Overview
This monograph covers investigational glucagon-like peptide-2 analogues designed to extend the duration of GLP-2 receptor activation beyond that of teduglutide, the first approved agent in the class. The best-known candidates are apraglutide, originally developed by VectivBio and later acquired by Ironwood Pharmaceuticals, and glepaglutide, developed by Zealand Pharma. Both are synthetic peptides engineered with amino acid substitutions that improve stability, slow clearance and prolong receptor engagement.
These compounds are not approved by the FDA or EMA and remain in phase 2 and phase 3 clinical research, primarily in short bowel syndrome with intestinal failure. The rationale for the class stems from rodent studies showing that GLP-2 promotes intestinal growth and adaptation after resection, and from experience with teduglutide establishing the GLP-2 receptor as a druggable target. Research questions centre on whether longer-acting designs change the magnitude or durability of intestinal adaptation, how pharmacokinetic engineering affects tolerability, and whether these analogues have roles in other conditions, such as intestinal graft-versus-host disease, which has been explored in early studies of apraglutide.
Mechanism studied
- GLP-2 analogue
- GLP-2 receptor
- Mucosal growth
- Absorptive capacity
Investigational GLP-2 analogues act as agonists of the GLP-2 receptor, a Gs-coupled GPCR expressed predominantly on enteroendocrine cells, enteric neurons and subepithelial myofibroblasts of the intestine. Receptor activation triggers the release of secondary mediators, including insulin-like growth factor-1 and keratinocyte growth factor, which stimulate crypt cell proliferation, reduce epithelial apoptosis and increase villus height. The result in animal models is an expanded mucosal surface with improved barrier function and nutrient uptake. Compared with native GLP-2, these analogues incorporate substitutions that resist DPP-4 cleavage and reduce renal clearance, giving prolonged receptor exposure.
Research highlights
- 01The class builds on mid-1990s rodent work identifying GLP-2 as an intestinal growth factor.
- 02Apraglutide and glepaglutide were engineered for slower clearance than teduglutide.
- 03Phase 3 programmes in short bowel syndrome have evaluated reductions in parenteral support requirements as endpoints.
- 04Apraglutide has also been explored in early research on intestinal graft-versus-host disease.
- 05Open questions include long-term safety of sustained trophic signalling and how analogue design affects adaptation.
Key references
- [1]PubMed — reviews on GLP-2 analogues apraglutide and glepaglutide
- [2]Ongoing clinical trials — public registries
FAQ
Teduglutide carries a single DPP-4-resistant substitution. Investigational analogues such as apraglutide and glepaglutide include further modifications intended to slow clearance and prolong receptor activation, which researchers are evaluating for effects on intestinal adaptation.
No. Apraglutide and glepaglutide are not approved by the FDA or EMA. They remain in clinical research, primarily in short bowel syndrome, and research-grade material is for laboratory use only.
After extensive bowel resection, the remaining intestine undergoes adaptive growth that increases absorptive capacity. GLP-2 signalling is a key driver of this process, so analogues are used to study and potentially enhance adaptation in experimental models.
FOR RESEARCH USE ONLY.Not for human or veterinary use. Not intended to diagnose, treat, cure, or prevent any disease.