Description
Summary Abstract
Cagrilintide (AM833; modified amylin analogue; 37-amino acid; C20 fatty diacid acylated; MW ~4,200 g/mol; CAS 2381868-24-1) is a next-generation Dual Amylin and Calcitonin Receptor Agonist (DACRA) developed by Novo Nordisk as a long-acting synthetic analogue of the endogenous pancreatic hormone amylin (Islet Amyloid Polypeptide, IAPP). Engineered with specific amino acid substitutions to prevent the amyloidogenic aggregation that limits native amylin’s therapeutic use, and acylated with a C20 fatty diacid for albumin binding, cagrilintide achieves a plasma half-life enabling once-weekly subcutaneous administration. Its mechanism addresses the satiety axis through the hindbrain amylin receptor complex (calcitonin receptor CTR + RAMP1/RAMP3), activating the area postrema and nucleus of the solitary tract (NTS) to generate potent satiation signals that reduce meal size. As a DACRA, cagrilintide also activates the calcitonin receptor directly, adding a distinct layer of metabolic regulation beyond selective amylin receptor agonism. The REDEFINE Phase 3 program established cagrilintide 2.4 mg monotherapy at 11.8% mean body weight reduction at 68 weeks (REDEFINE 1 sub-analysis), and the CagriSema fixed-dose combination (cagrilintide 2.4 mg + GLP-1 RA 2.4 mg) at a landmark 22.7% mean body weight reduction at 68 weeks in adults with obesity without T2D. Preclinical data additionally indicate that CagriSema blunts the metabolic adaptation response to weight loss, preserving resting energy expenditure.
Clinical Indications
Cagrilintide has been evaluated as monotherapy and in combination across metabolic disease settings:
- Obesity (Monotherapy): Phase 3 REDEFINE 1 sub-analysis of cagrilintide 2.4 mg alone (68 weeks) produced 11.8% mean body weight reduction vs. 2.3% placebo; 31.6% achieved ≥15% weight loss versus 4.7% placebo.
- Obesity Without T2D (CagriSema Combination): REDEFINE 1 (n=3,417; 68 weeks) — CagriSema 2.4/2.4 mg produced a mean weight reduction of 22.7% vs. 3.0% placebo; 60.2% achieved ≥20% loss and 40.4% achieved ≥25% loss.
- Obesity with Type 2 Diabetes: REDEFINE 2 (n=1,206; 68 weeks) — CagriSema produced 15.7% mean weight reduction in this historically difficult-to-treat population; 80.7% achieved HbA1c ≤6.5%; prediabetic participants showed 87.7% normoglycemia reversion.
- Cardiovascular Risk Factor Modification: CagriSema reduced systolic blood pressure by 9.9 mmHg (REDEFINE 1), improved lipid profiles, and reduced CRP, reflecting comprehensive cardiometabolic disease modification.
Contraindications
- Personal or Family History of Medullary Thyroid Carcinoma / MEN2: As with all incretin-class agents, C-cell hyperplasia in rodents necessitates contraindication in individuals with MTC history or Multiple Endocrine Neoplasia type 2; human risk has not been established but caution remains warranted.
- Prior History of Pancreatitis: Transient amylase/lipase elevations and rare acute pancreatitis signal associated with GLP-1-containing regimens; avoid in patients with prior pancreatitis episodes.
- Pregnancy: Rapid maternal weight loss is teratogenic risk; discontinue prior to planned conception.
Mechanism of Action (MOA)
Cagrilintide’s metabolic effects are mediated through a two-receptor system centered in the hindbrain, operating through pathways distinct from GLP-1 receptor agonism:
Hindbrain DACRA Action — Area Postrema and NTS
Cagrilintide acts on the area postrema (AP) and adjacent nucleus of the solitary tract (NTS) — circumventricular organs with permeable blood-brain barriers that directly sense circulating hormones. Activation of cFos in these hindbrain neurons is the consistent mechanistic marker of cagrilintide action; this signal relays to the lateral parabrachial nucleus (lPBN) and hypothalamic nuclei to reduce meal size and caloric intake via potent satiation signaling.
Amylin Receptor Complex Activation (AMY1R / AMY3R)
The amylin receptor is a heterodimer of the calcitonin receptor (CTR) and RAMP1 (AMY1R) or RAMP3 (AMY3R). Cagrilintide potently activates both subtypes. This engagement mimics and amplifies the endogenous postprandial amylin signal that is deficient in T2D (due to beta-cell dysfunction), correcting postprandial hyperglucagonemia and slowing gastric emptying beyond what is achieved by GLP-1 agonism alone.
Calcitonin Receptor Mono-Agonism — Additional Metabolic Layer
As a DACRA rather than a selective amylin mimetic, cagrilintide also activates the calcitonin receptor (CTR) monolithically — engagement that selective amylin agonists do not provide. This broader receptor profile appears to contribute an additional metabolic regulatory layer, explaining the superior weight-loss efficacy compared to selective amylin analogues in head-to-head preclinical comparisons.
Blunting Metabolic Adaptation — Preserved Energy Expenditure
Pivotal preclinical work demonstrated that CagriSema-treated animals achieving 12% body weight loss required only a 39% food intake reduction, while weight-matched calorie-restricted controls required 51% reduction — implying preserved total energy expenditure (TEE) in CagriSema-treated animals. Approximately one-third of the combination’s weight-loss efficacy appears attributable to counteracting the metabolic adaptation that normally accompanies caloric restriction, a hallmark of obesity pharmacotherapy failure.
Key Features & Specifications
Key pharmacological attributes of cagrilintide:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| Sequence | Modified 37-amino acid amylin analogue; specific substitutions to prevent amyloid aggregation; acylated at Lys with C20 fatty diacid for albumin binding |
| CAS Number | 2381868-24-1 |
| Molecular Weight | ~4,200 g/mol (lipopeptide conjugate) |
| Receptor Targets | AMY1R (CTR + RAMP1), AMY3R (CTR + RAMP3), CTR monomer (calcitonin receptor) |
| Synonyms | AM833; DACRA amylin analogue; component of CagriSema |
| Half-Life | ~7 days (once-weekly dosing enabled) |
| Form / Variation | 10 MG Lyophilized (P-003) |
Storage, Safety, and Handling
Storage Protocol
Store lyophilized cagrilintide at −20 °C, protected from light and humidity. Once reconstituted with bacteriostatic water for injection, stable at 2–8 °C for up to 28 days. Avoid freeze-thaw cycling of the reconstituted solution. The acylated lipopeptide structure requires low-binding polypropylene labware to prevent adsorption.
Handling & Compliance
Handle under aseptic conditions. Across the REDEFINE Phase 3 trials, treatment discontinuation due to adverse events was low (6–8.4%), despite high rates of transient gastrointestinal events; the safety-tolerability profile is consistent with the incretin-mimetic class. WADA classification applies to performance-modifying mechanisms; researchers should confirm jurisdiction-specific regulatory status.