Educational Reference · Research-Use-Only
Cagrilintide: Mechanism, Research, and Regulatory Status
A research-grade overview of Cagrilintide — what it is, how it works at the molecular level, what published studies have shown, and answers to the questions researchers ask most.
Last reviewed 2026-07-28
What is Cagrilintide?
Cagrilintide is a lipidated, fibrillation-resistant analogue of human islet amyloid polypeptide (amylin), a 37-residue beta-cell hormone co-secreted with insulin. The parent hormone is highly amyloidogenic, which historically limited its druggability; cagrilintide was engineered from a pramlintide-like backbone with three substitutions that suppress fibril formation and stabilize the helical segment, together with acylation of the Lys1 side chain by a C20 diacid via a gamma-glutamyl linker. The fatty diacid confers reversible, non-covalent albumin binding, which slows renal clearance and gives pharmacokinetics compatible with once-weekly subcutaneous administration in the published trial program.
Pharmacologically, cagrilintide is a non-selective agonist at the calcitonin receptor and at the amylin receptors AMY1R, AMY2R and AMY3R, which are calcitonin-receptor heterodimers formed with receptor activity-modifying proteins. Cryo-electron microscopy structures show cagrilintide adopting an amylin-like bypass binding mode across these receptors, with a phenylalanine anchor at the transmembrane bundle and an intramolecular salt bridge stabilizing the peptide helix, while inducing conformational dynamics distinct from native amylin. Downstream signalling is predominantly Gs-coupled cAMP accumulation in amylin-responsive nuclei of the hindbrain, notably the area postrema and nucleus tractus solitarius.
Rodent knockout work indicates that the effect on body weight depends on AMY1R and AMY3R specifically rather than on the calcitonin receptor alone. Because amylin and GLP-1 receptor signalling converge on partly non-overlapping central circuits, co-administration with semaglutide has been studied as a mechanistically complementary combination.
Research highlights
What published peer-reviewed research and preclinical studies have established about Cagrilintide:
- 01Cagrilintide was developed by structure-activity optimization of an amylin backbone to eliminate the amyloid-fibril propensity that limits native amylin (Kruse 2021).
- 02It is a non-selective agonist of the calcitonin receptor and of all three amylin receptor subtypes rather than a subtype-selective ligand.
- 03In AMY1R and AMY3R knockout mice, the body-weight-lowering effect is lost, establishing dependence on those two receptor subtypes (Carvas 2025).
- 04In a 26-week Phase 2 dose-finding trial, weight reduction was dose-dependent across the 0.3-4.5 mg range (6.0% to 10.8%) versus 3.0% for placebo (Lau 2021).
- 05In REDEFINE 1, the combination arm achieved -20.4% body weight versus -3.0% for placebo at 68 weeks, with cagrilintide and semaglutide monotherapy arms included as comparators (Garvey 2025).
- 06Gastrointestinal adverse events are the dominant tolerability signal across the program: 41-63% versus 32% placebo in Phase 2, and 79.6% versus 39.9% for the combination versus placebo in REDEFINE 1.
- 07LIMITATION: all published human data derive from a single sponsor's program; long-term multi-year outcome and cardiovascular outcome data were not available in the trials verified here.
Published clinical and preclinical research
Phase 2 dose-finding monotherapy trial
Phase 2 · 2021Dose-dependent weight reduction of 6.0% to 10.8% with cagrilintide 0.3-4.5 mg versus 3.0% with placebo (p<0.001); cagrilintide 4.5 mg achieved 10.8% versus 9.0% for liraglutide 3.0 mg (p=0.03). Gastrointestinal adverse events 41-63% versus 32% placebo.
REDEFINE 1
Phase 3 · 2025Cagrilintide 2.4 mg plus semaglutide 2.4 mg achieved -20.4% versus -3.0% for placebo; treatment difference -17.3 percentage points (95% CI -18.1 to -16.6; p<0.001). Semaglutide-alone and cagrilintide-alone arms were included as active comparators. Gastrointestinal adverse events 79.6% versus 39.9%.
REDEFINE 2
Phase 3 · 2025-13.7% with the combination versus -3.4% with placebo; difference -10.4 percentage points (95% CI -11.2 to -9.5; p<0.001). Gastrointestinal adverse events 72.5% versus 34.4%.
Frequently asked questions about Cagrilintide
What is cagrilintide?+
Cagrilintide (research code AM833) is a synthetic, lipidated 37-amino-acid analogue of human amylin, engineered for resistance to amyloid fibril formation and for extended duration of action. It is supplied as a lyophilized peptide for in vitro and preclinical research use only.
What receptors does cagrilintide act on?+
It is a non-selective agonist at the calcitonin receptor and at the three amylin receptor subtypes AMY1R, AMY2R and AMY3R, which are calcitonin-receptor/RAMP heterodimers. Structural work shows an amylin-like bypass binding pose with conformational dynamics distinct from native amylin, and knockout studies indicate the weight effect depends specifically on AMY1R and AMY3R.
How does cagrilintide differ structurally from pramlintide and native amylin?+
Relative to the pramlintide backbone, cagrilintide carries three substitutions and an acylation of the Lys1 side chain with a C20 diacid via a gamma-glutamyl linker. The substitutions reduce fibrillation and stabilize the helix; the diacid confers reversible albumin binding, which is why the published trial program uses once-weekly rather than multiple-daily administration.
How does cagrilintide relate to CagriSema?+
CagriSema is the investigational fixed combination of cagrilintide with the GLP-1 receptor agonist semaglutide. Published Phase 1b, Phase 2 and Phase 3 REDEFINE trials studied the combination, with cagrilintide and semaglutide monotherapy arms included as comparators, which allows the combination's incremental effect to be attributed.
What are the handling considerations for a lipidated peptide of this class?+
Standard laboratory practice applies: keep the lyophilized solid frozen, desiccated and protected from light; equilibrate the vial to room temperature before opening to avoid condensation; reconstitute in an appropriate sterile aqueous vehicle; aliquot to avoid repeated freeze-thaw. No peer-reviewed stability study specific to research-grade material was identified, so lot-specific analytical data should govern rather than generic guidance.
References & sources
Every citation below was resolved against its primary source before publication — each PMID against the PubMed record and each DOI through doi.org. Follow any link to read the paper at the publisher rather than taking our summary on trust.
- [1]Kruse T, Hansen JL, Dahl K, et al.. Development of cagrilintide, a long-acting amylin analogue. Journal of Medicinal Chemistry. 2021. PMID: 34288673 DOI: 10.1021/acs.jmedchem.1c00565
- [2]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. The Lancet. 2021. PMID: 34798060 DOI: 10.1016/S0140-6736(21)01751-7
- [3]Garvey WT, Blüher M, Osorto Contreras CK, et al.. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2025. PMID: 40544433 DOI: 10.1056/NEJMoa2502081
- [4]Davies MJ, Bajaj HS, Broholm C, et al.. Coadministered cagrilintide and semaglutide in adults with overweight or obesity and type 2 diabetes. New England Journal of Medicine. 2025. PMID: 40544432 DOI: 10.1056/NEJMoa2502082
- [5]Carvas AO, Leuthardt A, Kulka P, et al.. Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3. EBioMedicine. 2025. PMID: 40609154 DOI: 10.1016/j.ebiom.2025.105836
Where this data comes from
- —Citations & trial data: PubMed (NCBI, U.S. National Library of Medicine), Crossref and ClinicalTrials.gov.
- —Chemical identity: PubChem and UniProt. Where sources conflicted, the disputed value is omitted rather than guessed.
- —Regulatory status: U.S. FDA publications and, where applicable, the WADA Prohibited List. Compounding status changes frequently — verify against FDA directly before relying on it.
- —Purity, form and storage are handling and supplier conventions, not literature-derived values. Confirm against the lot-specific certificate of analysis.
Content last reviewed 2026-07-28. Compiled by Veridian Research from the primary literature. This page is an educational reference for laboratory researchers — it is not medical advice, and it describes no human use.
Regulatory status
Cagrilintide is an investigational new drug and is NOT approved by the FDA, EMA or any other regulatory authority for any indication, either alone or as the fixed combination with semaglutide. A US New Drug Application for the combination was submitted in December 2025; no regulatory decision had been issued as of mid-2026. Material supplied for laboratory use is not a drug, is not manufactured under pharmaceutical GMP for human use, and is intended strictly for in vitro and non-human research. No representation is made regarding safety, efficacy, dosing, or suitability for human or veterinary administration.
Research-Use-Only Material
Specifications and certificate of analysis
Cagrilintide is stocked as a research reagent. Analytical documentation — identity, purity and the lot-specific certificate of analysis — is published on the product record.
View specifications & COA →