Inside the body with Cagrilintide (and CagriSema)

Native amylin is a pancreatic hormone that induces satiety, but it forms amyloid fibrils readily, which makes it hard to develop as a drug. The earlier analogue pramlintide is approved as an add-on to insulin but needs three injections a day because of its short half-life. Cagrilintide was engineered from the human amylin backbone to be stable and long acting.[src][src]

Structure-activity work at Novo Nordisk combined stabilising amino-acid substitutions with lipidation, per the design paper. The PubChem structure shows a C20 diacid gamma-Glu lipid on the alpha-amino group of the N-terminal lysine. In otherwise healthy adults with overweight or obesity given cagrilintide together with semaglutide, the half-life was 159-195 h, with a median time to peak concentration of 24-72 h.[src][src][src]

Cryo-EM structures show cagrilintide bound to Gs-coupled human calcitonin receptor and AMY1R, AMY2R and AMY3R. It has an amylin-like binding mode but induces distinct receptor dynamics compared with other peptides. An E14-R17 salt bridge stabilises the helix, Phe23 anchors the peptide near the transmembrane bundle, and Pro37 contacts the extracellular domain. This supports non-selective activation across these receptors. These are structural data on purified proteins, not human tissue measurements.[src][src]

In high-fat-diet mice lacking RAMP1 and RAMP3, cagrilintide's potency for weight loss was impaired, showing dependence on AMY1R and AMY3R. In wild-type mice it reduced early food intake and activated cFos in the dorsal vagal complex and lateral parabrachial nucleus. This is animal-only evidence.[src]

A cross-species transcriptomic atlas of the caudal brainstem (rat, mouse, macaque) found Calcr-expressing populations regulated by cagrilintide. Long-term treatment in rats increased Prlh expression in nucleus of the solitary tract Calcr/Prlh neurons, and knocking down DVC Prlh abrogated the effects of cagrilintide but not semaglutide. The functional experiments were done in rats; the cell populations are described as conserved in macaques and humans.[src]

In a 26-week phase 2 trial, weight reductions across cagrilintide groups were 6.0%-10.8% versus 3.0% with placebo (trial product estimand). In REDEFINE 1 (68 weeks), cagrilintide alone gave 11.5% versus 3.0% with placebo (treatment-policy estimand), and cagrilintide-semaglutide gave 20.4% versus 3.0%. In REDEFINE 2 (type 2 diabetes), the combination gave 13.7% versus 3.4% with placebo.[src][src][src][src]

In the phase 2 trial, gastrointestinal adverse events occurred in 41%-63% of participants on cagrilintide versus 32% on placebo, mainly nausea (20%-47% versus 18%), and administration-site reactions were also among the most frequent events. In REDEFINE 1, gastrointestinal events affected 79.6% on the combination versus 39.9% on placebo and were mainly transient and mild to moderate.[src][src]