator has announced a decision and no application appears in Drugs@FDA or on the EMA website. Whether the new trial was requested by a regulator or chosen by the sponsor is not stated in any primary source, and this profile does not guess. The two completed extensions, 234 people in total, have posted no results, which is a finding in itself until they do.

The evidence, charted

Fig. 1 · evidence composition

6of 8 citations (75%) are in people

Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.

Fig. 2 · evidence over time

Evidence spans 4 distinct years, 2019 to 2026, counted from the citation list on this page.

Fig. 3 · legal status at a glance

Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.

Key studies & citations

  • Human2025

    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 SBS-1: 106 adults with short bowel syndrome and intestinal failure randomised 1:1:1 to 10 mg twice weekly, 10 mg once weekly or placebo for 24 weeks. Weekly parenteral support fell 5.13 litres on twice-weekly dosing against 2.85 on placebo (P equals 0.0039). Clinical response 65.7 against 38.9 percent; at least one fewer day on support 51.4 against 19.4 percent; enteral autonomy in 5 (14 percent) against 0. The once-weekly arm did not differ significantly from placebo on any primary or key secondary endpoint. Sponsor Zealand Pharma.

    Gastroenterology
  • Human2024

    Efficacy And Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome (EASE SBS-1)

    Phase 3, 106 participants, completed July 2022, results posted 21 October 2024. Sponsor Zealand Pharma.

    ClinicalTrials.gov
  • Human2019

    Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial

    Single-centre, double-blind crossover in 18 adults with faecal output of 1,500 g a day or more, two 3 week periods of daily injections at 0.1, 1 or 10 mg; 16 completed. Faecal wet weight fell 592 g per day at 1 mg (95 percent CI 272 to 913) and 833 g per day at 10 mg (515 to 1,152); no change at 0.1 mg. Treatment-related adverse events: stoma complications 72 percent, injection site reactions 61 percent, peripheral oedema 56 percent, nausea and abdominal pain 44 percent each. Funded by Zealand Pharma.

    Lancet Gastroenterology and Hepatology
  • Human2025

    Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome

    Single-centre open-label phase 3b in 10 patients (8 with intestinal failure) on 10 mg once weekly. Wet weight absorption rose 398 g per day at 24 weeks (P equals 0.0585, not significant); energy absorption rose 1,038 kJ per day (P equals 0.0215); parenteral support fell 800 mL per day at week 52 (P equals 0.0106). No control group. Four authors are Zealand employees. The registry record (NCT04991311) lists 12 enrolled against 10 reported.

    Clinical Nutrition ESPEN
  • Human2026

    Evaluation of Long Term Safety and Efficacy of Glepaglutide in Treatment of SBS

    Phase 3 long-term extension, 150 participants, completed with primary completion 30 April 2026; no results posted as of 11 September 2026. A second extension (NCT04881825, 84 participants) completed the same day, also without posted results.

    ClinicalTrials.gov
  • Human2026

    Efficacy And Safety Evaluation of Glepaglutide in Treatment of SBS (new phase 3)

    Phase 3, estimated 90 participants, recruiting since 11 February 2026, primary completion 23 October 2028. Registered purpose: to confirm the efficacy and safety of glepaglutide 10 mg twice weekly and to generate additional long-term safety data. A 28 person extension for prior trial participants (NCT07228403, EASE SBS 6) is active.

    ClinicalTrials.gov
  • Review2025

    Personalized Dosing Strategies: The Missing Link in Glepaglutide Therapy for Short Bowel Syndrome

    One of three letters published in response to EASE SBS-1 (with PMIDs 40517965 and 40516831), questioning the dosing strategy given the failure of the once-weekly arm and the generalisability of the result.

    Gastroenterology
  • Review2026

    Interpreting pooled GLP-2 analogue effects in chronic intestinal failure: transparency, attrition, and real-world generalisability

    Letter raising attrition and generalisability concerns about pooled estimates of GLP-2 analogue effect in intestinal failure, including the glepaglutide data.

    Clinical Nutrition ESPEN

Frequently asked questions

Is glepaglutide approved?

No. As of September 2026 there is no application in the FDA's Drugs@FDA database and no medicine page at the European Medicines Agency. The pivotal phase 3 is published and a further phase 3 is recruiting with completion expected in 2028.

How does it compare with teduglutide?

No randomised head to head trial exists. Teduglutide is a daily injection; glepaglutide was tested at once and twice weekly, and only twice weekly separated from placebo. Cross-trial comparisons between the two are not reliable because the populations and endpoint definitions differ.

What did the phase 3 show?

In 106 people with short bowel syndrome on intravenous support at least 3 days a week, 24 weeks of 10 mg twice weekly reduced weekly support volume by 5.13 litres against 2.85 litres on placebo. About two thirds versus two fifths achieved a 20 percent reduction, and 5 people on the drug came off support entirely against none on placebo. The once-weekly dose did not beat placebo.

What are the side effects?

In the 18 person phase 2 with daily dosing, stoma complications affected 72 percent, injection site reactions 61 percent, swelling of the legs 56 percent, and nausea and abdominal pain 44 percent each. Fluid retention and stoma changes are expected consequences of a drug that increases intestinal absorption and tissue growth. The phase 3 publication described the drug as well tolerated without giving comparable rates in its abstract.

Related compounds

TeduglutideGLP-2GLP-1