Avexitide

Avexitide is the development name for exendin (9-39), a 31-amino-acid peptide that acts as a competitive antagonist of the glucagon-like peptide-1 (GLP-1) receptor. It is a truncated form of exendin-4, a peptide isolated from the venom of the Gila monster, Heloderma suspectum, in the early 1990s by John Eng. Removing the first eight residues of exendin-4 eliminates receptor activation while preserving high-affinity binding, converting a potent agonist into an antagonist.

For decades exendin (9-39) has been a key research tool for defining the physiological role of GLP-1 in glucose regulation, used in both animal and human physiology studies to block endogenous incretin signalling. Avexitide is now in phase 3 clinical research for post-bariatric hypoglycaemia, a condition in which exaggerated GLP-1 responses after gastric bypass surgery contribute to inappropriate insulin secretion. It has also been investigated in congenital hyperinsulinism. Development was led by Eiger BioPharmaceuticals and subsequently taken over by Amylyx Pharmaceuticals. It is not approved by the FDA or EMA.

Avexitide binds the GLP-1 receptor on pancreatic beta cells and other tissues without activating it, competitively preventing endogenous GLP-1 from binding. GLP-1 normally potentiates glucose-stimulated insulin secretion through Gs-coupled cyclic AMP signalling. After gastric bypass, rapid nutrient delivery to the distal intestine can produce markedly elevated GLP-1 levels, which in some individuals drive excessive insulin release and subsequent hypoglycaemia. By blocking the receptor, avexitide attenuates this incretin amplification in physiology studies. In congenital hyperinsulinism research, it has been studied for its ability to reduce insulin secretion arising from dysregulated beta cell signalling.