Cagrilintide

Description

Cagrilintide is an amylin-analog, now being developed in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in persons with overweight and obesity. This drug is an investigational therapy that reduced body weight in a phase 2 trial when administered as monotherapy in participants without diabetes and with a BMI of at least 30 kg/m2 or at least 27 kg/m2 with hypertension or dyslipidaemia[1-2].

Mechanism of action

Cagrilintide, a non-selective agonist, is designed for weekly subcutaneous injection at low pH. It is based on the h-amylin backbone, drawing inspiration from calcitonin, and exhibits a prolonged action profile, likely attributed to reversible albumin binding similar to semaglutide. This amylin analog is currently under development in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in individuals with overweight and obesity. Amylin, co-secreted with insulin from pancreatic beta cells, exerts its satiating effect through both the homoeostatic and hedonic brain regions. On the other hand, semaglutide, a GLP-1 receptor agonist, reduces appetite by acting on GLP-1 receptors in the hypothalamus, increases insulin production, and decreases glucagon secretion, thus delaying gastric emptying. These distinct yet interconnected mechanisms of action of an amylin analog and a GLP-1 receptor agonist appear to synergistically reduce appetite[3-4].

Side effects

The most frequent adverse events were gastrointestinal disorders (e.g., nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3-4·5 mg had gastrointestinal adverse events compared with placebo (41%-63% vs 32%), primarily nausea (20%-47% vs 18%)[5].

References

[1] Antonella M D’Ascanio, William H Frishman, & Jamie A Mullally. “Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity.” Cardiology in Review (2024): 83–90.
[2] Juan P Frias. “Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial.” Lancet 402 10403 (2023): 720–730.
[3] Antonella M D’Ascanio, William H Frishman, Jamie A Mullally. “Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity.” Cardiology in Review (2024): 83–90.
[4] Thomas Kruse*. “Development of Cagrilintide, a Long-Acting Amylin Analogue.” Journal of Medicinal Chemistry 64 15 (2021): 11183–11194.
[5] David C W Lau. “Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial.” Lancet (2021): 2160–2172.