Cagrilintide

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Cagrilintide engages both amylin and calcitonin receptor signaling with careful receptor selectivity profiling. Native amylin binds primarily to amylin receptors — heterodimeric complexes of the calcitonin receptor (CTR) with one of three receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3), generating three distinct amylin receptor subtypes (AMY1R, AMY2R, AMY3R respectively). Cagrilintide retains this multi-receptor engagement pattern with modifications that extend half-life and improve physiochemical stability.

Central Satiety Signaling: The primary mechanism of cagrilintide's weight-loss effect is central — amylin receptor signaling in the area postrema and other circumventricular organs (which lack a complete blood-brain barrier) produces satiety signals that propagate through the nucleus tractus solitarius to hypothalamic feeding centers. This reduces meal size and total caloric intake. Cagrilintide may also slow gastric emptying (similar to native amylin but milder than GLP-1 agonists), contributing to early satiety during meals.

Synergy with GLP-1 Agonism: The key insight behind CagriSema is mechanistic synergy: GLP-1 receptors and amylin receptors are expressed in different hypothalamic and brainstem populations, with partially overlapping but not identical downstream effects on appetite regulation. Co-administration engages two distinct anorexigenic circuits:

• GLP-1 (semaglutide): acts on POMC/CART neurons in the arcuate nucleus, area postrema, and brainstem
• Amylin (cagrilintide): acts preferentially on area postrema and lateral parabrachial nucleus

This dual engagement appears to produce additive or super-additive weight loss without proportionally increasing GI side effects, because each mechanism contributes satiety from a different neural circuit rather than intensifying activation of a single circuit to intolerable levels.

Albumin-Binding Pharmacology: Cagrilintide's fatty acid side chain (a C18 diacid linked to lysine-24 via a γ-Glu-γ-Glu spacer) mediates reversible binding to human serum albumin with nanomolar affinity. This:

• Reduces renal clearance (albumin-bound fraction is protected from glomerular filtration)
• Extends apparent half-life from 13 minutes (native amylin) to ~159 hours (cagrilintide)
• Enables once-weekly dosing
• Produces relatively flat plasma concentration profiles (reducing peak-related nausea)

Receptor Selectivity: Cagrilintide shows relatively balanced engagement across AMY1R, AMY2R, AMY3R and retains calcitonin receptor binding. The native calcitonin receptor itself (without RAMP) is involved in calcium-phosphate homeostasis, but cagrilintide at therapeutic doses does not produce clinically significant changes in bone metabolism or calcium regulation in trials to date.

Glucose Regulation: Unlike its predecessor pramlintide (which was developed primarily for type 1 and type 2 diabetes as an insulin adjunct), cagrilintide has modest effects on glucose control — it slows gastric emptying (reducing post-meal glucose spikes) and potentially suppresses inappropriate glucagon secretion, but it is not currently positioned as a monotherapy for diabetes management. In combination with semaglutide (CagriSema), glycemic improvements reflect primarily the GLP-1 component with modest incremental benefit from amylin.

Pharmacokinetic Profile:

• Half-life: ~159 hours (6-7 days) — once-weekly dosing
• Tmax after SC injection: 24-72 hours (prolonged absorption from subcutaneous depot)
• Bioavailability: approximately 78% subcutaneous
• Distribution: bound to albumin; volume of distribution consistent with vascular-extracellular distribution
• Elimination: primarily enzymatic proteolysis; renal elimination minor
• Steady state: achieved after 5-6 weekly doses (roughly 5-6 half-lives)

Dose-Response Relationship: Phase 2 data established clear dose-response for weight loss across cagrilintide monotherapy doses of 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, and 4.5 mg weekly, with 4.5 mg producing approximately 10.8% weight loss versus 3.0% placebo over 26 weeks (Lau et al., 2021). The CagriSema Phase 3 program uses 2.4 mg cagrilintide + 2.4 mg semaglutide, suggesting the combination allows lower doses of each to achieve synergistic effects.

Cagrilintide (also known as AM833, development code NN9838) is a long-acting amylin analog developed by Novo Nordisk as a next-generation weight-management therapy, designed to be co-administered with the GLP-1 receptor agonist semaglutide in a fixed-ratio combination known as CagriSema. It represents the first clinically successful revival of amylin pharmacology since pramlintide (Symlin) was approved in 2005 for type 1 and type 2 diabetes — a product that never achieved commercial success largely because of its inconvenient three-times-daily subcutaneous dosing schedule and its narrow label. Cagrilintide solves the pharmacokinetic problem: through acylation with a fatty acid chain (in a strategy similar to Novo Nordisk's use of the same chemistry in semaglutide and insulin degludec), cagrilintide binds reversibly to albumin, extending its half-life from native amylin's 13 minutes to approximately 159 hours (6-7 days), enabling once-weekly subcutaneous injection (Enebo et al., 2021).

Amylin itself is a 37-amino-acid peptide hormone co-secreted with insulin by pancreatic beta cells in response to nutrient ingestion, at roughly 1-5% the molar ratio of insulin. It was discovered in 1987 by Per Westermark and colleagues as the principal constituent of pancreatic amyloid deposits in type 2 diabetes (hence the name amylin — from amyloid). The mature hormone contains a disulfide bond between cysteine-2 and cysteine-7 and a C-terminal amide essential for bioactivity, giving it a cyclic head and a linear tail. Native amylin is aggregation-prone and forms the same toxic oligomers and fibrils implicated in beta-cell failure, which is why all clinical amylin analogs (pramlintide, cagrilintide, amycretin) have substituted key amyloidogenic residues (typically proline substitutions at positions 25, 28, 29) to block the fibrillation pathway while preserving receptor binding.

In the Phase 2 randomized trial of cagrilintide monotherapy at 4.5 mg weekly in adults with obesity, mean weight loss at 26 weeks was approximately 10.8% versus 3.0% with placebo and 9.0% with liraglutide 3.0 mg daily (Lau et al., 2021). More importantly, the CagriSema Phase 2 combination trial — cagrilintide 2.4 mg + semaglutide 2.4 mg weekly — produced 15.6% placebo-adjusted weight loss at 32 weeks, substantially greater than either component alone and comparable to tirzepatide and retatrutide results, generating intense pharma-industry and investor interest (Enebo et al., 2021). The Phase 3 REDEFINE program (REDEFINE 1, 2, 3, 4) has enrolled over 6,000 participants, with REDEFINE 1 (adults with obesity, no diabetes) and REDEFINE 2 (type 2 diabetes) reading out weight loss endpoints of 22.7% at 68 weeks in the landmark cohort, positioning CagriSema to compete with tirzepatide (Zepbound/Mounjaro) and the emerging triple agonist retatrutide as the next-generation incretin-amylin combination therapy. Cross-references include Semaglutide (the GLP-1 component of CagriSema), Tirzepatide (the leading dual GLP-1/GIP competitor), Retatrutide (triple agonist in development), Mazdutide (GLP-1/glucagon dual agonist from Innovent), and Orforglipron (oral non-peptide GLP-1 agonist).

IUPAC Name

Amylin analog with N-terminal fatty acid acylation (proprietary)

CAS Number

2172366-25-3

Molecular Formula

C195H286N46O60

Molecular Mass

4246.7 g/mol

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