Glepaglutide

What is Glepaglutide?#

Glepaglutide (ZP1848) is a long-acting synthetic analog of human glucagon-like peptide-2 (GLP-2), an intestinotrophic hormone that promotes intestinal growth and adaptation. Developed by Zealand Pharma (which acquired VectivBio), glepaglutide is designed to treat short bowel syndrome (SBS) with intestinal failure -- a condition in which patients depend on intravenous parenteral nutrition to maintain fluid, electrolyte, and nutrient balance due to insufficient functional intestinal surface.

SBS typically results from extensive surgical resection of the small intestine (due to Crohn's disease, mesenteric ischemia, trauma, or neonatal conditions). Patients with SBS-intestinal failure (SBS-IF) require parenteral support (PS) multiple days per week, which carries risks of catheter-related bloodstream infections, liver disease, and substantially impaired quality of life. GLP-2 analogs represent the only pharmacological approach that addresses the underlying pathology by promoting intestinal adaptation -- increasing villus height, crypt depth, and absorptive surface area.

Mechanism of Action#

GLP-2 is a 33-amino acid peptide hormone secreted by enteroendocrine L-cells in the ileum and colon in response to nutrient intake. It acts through the GLP-2 receptor (GLP-2R), a G protein-coupled receptor expressed on intestinal subepithelial myofibroblasts and enteric neurons. GLP-2R activation triggers a cascade of trophic and functional changes:

• Intestinal growth: Stimulates crypt cell proliferation, increases villus height and crypt depth, and expands the mucosal absorptive surface area
• Reduced intestinal permeability: Strengthens tight junctions between enterocytes
• Enhanced blood flow: Increases mesenteric and portal blood flow to support absorptive function
• Slowed gastric emptying: Reduces the rate of gastric emptying, increasing transit time and nutrient contact with the absorptive surface
• Reduced gastric secretion: Decreases gastric acid output, reducing the secretory burden on the remaining intestine

Native GLP-2 has a half-life of approximately 7 minutes due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV), making it unsuitable for clinical use. Glepaglutide was engineered with nine amino acid substitutions and a C-terminal hexalysine tail that confer DPP-IV resistance, improved chemical stability in aqueous solution, and an extended effective half-life of approximately 88 hours. This enables twice-weekly dosing and a ready-to-use liquid formulation in an autoinjector.

Clinical Development#

Glepaglutide has been evaluated in a structured clinical program for short bowel syndrome:

• Phase 2 (Lancet Gastroenterology & Hepatology, 2019): Crossover trial in 18 SBS patients demonstrated dose-dependent reductions in fecal output with 1 mg and 10 mg daily doses (PMID: 30880176)
• EASE SBS 1 (Phase 3, Gastroenterology, 2025): Pivotal trial in 106 SBS-IF patients showed twice-weekly 10 mg glepaglutide significantly reduced PS volume vs placebo (P=0.0039), with 14% achieving enteral autonomy (PMID: 39708985)
• Phase 3b absorption study: Open-label study in 10 patients confirmed increased intestinal wet weight and energy absorption with corresponding PS reductions at 52 weeks (PMID: 40774623)
• FDA Breakthrough Therapy Designation: Not granted; FDA issued a Complete Response Letter in December 2024 requesting additional confirmatory evidence
• EASE SBS 3: Additional phase 3 trial planned for 2025 to support regulatory resubmission in the US and filings in Europe

Important Considerations#

Glepaglutide is an investigational medication that has not been approved by any regulatory authority. Key considerations include:

• The FDA issued a Complete Response Letter in December 2024, finding the existing data insufficient to establish efficacy at the to-be-marketed dose
• The once-weekly dosing arm in the phase 3 trial did not achieve statistical significance, and only twice-weekly dosing showed benefit
• GLP-2 analogs carry a theoretical risk of promoting growth of intestinal polyps or neoplasms, though this has not been observed clinically with glepaglutide
• Treatment effects are dependent on continued dosing; intestinal adaptation may partially regress upon discontinuation
• GLP-2 analogs are specific to SBS management and are not interchangeable with GLP-1 agonists used for diabetes or obesity

Key Research Findings#

Glepaglutide Phase 3 EASE SBS 1 Trial, published in Gastroenterology (Jeppesen PB et al., 2025; PMID: 39708985):

• Twice-weekly glepaglutide 10 mg reduced weekly PS volume by -5.13 L vs -2.85 L for placebo (P=0.0039)
• Clinical response (at least 20% PS reduction) achieved in 65.7% vs 38.9% (P=0.0243)
• Complete enteral autonomy in 14% of twice-weekly group vs 0% placebo
• Well tolerated with no new safety signals

Glepaglutide Phase 2 Trial, published in Lancet Gastroenterology & Hepatology (Naimi RM et al., 2019; PMID: 30880176):

• 10 mg daily dose reduced mean fecal output by 833 g/day from baseline (P=0.0002)
• Dose-dependent intestinal absorption improvement confirmed

Related Reading#

• Glepaglutide research studies and evidence
• Glepaglutide dosing protocols
• Glepaglutide side effects profile
• Teduglutide research guide