Glepaglutide

A synthetic, long-acting glucagon-like peptide-2 analog from Zealand Pharma that reduced parenteral-support volume in the phase 3 EASE SBS 1 trial in short bowel syndrome, drew an FDA complete response letter in December 2024, received a positive CHMP opinion in Europe in September 2026, with a confirmatory trial, EASE SBS 5, underway in response to the FDA's request for a second trial.

Also referenced as: ZP1848, ZP-1848, glepaglutide acetate, Zeydovio

Also appears in: Metabolic

COA Public product evidence No certificate records are bound to a tracked Glepaglutide product page A record counts here only when a vendor publishes a certificate against one of its own tracked Glepaglutide product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

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What is Glepaglutide?

Glepaglutide (development code ZP1848) is a synthetic 39-amino-acid analog of human glucagon-like peptide-2 (GLP-2), the intestinotrophic hormone that intestinal L-cells release from the same proglucagon precursor that yields glucagon and GLP-1. Zealand Pharma built it from the 33-residue native sequence with nine substitutions (glycine at position 2, the DPP-4-protecting change that also defines teduglutide, plus glutamate at 3, threonine at 5, serine at 8, leucine at 10, and alanine at 11, 16, 24, and 28), followed by a C-terminal amidated tail of six lysines added to improve synthesis yield; the combination gave a peptide with enough chemical and physical stability to be supplied as a ready-to-use liquid in an autoinjector rather than a powder that must be reconstituted (Larsen et al., Journal of Medicinal Chemistry, 2025;68(3):3134–3145).

It is developed for short bowel syndrome with intestinal failure (SBS-IF), the indication teduglutide holds and the indication apraglutide is also being developed for, where the goal is to shrink a patient’s dependence on intravenous fluids and nutrition. The FDA granted orphan drug designation for short bowel syndrome on October 24, 2017. Glepaglutide acetate is listed by laboratory-reagent suppliers as research-use-only reference material and is not a research-market product.

How it works

• GLP-2 receptor agonism. Glepaglutide activates the GLP-2 receptor, which sits on enteroendocrine cells, subepithelial myofibroblasts, and enteric neurons rather than on absorptive enterocytes, so the mucosal growth signal is relayed indirectly through local mediators such as IGF-1. In a head-to-head in vitro comparison run by apraglutide’s developer, glepaglutide was less potent and less selective at the GLP-2 receptor than native GLP-2, teduglutide, or apraglutide; in rat intravenous studies its clearance was 2.8 mL/kg/min and its elimination half-life 16 minutes, against 9.9 mL/kg/min and 19 minutes for teduglutide and 25 mL/kg/min and 6.4 minutes for native GLP-2 (Hargrove et al., Journal of Pharmacology and Experimental Therapeutics, 2020;373(2):193–203).
• A subcutaneous depot, not a long-lived parent molecule. The long action comes from slow release from the injection site rather than from slow clearance in blood. In healthy adults the two main metabolites accounted for more than 98% of steady-state exposure and the parent peptide for less than 1%, and the estimated effective half-life was 124 hours at 5 mg and 88 hours at 10 mg, with plasma citrulline, a marker of enterocyte mass, rising on both doses (Agersnap et al., Clinical Drug Investigation, 2022;42(12):1093–1100). That depot behavior is what supports weekly and twice-weekly dosing.
• Mucosal expansion and reduced output. In the phase 2 crossover trial, three weeks of daily injections at 1 mg and 10 mg increased plasma citrulline by 15.3 and 15.6 µmol/L, respectively, with trends toward greater villus height, crypt depth, and epithelial height on biopsy but no change in stomal perfusion (Naimi et al., JPEN Journal of Parenteral and Enteral Nutrition, 2023;47(1):140–150). The same trial’s primary readout was a fall in fecal wet-weight output of 592 g/day at 1 mg and 833 g/day at 10 mg (Naimi et al., Lancet Gastroenterology & Hepatology, 2019;4(5):354–363).
• Slower transit. At the 10 mg dose, glepaglutide delayed the time to 10% gastric emptying of solids by 27 minutes and to 50% emptying of fluids by 40 minutes, with a 21-minute delay in early small-bowel emptying of solids, giving the remnant bowel more contact time with luminal content (Hvistendahl et al., JPEN Journal of Parenteral and Enteral Nutrition, 2020;44(8):1535–1544).

Research status

Glepaglutide has one completed pivotal trial with a positive primary endpoint at one of its two doses, an FDA rejection that asked for a second trial, a European recommendation for approval that was still awaiting the European Commission’s decision as of November 2026, and a confirmatory phase 3 trial that is enrolling.

Phase 2 (NCT02690025). A single-center, double-blind, crossover, dose-finding trial at Rigshospitalet in Copenhagen randomized 18 adults with short bowel syndrome and fecal output of at least 1,500 g/day to two of three doses (0.1, 1, or 10 mg) given as daily subcutaneous injections for three weeks each, separated by a 4–8-week washout; 16 completed. Fecal wet weight fell by an adjusted 592 g/day on 1 mg (p = 0.002) and 833 g/day on 10 mg (p = 0.0002), with no effect at 0.1 mg. Treatment-related adverse events were frequent: stoma complications in 72% of patients, injection-site reactions in 61%, peripheral edema in 56%, and nausea and abdominal pain in 44% each (Naimi et al., Lancet Gastroenterology & Hepatology, 2019;4(5):354–363). Companion analyses from the same cohort covered transit time, mucosal morphology, liver markers (Naimi et al., EBioMedicine, 2019;46:444–451), and the bile acid–FGF19 axis (Hvistendahl et al., JPEN Journal of Parenteral and Enteral Nutrition, 2022;46(4):923–935).

EASE SBS 1 (NCT03690206), the pivotal trial. An international, double-blind, placebo-controlled phase 3 trial that ran from October 4, 2018 to July 26, 2022 and randomized 106 adults with SBS-IF needing parenteral support at least three days per week 1:1:1 to 24 weeks of glepaglutide 10 mg twice weekly, 10 mg once weekly, or placebo. Zealand announced topline results on September 30, 2022. The twice-weekly arm met the primary endpoint: mean weekly parenteral-support volume fell by 5.13 L versus 2.85 L on placebo (p = 0.0039), with similar results across anatomic subgroups. Key secondary endpoints also favored twice-weekly dosing: 65.7% versus 38.9% achieved at least a 20% volume reduction at both weeks 20 and 24 (p = 0.0243), and 51.4% versus 19.4% gained at least one day per week off parenteral support (p = 0.0043). Five twice-weekly patients (14%) and no placebo patients reached enteral autonomy; Zealand counted nine across both glepaglutide arms. The once-weekly arm reduced volume by 3.13 L/week and produced a 45.7% response rate, neither statistically different from placebo (Jeppesen et al., Gastroenterology, 2025;168(4):701–713.e6; an erratum followed in October 2025). Results were posted to the registry on October 21, 2024: no deaths occurred, serious adverse events affected 9 of 35 twice-weekly, 10 of 35 once-weekly, and 7 of 36 placebo patients, and injection-site reactions were recorded in 9, 15, and 1 patients, respectively. Of the 106 patients, 102 completed; all four withdrawals were in the twice-weekly arm.

Extensions and mechanistic work. EASE SBS 2 (NCT03905707) was a double-blind extension open to completers of EASE SBS 1 and of the phase 2 trial, in which former placebo patients were moved onto one of the two glepaglutide regimens; the registry lists 150 participants and completion on April 30, 2026. EASE SBS 3 (NCT04881825), a 104-week single-arm extension that evaluated once-weekly autoinjector dosing in 84 patients rolling over from EASE SBS 2, completed the same day. Zealand’s NDA and MAA cited interim analyses from both showing that parenteral-support reductions were generally maintained or improved; neither has been published in full. EASE SBS 4 (NCT04991311), a single-center open-label phase 3b metabolic balance study in 10 treated patients on once-weekly dosing, reported a 398 g/day increase in wet-weight absorption at week 24 that did not reach significance (p = 0.0585), a 1,038 kJ/day increase in energy absorption (p = 0.0215), and an 800 mL/day reduction in parenteral-support volume at week 52 (Pinar et al., Clinical Nutrition ESPEN, 2025;69:590–598). EASE SBS 6 (NCT07228403), a further 104-week open-label extension for patients leaving EASE SBS 2 or 3, began December 11, 2025 with 28 participants and is active but not recruiting.

The FDA complete response letter. Zealand announced submission of a New Drug Application on December 22, 2023 for twice-weekly glepaglutide in adults with parenteral-support-dependent short bowel syndrome. On December 19, 2024, the company announced a complete response letter stating that the application did not meet the requirements for substantial evidence of efficacy and safety at the to-be-marketed dose and recommending an additional clinical trial at that dose. The letter reflected the structure of the evidence: one pivotal trial in which only one of two arms separated from placebo, supported by extensions that could not themselves establish efficacy.

EASE SBS 5 (NCT07197944), the confirmatory trial. First posted on September 30, 2025 and started February 11, 2026, EASE SBS 5 is a double-blind, placebo-controlled phase 3 trial planned for 90 adults with SBS-IF, randomized 1:1 to glepaglutide 10 mg twice weekly or placebo, with change in weekly parenteral-support volume from baseline to week 24 as the primary endpoint and response, days off support, and complete weaning assessed through week 52, followed by a long-term open-label safety phase. The registry lists it as recruiting with an estimated primary completion date of October 23, 2028 and study completion in February 2032. Zealand has said the trial is intended to support a US resubmission; no resubmission date has been given.

Europe. Zealand submitted a Marketing Authorization Application to the European Medicines Agency on June 2, 2025, resting on EASE SBS 1 with support from the extension interim analyses and EASE SBS 4. On September 17, 2026, the CHMP adopted a positive opinion recommending approval of Zeydovio (glepaglutide) for the treatment of adults with short bowel syndrome who are stable after a period of intestinal adaptation following surgery, as a 10 mg solution for injection in a pre-filled pen; the company announced it the next day. As of November 2026, the EMA’s product page still showed only the CHMP opinion, with no Commission authorization published.

What has not been studied. No pediatric trial, no trial in Crohn’s disease or other inflammatory bowel disease in humans (the anti-inflammatory signal is limited to an indomethacin-induced rat model; Skarbaliene et al., BMC Gastroenterology, 2023;23(1):79), and no trial in people with an anatomically intact gut.

Common dosage forms

• Investigational autoinjector. A ready-to-use aqueous solution of glepaglutide in a single-dose autoinjector, supplied to clinical-trial sites; this is the presentation that EASE SBS 3 evaluated.
• Vial and syringe. The earlier clinical presentation, bridged to the autoinjector in a pharmacokinetic comparison in healthy volunteers (NCT04318743, completed June 10, 2021).
• Pre-filled pen. The European presentation of Zeydovio, a 10 mg solution for injection in a pre-filled pen.

Key considerations

• Regulatory status. The Investigational status reflects that no glepaglutide product is authorized in any country. The FDA issued a complete response letter in December 2024 asking for a second trial, the confirmatory EASE SBS 5 trial began enrolling in February 2026, and the CHMP recommended approval in September 2026 without a European Commission decision as of November 2026.
• One effective dose of two. The once-weekly arm of EASE SBS 1 did not separate from placebo on any primary or key secondary endpoint, and the twice-weekly result rests on 35 treated patients. Three letters published in Gastroenterology in October 2025 (169(5):1077–1079) raised questions about dose selection and what the single trial left unresolved.
• Class safety signals. Injection-site reactions, nausea, edema, dehydration, and stoma complications recur across the trials, and long-term safety data from the extensions remain unpublished. GLP-2 agonism can accelerate the growth of existing gastrointestinal neoplasia, the reason teduglutide’s label requires endoscopic surveillance, and a depot that keeps active metabolites circulating for days does not remove that mechanism.
• Competitor-reported pharmacology. The only published head-to-head receptor comparison was conducted by apraglutide’s developer. Because glepaglutide’s long action depends on a subcutaneous depot rather than on intrinsic receptor properties, in vitro potency and clinical effect are not directly comparable across the three analogs.
• Naming confusion. The “-glutide” suffix is shared with GLP-1 drugs such as semaglutide and liraglutide, but glepaglutide acts on the GLP-2 receptor and has no weight-loss, appetite, or glycemic evidence. The brand name Zeydovio belongs to the European application only; the development code ZP1848 appears on the trial registrations.