Cagrilintide

Cagrilintide is a long-acting analogue of amylin, the 37-residue hormone that pancreatic beta cells secrete together with insulin. It keeps amylin's disulfide and amidated C-terminus, carries prolines that curb the fibril formation human amylin is known for, and has a C20 fatty diacid on its N-terminal lysine. This listing is the 10 mg vial of freeze-dried powder, the main of two fills. Research on cagrilintide covers its design, amylin receptor pharmacology and clinical trials alone and with semaglutide.

How cagrilintide differs from human amylin

The certificate writes cagrilintide as (C20 diacid-γGlu)-KCNTATCATQRLAEFLRHSSNNFGPILPPTNVGSNTP-NH₂. Like the native hormone it has 37 residues, a disulfide between cysteines 2 and 7 and an amidated C-terminus. Six positions are changed, as the cagrilintide and CagriSema guide sets out: glutamate 14 and arginine 17, which the developers described as a pair that stabilises the helical core, a proline at 37, and prolines at 25, 28 and 29. Human amylin has Ala-Ile-Leu-Ser-Ser at positions 25 to 29, a stretch Westermark and colleagues found strongly amyloidogenic¹; cagrilintide reads Pro-Ile-Leu-Pro-Pro there.

The N-terminal lysine carries eicosanedioic acid, a C20 diacid, through a γ-glutamic acid linker, the same albumin-binding approach used for semaglutide but with a longer chain. The theoretical mass is 4409.0 Da, so 10 mg is about 2.3 µmol before allowing for the water the certificate reports, and the LC-MS identity result is the figure to compare with that mass.

What the research covers

Amylin and its aggregation problem

Amylin, also called islet amyloid polypeptide (IAPP), is one of the main secretory products of pancreatic beta cells². Inside the islets it inhibits insulin and glucagon secretion; elsewhere it has binding sites in the brain, may contribute to satiety and slows gastric emptying². It was discovered through its tendency to aggregate into islet amyloid, seen in type 2 diabetes in humans and in diabetic monkeys and cats, and the aggregated peptide is cytotoxic². In 1990 Westermark and colleagues traced fibril formation to positions 20 to 29: the human and cat segments formed fibrils in vitro, three rodent segments did not, and a proline in place of serine at position 28, as in several rodents, almost completely blocked fibril formation¹.

From pramlintide to a long-acting analogue

That tendency to form fibrils made amylin a hard starting point for drug design³. Pramlintide, an earlier analogue, is available for diabetes as an adjunct to insulin but has a short half-life³. Kruse and colleagues reported the structure-activity work that led to cagrilintide, compound 23 in their paper, a stable and lipidated long-acting analogue selected for clinical development with obesity as the indication³.

Receptors

Amylin acts through multi-subunit G protein-coupled receptors formed when a core receptor protein is co-expressed with receptor activity-modifying proteins (RAMPs), which gives several receptor subtypes⁴. In the 2015 review by Hay and colleagues, amylin acted mainly in the circumventricular organs of the central nervous system and interacted with other metabolic hormones, among them cholecystokinin, leptin and estradiol⁴. The core protein is the calcitonin receptor, and cagrilintide acts at the calcitonin receptor as well as at the amylin receptor complexes; the developer's potency data are in the cagrilintide guide.

Clinical trials

A phase 2 trial at 57 sites in ten countries randomly assigned adults without diabetes, who had obesity or had overweight with hypertension or dyslipidaemia, to one of five cagrilintide strengths, liraglutide or placebo for a 26-week treatment period⁵. Its primary endpoint was the percentage change in body weight from baseline to week 26⁵. A phase 1b trial at one US centre then paired cagrilintide with semaglutide in otherwise healthy adults with a BMI of 27.0 to 39.9, with treatment-emergent adverse events as the primary endpoint and pharmacokinetics among the secondary endpoints⁶. Phase 3a trials of the combination followed⁷,⁸; they are summarised on the Cagrilintide 5mg + Semaglutide 5mg page.

What is not established

The abstracts for the phase 2 and phase 1b trials cited here end before their results, so this page does not report them⁵,⁶. Cagrilintide is investigational, and its design history rests on one medicinal chemistry paper³.

Frequently asked questions

References

1. Westermark P, Engström U, Johnson KH, et al. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A. 1990;87(13):5036-40. DOI · PubMed
2. Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011;91(3):795-826. DOI · PubMed
3. Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021;64(15):11183-11194. DOI · PubMed
4. Hay DL, Chen S, Lutz TA, et al. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev. 2015;67(3):564-600. DOI · PubMed
5. Lau DCW, Erichsen L, Francisco AM, et al. 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;398(10317):2160-2172. DOI · PubMed
6. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397(10286):1736-1748. DOI · PubMed
7. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):635-647. DOI · PubMed
8. Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. N Engl J Med. 2025;393(7):648-659. DOI · PubMed