Research libraryIncretin and amylin analogues
Cagrilintide: Amylin Analogue Receptor Pharmacology
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Cagrilintide is a long acting take on amylin, a small hormone most people have never heard of. The short version? It’s amylin with a fatty acid tail, built to survive for days instead of minutes, and it talks to the whole calcitonin receptor family rather than one tidy target. Below: the molecule, the receptors, why it lasts so long, and what the papers actually measured. Each claim has a link.
Key findings
- Cagrilintide, developed at Novo Nordisk and also known as AM833, is a lipidated, long acting analogue of the pancreatic hormone amylin [1].
- Amylin receptors are heterodimers: a calcitonin receptor core paired with a receptor activity modifying protein (RAMP), and cagrilintide also activates the calcitonin receptor on its own [2].
- Native amylin is notoriously prone to forming amyloid fibrils; the lipidation and sequence changes in cagrilintide address that instability and extend its duration [1].
- In early phase pharmacokinetic work, cagrilintide showed a half life of roughly 159 to 195 hours [3].
What cagrilintide is
Amylin comes out of beta cells together with insulin. Working with it directly is a pain, though. It clumps into amyloid fibrils at the drop of a hat, and anyone who has tried to keep a solution of it clear knows the feeling. The existing amylin analogue pramlintide got around some of that but has a short half life [1].
Cagrilintide is Novo Nordisk’s answer to both issues at once. Kruse and colleagues described the structure activity work that produced it: a stable, lipidated, long acting analogue selected out of a design effort aimed squarely at amyloid propensity and duration [1]. The lipid chain is the headline feature, since attaching a fatty acid is a well established way to extend a peptide’s circulating life.
The receptors it binds
This is where cagrilintide gets genuinely interesting at the pharmacology level. Amylin does not have a single dedicated receptor. Instead, amylin receptors are built from a calcitonin receptor combined with one of several receptor activity modifying proteins. Swap the RAMP and you change the binding profile. So any assay claiming to measure “the” cagrilintide receptor has to specify which complex it is looking at.
Fletcher and colleagues profiled cagrilintide (AM833) across 25 endpoints against six other agonists, selective and non selective, and reported that it is a non selective agonist of calcitonin family receptors with a pharmacological fingerprint distinct from pramlintide, salmon calcitonin, and the others they tested [2]. So in a lab it hits two things: the amylin receptor complexes and the bare calcitonin receptor. A decent binding and signaling setup can pull those apart.
Pharmacokinetics and stability
The long half life is the whole point of the molecule, and early human pharmacokinetic data put numbers on it. In a phase 1b study, cagrilintide exposure scaled proportionally with the amount given, and its half life came out around 159 to 195 hours, with exposure that did not alter the elimination of a GLP-1 analogue given alongside [3]. A half life in that range is what lets a peptide be studied on a weekly schedule rather than a daily one, which is unusual for a molecule derived from a hormone that native amylin clears in minutes.
If you want the GLP-1 side of that pairing, our semaglutide research overview covers the incretin analogue that cagrilintide is frequently studied next to.
What the trials measured
We will keep this short, because these are the measured endpoints and nothing more. The phase 1b study looked at safety, tolerability and pharmacokinetics with semaglutide in the mix [3], and a 26 week phase 2 study ran several cagrilintide amounts against placebo and an active comparator [4]. GI complaints topped the adverse event lists in both. Want the full numbers? Read the abstracts; we’re not going to paraphrase them into something they aren’t.
Comparing compounds responsibly
A recurring theme in the cagrilintide papers is that structural similarity between two peptides tells you very little about how they will behave in the same assay. Cagrilintide, pramlintide and salmon calcitonin all touch calcitonin family receptors, yet Fletcher’s comparison across many endpoints showed clearly different profiles [2]. If a comparison doesn’t pin down the model, the receptor complex and the assay, we wouldn’t lean on it much.
Handling and characterization
It ships lyophilized and likes the same treatment as any lipidated peptide: cold, dry, dark. HPLC separates it from near-miss byproducts. Mass spec checks the mass, lipid chain and all. Those methods are what any honest purity claim depends on, and we document ours on our certificates of analysis. For the broader family it belongs to, the peptides and polypeptides primer is a useful companion.
FAQ
Is cagrilintide the same as amylin?
No. It is a lipidated, long acting analogue of amylin, engineered to resist the amyloid aggregation and rapid clearance that limit native amylin [1].
What receptors does cagrilintide bind?
Amylin receptor complexes, which are a calcitonin receptor paired with a receptor activity modifying protein, and the calcitonin receptor itself [2].
Why does cagrilintide have such a long half life?
Lipidation extends its circulating life; early pharmacokinetic work put the half life near 159 to 195 hours [3].
References
- Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021. PMID 34288673.
- Fletcher MM, Keov P, Truong TT, et al. AM833 is a novel agonist of calcitonin family G protein-coupled receptors: pharmacological comparison with six selective and nonselective agonists. J Pharmacol Exp Ther. 2021. PMID 33727283.
- Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant […] cagrilintide with semaglutide: a randomised, controlled, phase 1b trial. Lancet. 2021. PMID 33894838.
- Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide […]: a randomised, double-blind, phase 2 trial. Lancet. 2021. PMID 34798060.
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