— Research note —
Cagrilintide
Long-acting amylin receptor agonist investigated as a monotherapy and in fixed-combination research with semaglutide for body-weight regulation.
Cagrilintide is a 37-amino-acid synthetic analog of human amylin, engineered by Novo Nordisk for once-weekly subcutaneous administration in research protocols. The peptide backbone contains multiple substitutions that increase stability and confer pan-amylin-receptor agonism, and a C18 fatty diacid is conjugated via a linker at position 37 to enable albumin binding. The resulting pharmacokinetic profile supports a plasma half-life of approximately 159 hours in human research populations.
Amylin is a peptide hormone co-secreted with insulin from pancreatic beta cells and contributes to postprandial satiety, gastric emptying, and glucagon suppression. Native amylin has limited utility as a research tool because of aggregation tendencies and short half-life; cagrilintide was designed to overcome these limitations while retaining activity across the heterodimeric amylin receptor family (AMY1, AMY2, AMY3) formed by the calcitonin receptor coupled with receptor activity-modifying proteins.
The molecule has been most extensively studied in the context of body-weight regulation, both as monotherapy and in combination with semaglutide (the investigational combination designated CagriSema). Phase 2 research published in The Lancet demonstrated dose-dependent reductions in body weight as monotherapy, with combination studies suggesting additive or synergistic effects when paired with GLP-1 receptor agonism. The compound has become a reference probe for academic research on amylin biology, brainstem satiety circuits, and the complementary nature of amylin and incretin signaling.
Cagrilintide is supplied here for laboratory research use only and is not intended for human consumption. Researchers interested in receptor pharmacology, energy balance physiology, and combination peptide pharmacology have made it a frequently requested reference compound.
Mechanism
Cagrilintide acts as an agonist at the amylin receptor complexes AMY1, AMY2, and AMY3, which are formed by heterodimerization of the calcitonin receptor with receptor activity-modifying proteins 1, 2, or 3. Receptor activation couples through Gas to adenylyl cyclase, elevating intracellular cAMP. Cagrilintide also retains affinity for the calcitonin receptor itself, distinguishing it from earlier amylin analogs such as pramlintide.
Within the brainstem, amylin receptors in the area postrema and nucleus tractus solitarius mediate observed reductions in food intake and meal size in preclinical feeding studies. The molecule also engages receptors in the hypothalamic arcuate nucleus and lateral parabrachial nucleus, contributing to homeostatic satiety. Peripheral actions include slowed gastric emptying and suppression of postprandial glucagon secretion. The complementary anatomical distribution of amylin and GLP-1 receptors provides a mechanistic rationale for combination studies with semaglutide.
Research history
The amylin signaling pathway has been investigated since the late 1980s following the identification of islet amyloid polypeptide as a beta-cell co-secretory product. Pramlintide, the first synthetic amylin analog, was approved for adjunctive insulin therapy in the mid-2000s but required multiple daily injections, limiting its utility as a research probe.
Novo Nordisk disclosed cagrilintide (originally AM833) in the late 2010s with the explicit design goal of weekly dosing through fatty acid conjugation. Phase 1 single- and multiple-ascending-dose studies appeared in 2020, confirming the predicted pharmacokinetic profile. A phase 2 dose-ranging monotherapy study published in The Lancet in 2021 reported dose-dependent body-weight reductions across cohorts.
The combination program with semaglutide (CagriSema) advanced through phase 2 and into the REDEFINE phase 3 series, with REDEFINE-1 reporting topline results in late 2024 and additional readouts in 2025. Concurrent academic investigations have used cagrilintide as a tool molecule to dissect amylin receptor subtype contributions to satiety, to characterize the role of the calcitonin receptor in energy balance, and to explore amylin biology in neurodegenerative research contexts where islet amyloid and brain amyloid pathways may intersect.
References
- Lau DCW, et al. 2021. Once-weekly cagrilintide for weight management in people with overweight and obesity. Lancet. PMID: 34774192
- Enebo LB, et al. 2021. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management. Lancet. PMID: 34774193
- Hay DL, et al. 2015. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacol Rev. PMID: 25767347
- Larsen AT, et al. 2020. Dual amylin and calcitonin receptor agonists (DACRAs) for the treatment of obesity. Curr Diab Rep.
- Kruse T, et al. 2021. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. PMID: 34870992
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Information presented in third-person scientific context. Research use only. Not medical advice; not for human consumption.