Glepaglutide

Glepaglutide (ZP1848) is a long-acting, synthetic peptide analog of human glucagon-like peptide-2 (GLP-2) developed by Zealand Pharma A/S (Soeborg, Denmark) for the treatment of short bowel syndrome (SBS) with intestinal failure in patients dependent on parenteral support. The compound comprises 39 amino acids and differs from native human GLP-2(1-33) by the incorporation of nine amino acid substitutions at positions 2, 3, 5, 8, 10, 11, 16, 24, and 28, together with a C-terminal amidated hexalysine tail ([Lys]6-NH2) derived from Zealand Pharma's proprietary Structure Inducing Probe (SIP) technology. The substitutions confer resistance to dipeptidyl peptidase-4 (DPP-4) degradation, improved physicochemical stability enabling a ready-to-use aqueous liquid formulation, and formation of a subcutaneous depot from which the parent compound and its active C-terminally truncated metabolites (M1, 35 amino acids; M2, 34 amino acids) are slowly released into systemic circulation. The resulting effective half-life of approximately 50 to 124 hours in humans permits or subcutaneous dosing, a substantial advance over the injection requirement of teduglutide (Gattex), the first-in-class approved GLP-2 analog. Glepaglutide binds and activates the GLP-2 receptor (GLP-2R), a class B G-protein-coupled receptor expressed on intestinal subepithelial myofibroblasts, enteroendocrine cells, and enteric neurons. Receptor activation triggers downstream release of intestinal growth mediators including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and keratinocyte growth factor, resulting in crypt cell proliferation, villus elongation, inhibition of enterocyte apoptosis, enhanced intestinal barrier function, increased mesenteric blood flow, and suppression of gastric acid hypersecretion and accelerated gastrointestinal motility. The net physiological effect is increased intestinal absorptive capacity for fluid, electrolytes, and macronutrients in patients with anatomically shortened bowel. Clinical development has progressed through Phase 1 healthy volunteer pharmacokinetic studies, a Phase 2 randomized crossover trial in 18 SBS patients published in The Lancet Gastroenterology and Hepatology (Naimi et al., 2019) demonstrating dose-dependent improvements in intestinal wet weight absorption and plasma citrulline, and the pivotal Phase 3 EASE-SBS 1 trial (NCT03690206), a multinational, double-blind, placebo-controlled study in 106 patients that met its primary endpoint of significant reduction in weekly parenteral support volume at 24 weeks (mean change minus 5.13 versus minus 2.85 liters in the published literature for glepaglutide twice weekly versus placebo; P equals 0.0039). The compound received orphan drug designation from both the United States Food and Drug Administration and the European Medicines Agency. Zealand Pharma submitted a New Drug Application to the FDA in late 2023; in December 2024, the FDA issued a Complete Response Letter citing insufficient evidence to confirm efficacy and safety at the proposed marketed dose and recommending an additional confirmatory trial. A Marketing Authorization Application was submitted to the European Medicines Agency in June 2025, and Zealand Pharma plans an additional Phase 3 trial to support regulatory resubmission in the United States. The safety profile is consistent with the known GLP-2 class effects. The most frequent adverse events in clinical trials are injection site reactions, stoma complications (primarily swelling or enlargement of the stoma nipple), gastrointestinal events (nausea, vomiting, abdominal pain), peripheral edema, fatigue, and headache. Anti-drug antibodies develop in a proportion of treated patients with a trend toward higher injection site reaction incidence in antibody-positive individuals, though no firm causal relationship has been established. The compound does not require reconstitution and is administered as a fixed-dose, ready-to-use subcutaneous injection via autoinjector, representing a practical advantage over lyophilized GLP-2 analogs requiring daily preparation. This monograph documents the chemistry, design rationale, and synthesis of glepaglutide; the GLP-2 receptor pharmacology and downstream intestinotrophic signaling; the comprehensive human pharmacokinetic profile including depot formation and metabolite characterization; the preclinical pharmacology in intestinal growth and inflammatory bowel disease models; the clinical evidence base from Phase 1 through Phase 3; sourcing and quality verification; reconstitution and handling; stack interaction considerations; adverse events and safety signals; and a comparative assessment of five GLP-2 receptor agonist candidates (teduglutide, apraglutide, dapiglutide, elsiglutide, and native GLP-2) against glepaglutide on five competency standards.