Cagrilintide

Cagrilintide (NN9838/AM833) is a long-acting acylated analog of human amylin developed by Novo Nordisk. Amylin is a 37-amino acid peptide hormone co-secreted with insulin from pancreatic beta cells that plays a role in post-prandial glucose regulation and satiety signaling. Cagrilintide was engineered with a C18 fatty diacid modification that enables albumin binding and extends its pharmacokinetic half-life, allowing for once-weekly subcutaneous dosing in clinical studies. The compound activates amylin receptors (AMY1 and AMY3), which are heterodimers of the calcitonin receptor with receptor activity-modifying proteins (RAMPs). Cagrilintide has been investigated in Phase 2 and Phase 3 clinical trials both as monotherapy and in combination with semaglutide (the CagriSema combination). It represents a novel approach to amylin receptor pharmacology with an extended duration of action.

Cagrilintide has been investigated for its agonist activity at amylin receptors, particularly AMY1R and AMY3R. These receptors are heterodimeric complexes of the calcitonin receptor (CTR) with RAMP1 or RAMP3, respectively. Researchers observed that cagrilintide binding activates Gs-coupled cAMP signaling and downstream pathways in the area postrema and nucleus tractus solitarius, brain regions involved in satiety and food intake regulation. Studies suggest that amylin receptor activation slows gastric emptying, reduces glucagon secretion, and modulates appetite through central nervous system signaling. The C18 fatty diacid acylation allows non-covalent albumin binding in circulation, extending the half-life from minutes (native amylin) to approximately one week. In clinical studies, researchers observed that cagrilintide administration was associated with changes in body weight, appetite scores, and glycemic parameters. The compound’s selectivity profile across calcitonin family receptors has been characterized in receptor binding studies.

Phase 2 Clinical Trial

Lau et al. (2021) investigated cagrilintide in a randomized, dose-ranging Phase 2 trial in subjects with overweight or obesity. Researchers observed dose-dependent changes in body weight over 26 weeks compared to placebo, establishing the compound’s clinical activity profile [1].

CagriSema Combination

Enebo et al. (2021) investigated the combination of cagrilintide with semaglutide in a Phase 1b study. Researchers observed that the combination was associated with greater changes in body weight than either compound alone, suggesting complementary mechanisms of amylin and GLP-1 receptor agonism [2].

Amylin Receptor Pharmacology

Hay et al. (2015) reviewed the pharmacology of amylin receptors, describing the receptor heterodimer structures, signaling pathways, and physiological functions that provide the foundation for cagrilintide’s mechanism of action [3].