Avexitide (DB14806): A Comprehensive Profile of a First-in-Class GLP-1 Receptor Antagonist for Hyperinsulinemic Hypoglycemia

Executive Summary

Avexitide is an investigational, first-in-class, small molecule peptide therapeutic being developed for the treatment of hyperinsulinemic hypoglycemia. Structurally, it is a 31-amino acid truncated form of exendin-4, functioning as a specific and competitive antagonist of the glucagon-like peptide-1 receptor (GLP-1R). Its mechanism of action is precisely targeted to the core pathophysiology of conditions like post-bariatric hypoglycemia (PBH) and congenital hyperinsulinism (HI), where excessive or dysregulated GLP-1R signaling drives inappropriate insulin secretion. By competitively binding to and inhibiting GLP-1R on pancreatic beta cells, Avexitide blocks downstream signaling, thereby reducing excessive insulin release and stabilizing blood glucose levels.

The clinical development program for Avexitide has yielded a robust and consistent body of evidence supporting its efficacy and safety. In a comprehensive Phase 2 program for PBH, including the placebo-controlled PREVENT trial and a dose-optimizing Phase 2b study, Avexitide demonstrated highly statistically significant and clinically meaningful reductions in the frequency and severity of hypoglycemic events. The 90 mg once-daily subcutaneous dose, selected for pivotal development, has been shown to reduce severe (Level 3) hypoglycemic events by approximately 66%. This clinical efficacy is underpinned by a strong pharmacokinetic/pharmacodynamic profile, with the 90 mg dose maintaining plasma concentrations sufficient for robust target engagement over a 24-hour period. Furthermore, Avexitide has established proof-of-concept in congenital hyperinsulinism, significantly reducing the need for exogenous glucose infusion in critically ill neonates.