Cagrilintide

Cagrilintide is a long-acting acylated amylin analog developed by Novo Nordisk for obesity treatment. Amylin is a 37-amino acid peptide co-secreted with insulin from pancreatic beta cells that promotes satiety, delays gastric emptying, and suppresses glucagon. Cagrilintide features amino acid modifications and a C18 fatty acid chain enabling once-weekly dosing through albumin binding. Most notably, cagrilintide is being developed in combination with semaglutide (CagriSema), which targets two complementary satiety pathways — amylin (hindbrain area postrema/NTS) and GLP-1 (hypothalamic and brainstem). The Phase 2 REDEFINE trial of CagriSema showed 15.6% weight loss at 32 weeks, with Phase 3 trials (REDEFINE program) underway.

Amylin Receptor Complex Activation Cagrilintide activates the amylin receptor — a heterodimer of the calcitonin receptor (CTR) with receptor activity-modifying proteins (RAMPs, primarily RAMP1-3). This receptor complex is distinct from GLP-1R, providing complementary satiety signaling primarily through the area postrema and nucleus tractus solitarius in the brainstem. Satiety Through Distinct Pathways While GLP-1 acts primarily on hypothalamic appetite centers, amylin acts on brainstem satiety circuits — a fundamentally different neural pathway. This explains the additive weight loss observed with CagriSema (cagrilintide + semaglutide) combination.

Obesity (CagriSema Combination) Phase 3 REDEFINE program testing cagrilintide + semaglutide 2.4 mg. Phase 2 showed 15.6% weight loss at 32 weeks. Obesity (Monotherapy) Phase 2 data showed ~10% weight loss with cagrilintide alone, establishing independent efficacy. Type 2 Diabetes Being studied for glycemic control in combination with semaglutide.

CTR/RAMP/cAMP signaling in area postrema neurons. Brainstem NTS integration of satiety signals. Vagal afferent activation for gastric emptying delay. ERK1/2 signaling for neuronal activation in satiety centers.

GI effects (nausea 20-30%, vomiting, diarrhea) similar to other incretin-based therapies. Injection site reactions. The combination with semaglutide shows GI effects comparable to semaglutide alone, suggesting amylin agonism does not substantially add to GI burden.

Investigational compound. Once-weekly subcutaneous injection. The C18 fatty acid acylation provides albumin binding for extended half-life. Store investigational supply at 2-8°C.

Investigational — Phase 3 clinical trials ongoing (REDEFINE program for CagriSema). Not yet approved by any regulatory authority. Novo Nordisk plans regulatory submissions based on Phase 3 data.