Glepaglutide

Glepaglutide carries nine amino acid substitutions relative to native GLP-2 plus a C-terminal 'structure-inducing probe' tail of six lysines, giving only about 64% backbone sequence identity with the native hormone. The lysine tail promotes self-assembly and slow release from the subcutaneous depot rather than relying purely on plasma protein binding. After injection it is progressively trimmed to two functionally active metabolites, ZP1848(1-34) and ZP1848(1-35), with the 1-34 form carrying most of the receptor activity. Downstream it does what every GLP-2 agonist does: villus hypertrophy, crypt cell proliferation, slower transit and greater fluid and nutrient absorption. It is formulated as a ready-to-use liquid autoinjector, which is a meaningful practical advantage over reconstituting a daily vial.

Targets: GLP-2 receptor, Intestinal subepithelial myofibroblasts, IGF-1 / KGF downstream signalling

• · 10 mg twice weekly is the dose carried forward into EASE-5, the confirmatory 52-week trial. EASE-1 also tested 10 mg once weekly; the twice-weekly arm carried the stronger effect.

Work out your exact syringe units →

• very commonInjection-site reactions— Notably more prominent than with teduglutide, likely related to the lysine-tail depot chemistry.
• very commonNausea, abdominal pain and distension— GLP-2 class effect.
• commonVomiting
• commonPeripheral oedema and fluid overload— Requires active reduction of parenteral fluid.
• commonStoma complications
• uncommonColonic polyps and theoretical neoplastic risk— Class effect requiring colonoscopy surveillance.

• Active gastrointestinal malignancy — class contraindication for all GLP-2 agonists.
• Not commercially available; grey-market 'glepaglutide' is unverified material.

• redundantteduglutide — Same receptor; a substitute, not an addition.
• redundantapraglutide — Same receptor and same indication.
• cautionoral-medications — Class effect — improved absorption can raise exposure to concurrent oral drugs.

• · Colonoscopy before initiation and on the GLP-2 class schedule.
• · Fluid balance, body weight, urine output and electrolytes during parenteral weaning.
• · Hepatobiliary and pancreatic labs periodically.

Investigational. Not approved by the FDA (Complete Response Letter, December 2024) or by the EMA; a European marketing authorisation application and a confirmatory US trial are both in progress.

• EASE-1 phase 3 trial of glepaglutide in short bowel syndrome (NCT03690206) (trial)
• Zealand Pharma announcement of FDA Complete Response Letter for glepaglutide, December 2024 (other)
• EASE-5 confirmatory phase 3 trial of 10 mg twice-weekly glepaglutide (trial)

The receptor-level story is the same as every GLP-2 analogue: agonism at GLP2R on subepithelial myofibroblasts and enteric neurons, paracrine IGF-1 and KGF release, crypt cell proliferation, greater villus height and absorptive surface, slowed transit, increased mesenteric blood flow. Where glepaglutide differs is entirely in how it gets there and stays there. The hexalysine tail is the design centrepiece. Six consecutive lysines at the C-terminus make the peptide amphipathic and highly cationic, promoting self-association into a poorly soluble aggregate at the injection site. The peptide then leaks out of that depot over days. This is flip-flop pharmacokinetics — the apparent half-life is dominated by absorption, not elimination — and it means plasma concentration is smoother and lower-peaking than a fast-absorbed peptide would give. The metabolite story is the second distinctive feature. In circulation the lysine tail is progressively trimmed, generating ZP1848(1-34) and ZP1848(1-35). The 1-34 form is where most of the receptor activity sits. So the molecule you inject is partly a carrier for the molecule that does the work, and total pharmacological exposure has to be measured across three species. This is almost certainly part of why the FDA's Complete Response Letter focused on whether substantial evidence had been established for the to-be-marketed dose — dose-exposure-response relationships are harder to pin down when the active species is a metabolite. The published phase 3 result is worth stating precisely, because the Core record overstates it. Twice-weekly 10 mg significantly reduced weekly parenteral support volume versus placebo (mean change -5.13 versus -2.85 L/week, P = .0039), with 65.7% versus 38.9% achieving at least a 20% reduction (P = .0243) and five patients (14%) weaned off parenteral support entirely versus none on placebo. The once-weekly arm showed no statistically significant difference from placebo on the primary or key secondary endpoints. Once weekly does not work. Twice weekly does.

The regulatory story is the headline. EASE-1 met its primary endpoint and the FDA issued a Complete Response Letter on 19 December 2024, stating the application did not establish substantial evidence for the to-be-marketed dose. Read that carefully: it is not a safety objection and it is not a claim the drug does nothing. It is a dose-justification objection, and given that the once-weekly arm failed while twice-weekly worked, and that the active species is a metabolite of the injected molecule, that objection is not unreasonable. Clinically the dominant complaint is injection-site reactions, materially more frequent than with teduglutide. That is the predictable cost of a depot-forming lysine tail, and it is the thing most likely to make a patient stop. After that, the class failures: fluid overload from failing to wean parenteral support, GI pain and distension in the first weeks, stoma hypertrophy, and the colonoscopy surveillance burden. The practical failure is availability. This is an investigational drug supplied through trials. There is no commercial autoinjector to buy. Grey-market material sold as glepaglutide is unverified, and a 39-residue peptide with a hexalysine tail and an amidated C-terminus is not something a low-quality synthesis gets right by accident.

1. 10 mgWeek 1 onward — 10 mg twice weekly, on two fixed days spaced roughly evenly. Fixed dose, no titration, not weight-banded. This is the regimen carried into EASE-5, the confirmatory 52-week trial.
2. 10 mgTested and failed — 10 mg once weekly was tested in the same phase 3 and did not differ significantly from placebo on the primary or key secondary endpoints. This is an important negative: the convenient schedule is the one that did not work. Twice weekly or nothing.
3. —From week 4 — Parenteral support volume is the thing that descends, in 10-20% steps guided by urine output, weight and electrolytes. In EASE-1 the twice-weekly arm achieved a mean reduction of 5.13 L/week by week 24, with 14% weaned off parenteral support entirely.

• GLP-2 receptor (GLP2R), human — No pEC50 resolved for glepaglutide itself in this session. By class, teduglutide sits at pEC50 10.7 and apraglutide at 10.5; glepaglutide is a full agonist at the same receptor but I will not assign it a number I did not verify.

  Gs-coupled agonism raising cAMP in GLP-2R-bearing subepithelial myofibroblasts and enteric neurons, driving the intestinotrophic response.

• GLP-2 receptor via metabolite ZP1848(1-34) — Not resolved.

  The principal active species in circulation. Receptor activity is carried mostly by this trimmed fragment rather than by the injected parent molecule.

• IGF-1 / KGF paracrine axis — Not a direct target.

  Effector arm: crypt cell proliferation, villus hypertrophy, increased absorptive surface. Phase 2 imaging work specifically documented changes in intestinal morphology and perfusion in short bowel patients.

• Enteric neurons / gastrointestinal transit — Same receptor.

  Slowed gastrointestinal transit and altered motility, formally measured in a dedicated randomised phase 2 transit study. In a short bowel this contributes materially to absorptive gain.

• EASE-1 / EASE SBS-1 — Glepaglutide, a long-acting GLP-2 analogue, reduces parenteral support in patients with short bowel syndrome (NCT03690206) Phase 3 · n=106 · 24 weeks · 2025

  Change in weekly parenteral support volume from baseline to week 24. Twice-weekly 10 mg: mean change -5.13 versus -2.85 L/week for placebo, P = .0039. Clinical response (at least 20% PS reduction) 65.7% versus 38.9%, P = .0243. Reduction of at least one PS day per week 51.4% versus 19.4%, P = .0043. Five patients (14%) on twice-weekly glepaglutide were weaned off parenteral support entirely versus none on placebo. The once-weekly arm showed no significant difference from placebo.

• Randomised phase 2 trial of glepaglutide effects on gastrointestinal transit time and motility in short bowel syndrome Phase 2 · 2020

  Gastrointestinal transit time and motility in patients with short bowel syndrome.

• Randomised phase 2 trial of glepaglutide effects on intestinal morphology and perfusion in short bowel syndrome Phase 2 · 2023

  Intestinal morphology and perfusion in patients with short bowel syndrome.

• EASE-5 — confirmatory 52-week phase 3 trial of 10 mg twice-weekly glepaglutide Phase 3 · 52 weeks

  Confirmatory efficacy of 10 mg twice-weekly glepaglutide in short bowel syndrome, run in response to the FDA Complete Response Letter. Referenced in the Core record; I did not resolve a registration record for it in this session.

Tissue growth timescale, as with the rest of the class. Little in the first two weeks except side effects. Parenteral support reduction accrues over the 24-week trial window, and EASE-5 is specifically testing durability out to 52 weeks — a reasonable question, since mucosal adaptation and the sustainability of weaning are different things.

Never with teduglutide or apraglutide. Same receptor, same indication, additive risk without additive benefit. The oral drug absorption interaction is the class effect and applies here: improved absorptive surface plus slowed transit raises exposure to concurrent oral medications. Reassess psychotropics, benzodiazepines, anticoagulants and antiepileptics in the first month, and check levels where a level exists. Avoid combining with GLP-1 agonists in a short bowel — both slow transit, and the combination can tip into functional obstruction. One glepaglutide-specific point: because injection-site reactions are the dominant tolerability issue, anything else being injected subcutaneously should use different sites and a different rotation schedule. Do not stack injections in the same region.

Glepaglutide's product thesis is convenience: a ready-to-use liquid autoinjector with no reconstitution, versus teduglutide's daily lyophilised vial. That is a real advantage for a patient population already carrying an enormous daily treatment burden. It is undercut by two things — twice-weekly rather than the weekly interval apraglutide offers, and injection-site reactions that are worse than teduglutide's. Structurally it is the outlier of the three. Teduglutide is native GLP-2 with one substitution. Apraglutide has four. Glepaglutide has nine plus a six-lysine tail, giving roughly 64% identity with the native hormone, and it works partly through metabolites. It is the most engineered and the least like the endogenous ligand. On evidence, glepaglutide is currently the best-documented of the two investigational agents, because its phase 3 is published in full in Gastroenterology with hard numbers while apraglutide's STARS results are not yet indexed. That is worth weighing: glepaglutide's data are checkable, apraglutide's are currently press-release grade. Both received regulatory pushback in the same twelve-month window, and for the same underlying reason — dose justification. Teduglutide remains the only GLP-2 analogue you can actually be prescribed.

No commercial price exists; the drug is not approved in any jurisdiction. If approved it would be priced as a specialty orphan biologic alongside teduglutide.

• ?No verified clearance, volume of distribution, protein binding or terminal half-life figures exist in publicly accessible form. The Core record's statement that a single clean human terminal half-life is not well established publicly matches what I found.
• ?No pEC50 or Ki at the GLP-2 receptor was resolvable for glepaglutide or for its ZP1848(1-34) metabolite, so no affinity number is asserted.
• ?EASE-5 could not be verified — I did not resolve a ClinicalTrials.gov registration record for the confirmatory trial in this session, so the 52-week design and January 2026 recruitment timing come from the Core record rather than from a source I checked.
• ?The FDA Complete Response Letter of December 2024 is reported in the Core record and is consistent with the drug's continued unapproved status, but I did not independently verify the announcement.
• ?The Core record states EASE-1 showed significant reductions with 10 mg once or twice weekly. The published phase 3 explicitly reports that the once-weekly arm showed no statistically significant difference from placebo on the primary or key secondary endpoints. The Core text should be corrected.
• ?The phase 2 transit and morphology trials were verified as publications; their enrolment numbers were not resolved and are left null.
• ?The claim that injection-site reactions relate specifically to lysine-tail depot chemistry is mechanistically sensible and consistent with the formulation, but I did not find a study attributing them causally.

• Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 Randomized Controlled Trial Jeppesen PB, et al., Gastroenterology, 2025 · PMID 39708985

  The published phase 3. This is the source for every efficacy number above, and for the crucial finding that the once-weekly arm did not separate from placebo.

• Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial Hvistendahl MK, et al., JPEN. Journal of Parenteral and Enteral Nutrition, 2020 · PMID 32022286

  Direct measurement of the transit-slowing arm of the mechanism in actual short bowel patients rather than in animals.

• 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 Naimi RM, et al., JPEN. Journal of Parenteral and Enteral Nutrition, 2023 · PMID 35511704

  Documents the mucosal growth and perfusion changes directly, which is the mechanistic bridge between receptor agonism and clinical weaning.

• Exploring the disease burden and quality of life in patients with short bowel syndrome with intestinal failure: insights from exit interviews in the glepaglutide EASE SBS-1 phase 3 trial Mercer DF, et al., Nutrition in Clinical Practice, 2026 · PMID 41816796

  Patient-reported experience from the phase 3, which matters more than usual here because the whole rationale for long-acting GLP-2 analogues is reducing treatment burden.

• NCT03690206 — EASE-1 phase 3 trial registration record ClinicalTrials.gov

  Confirms phase 3, 106 participants, Completed status, and the primary outcome of change in weekly parenteral support volume.

• PubChem CID 146170995 — glepaglutide (ZP1848), C197H325N53O55, MW 4316, CAS 914009-86-2 PubChem, National Library of Medicine

  Sequence verification: HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2, 39 residues including the hexalysine tail, 4316 Da.