Amylin receptor agonist (revision 5)

Amylin receptor agonists are engineered analogues of amylin designed to reproduce its actions on gastric emptying, glucagon secretion and food intake without the aggregation behaviour of the native human sequence.^[1]

Two generations exist. Pramlintide, approved in 2005 as an adjunct to insulin, substitutes three prolines into the human sequence to disrupt β-sheet formation; its short half-life requires injection at each meal, which limited uptake. Cagrilintide is a long-acting analogue employing acylation for weekly dosing and is under development principally in combination with semaglutide as CagriSema.^[2]

The clinical interest in the class rests on the observation that amylin-mediated satiety is mechanistically distinct from GLP-1-mediated satiety and appears additive to it, so that a combination produces more weight loss than either component alone at the doses studied.^[2]

The problem to be solved is amyloidogenicity. Human amylin forms cross-β fibrils at concentrations well below those needed for a pharmaceutical formulation, and a peptide that aggregates in the vial is not a medicine.^[1]

Pramlintide takes the rodent solution: rat amylin does not aggregate because prolines at three positions in the central region prevent β-sheet stacking, and pramlintide introduces those substitutions into the human sequence. The result is soluble and stable but retains a short half-life of about 48 minutes, and its acidic formulation cannot be mixed in a syringe with insulin.