Cagrilintide

What Is Cagrilintide?

Cagrilintide is a stable, lipidated, long-acting analog of amylin, a pancreatic hormone, and was selected for clinical development with obesity as its indication.^[1] Amylin is co-secreted with insulin from pancreatic beta cells after meals and is known to induce satiety, inhibit homeostatic and hedonic feeding, and lower body weight.^[2]

Native amylin forms amyloid fibrils readily, which makes it difficult to develop as a drug. The earlier amylin analog pramlintide, used as an adjunct to insulin therapy in diabetes, has a short half-life.^[1] Cagrilintide was designed as a long-acting alternative and is now being developed mainly in combination with semaglutide for weight management.^[3]

Pharmacologically, cagrilintide is classed as a dual amylin and calcitonin receptor agonist, a group of compounds in phase 2 and phase 3 trials for obesity.^[4]

Chemical Structure and Molecular Identity

Cagrilintide is a 37-residue peptide with an intramolecular disulfide bond and a fatty-acid chain at its N-terminus. PubChem (CID 171397054) lists the molecular formula as C194H312N54O59S2 and the molecular weight as 4409 g/mol; the CAS Registry Number is 1415456-99-3.

Structural features

• Backbone: 37 standard L-amino acids based on the human amylin sequence, with the proline substitutions also found in pramlintide plus further changes, including glutamic acid at position 14, arginine at position 17 and proline at position 37.
• Disulfide bridge: a ring formed between cysteine 2 and cysteine 7, as in native amylin.
• Lipidation: an eicosanedioic acid (C20 diacid) attached through a gamma-glutamic acid spacer to the N-terminal amino group of lysine 1.
• C-terminus: a proline amide.

The published development work describes structure-activity studies that addressed amylin’s tendency to aggregate and led to the selection of this lipidated analog as a stable, long-acting molecule.^[1] PubChem also lists the INN “cagrilintide” and the UNII code AO43BIF1U8 among its synonyms.

Research History and Development

Cagrilintide moved from medicinal chemistry work into phase 1 and phase 2 trials alone and with semaglutide, and its combination with semaglutide entered phase 3.^[1][5]

Early clinical trials

A phase 1b trial at a single US center enrolled otherwise healthy adults with a BMI of 27.0 to 39.9 kg/m² in six sequential cohorts, combining ascending levels of cagrilintide or placebo with semaglutide. Its primary endpoint was the number of treatment-emergent adverse events, with pharmacokinetic and pharmacodynamic measures as secondary and exploratory endpoints.^[6]

A dose-finding phase 2 trial at 57 sites in ten countries compared five dose levels of cagrilintide with liraglutide and placebo over 26 weeks in adults without diabetes who had obesity, or overweight with hypertension or dyslipidemia.^[7] A separate 32-week phase 2 trial at 17 US sites tested cagrilintide, semaglutide and the combination in 92 adults with type 2 diabetes. Its primary endpoint was HbA1c change, and secondary endpoints included body weight, fasting plasma glucose and continuous glucose monitoring measures.^[8]

Phase 3

A phase 3a, 68-week trial randomized 3,417 adults without diabetes who had obesity, or overweight with at least one obesity-related complication, to cagrilintide-semaglutide, either component alone or placebo.^[9] REIMAGINE 2, a phase 3 trial in 30 countries, compared the fixed-dose combination with each component in adults with type 2 diabetes and overweight or obesity over 68 weeks. Its primary endpoint was the change in HbA1c at week 68 for the higher-dose combination versus semaglutide alone.^[10]

Mechanisms Studied in Research

Cagrilintide reduces food intake and body weight in animals by acting on amylin receptors in the brainstem. These receptors are heterodimers of the calcitonin receptor with receptor activity-modifying proteins (RAMPs).^[4]

Amylin receptor subtypes in mice

Amylin binds a receptor made of the calcitonin receptor paired with RAMP1, RAMP2 or RAMP3. In high-fat-diet-fed mice, cagrilintide reduced body weight in wild-type animals (−3.4 g over three weeks), whereas salmon calcitonin increased it. Knocking out RAMP1 and RAMP3, which form the AMY1 and AMY3 receptors, reduced cagrilintide’s potency. Cagrilintide cut day-1 food intake from 2.7 g to 1.2 g in wild-type mice.^[4]

Cagrilintide activated c-Fos in neurons of the dorsal vagal complex and lateral parabrachial nucleus. In RAMP1/3 knockout mice, c-Fos signal in the area postrema was 57% lower than in wild-type mice. After three weeks of treatment, cagrilintide did not significantly change gene expression in the dorsal vagal complex or lateral parabrachial nucleus of wild-type mice.^[4]

Rationale for combining with semaglutide

Amylin acts on homeostatic and hedonic brain regions to produce satiety, while semaglutide reduces appetite through hypothalamic GLP-1 receptors, increases insulin and lowers glucagon. Reviewers describe these related but separate mechanisms as having an additive effect on appetite reduction.^[3]

Key Findings From Published Studies

In clinical trials, cagrilintide alone produced weight loss similar to established GLP-1 receptor agonists. Its combination with semaglutide produced greater weight and HbA1c reductions than either component alone.^[11][8][9]

Cagrilintide alone

A 2024 meta-analysis found that cagrilintide alone produced weight loss similar to semaglutide or liraglutide at 26 to 32 weeks (mean difference −1.83%, not significant), with significantly less vomiting. Treatment-emergent and serious adverse events were comparable between groups.^[11]

Combination with semaglutide

In the same meta-analysis, gastrointestinal adverse events and vomiting were more frequent with the combination than with semaglutide alone.^[11] In the phase 3a trial, 2,108 of the 3,417 participants were assigned to the combination, and the estimated difference in weight change versus placebo was −17.3 percentage points.^[9] A 2026 network meta-analysis of 262 trials and 99,791 participants estimated one-year weight loss of 14.8% for cagrilintide-semaglutide compared with lifestyle modification alone, with moderate to high certainty, close to the 14.9% estimated for tirzepatide. The combination was also among the agents with the highest rates of discontinuation due to adverse events.^[12] Gastrointestinal effects such as nausea and vomiting are the main adverse events across GLP-1-based therapies.^[5]

Because cagrilintide combines a disulfide bridge with N-terminal lipidation, HPLC and mass-spectrometry certificates of analysis are the practical way to confirm a sample's identity.

Regulatory and Research Status

Cagrilintide is not FDA approved, either alone or in combination. Its fixed-dose combination with semaglutide is in phase 3 development for obesity and type 2 diabetes.^[5][10]

Research questions include how weight loss is maintained over the long term and which amylin receptor subtypes mediate cagrilintide’s effects.^[5][4] Reviewers see combination therapy with several targets as a logical approach to obesity treatment, given the condition’s heterogeneity.^[3] A 2025 pipeline review places the cagrilintide-semaglutide combination in phase 3 alongside oral semaglutide and several non-peptide oral GLP-1 agonists.^[5]

Outside registered clinical trials, cagrilintide is not approved for human use, and material described as cagrilintide is intended for laboratory research only.