Cagrilintide: Published Research

Introduction

This article summarizes published peer-reviewed research on cagrilintide, a long-acting amylin receptor agonist developed by Novo Nordisk. Studies span medicinal chemistry, structural pharmacology, and controlled clinical trials through Phase 3, including the Phase 3 REDEFINE pivotal trials published in the New England Journal of Medicine in 2025. All findings are attributed to their original authors and study designs, in keeping with the educational framing of this library. The receptor pharmacology underlying these findings is examined in the cagrilintide mechanism of action article.

Methodology Types in the Published Literature

Published cagrilintide research spans four methodological categories. First, medicinal chemistry and structure-activity studies in which multiple lipidated amylin analogs were synthesized and characterized using in vitro receptor binding assays and in vivo pharmacokinetic and pharmacodynamic measurements in rat and rodent models. Second, structural biology investigations using cryo-electron microscopy to determine high-resolution receptor complex structures. Third, receptor pharmacology studies using genetically modified mouse models with targeted deletion of receptor subunits. Fourth, randomized controlled clinical trials across Phase 1, Phase 2, and Phase 3 designations in humans, employing placebo or active comparator controls and conducted under Good Clinical Practice standards.

Summary of Published Studies

Medicinal Chemistry: Identification of Cagrilintide (2021)

The primary medicinal chemistry disclosure describing the development of cagrilintide was published by Andreassen and colleagues in the Journal of Medicinal Chemistry in 2021 [1]. The authors reported on structure-activity relationship (SAR) studies that evaluated a library of acylated amylin analogs derived from the human amylin sequence with modifications intended to prevent amyloid fibril formation at pharmaceutical concentrations. Key findings included identification of a proline substitution at position 37 as critical for preventing aggregation, and introduction of an N-terminal C20 fatty acid chain attached via a hydrophilic linker as the mechanism for albumin-mediated plasma half-life extension. The authors reported that compound 23 — subsequently named cagrilintide — reduced food intake in rat models for several days following single administration, at doses orders of magnitude lower than pramlintide required for shorter-duration effects. Pharmacokinetic modeling indicated a projected half-life consistent with once-weekly dosing in humans.

Structural Pharmacology: Receptor Complex Structures (2025)

A structural pharmacology study published in Nature Communications in April 2025 by Deganutti and colleagues determined cryo-electron microscopy structures of cagrilintide bound to Gs-coupled active states of all four calcitonin-family receptors: CTR, AMY1R, AMY2R, and AMY3R [2]. The study compared these structures to those obtained with rat amylin, salmon calcitonin, and other amylin-class peptides. Authors reported that cagrilintide adopted an amylin-like binding mode across all receptor subtypes, but induced distinct conformational dynamics at each receptor complex compared to other peptides tested. An intra-peptide ionic interaction designated the R17–E14 ionic lock was identified as a structural feature unique to cagrilintide that biases the peptide toward a bypass conformation at the CTR. Authors concluded that cagrilintide's distinct receptor dynamics, relative to other calcitonin-family peptides, may contribute to its differentiated pharmacological profile. This study was accompanied by open-access molecular dynamics trajectory data enabling independent analysis.

Receptor Biology: AMY1R and AMY3R Mediation of Body Weight Effects (2025)

A study published in eBioMedicine in 2025 by Carvas and colleagues investigated the receptor subtype specificity of cagrilintide's in vivo effects using RAMP-knockout mouse models [3]. Wild-type mice administered cagrilintide demonstrated body weight reductions over the observation period. Mice with genetic deletion of RAMP1 (which forms AMY1R in complex with CTR) and RAMP3 (which forms AMY3R) showed substantially attenuated responses to cagrilintide, while the response was preserved in mice lacking RAMP2 (which forms AMY2R). By contrast, administration of salmon calcitonin — which preferentially activates CTR over the RAMP-containing subtypes — did not replicate cagrilintide's body weight profile and in some conditions produced opposing directional changes. The authors concluded that cagrilintide's pharmacological effects on body weight in mice are principally mediated through AMY1R and AMY3R expressed in brain regions associated with energy homeostasis signaling, rather than through CTR or AMY2R.

Phase 1b Clinical Trial: Safety, Pharmacokinetics, and Pharmacodynamics (2021)

Enebo and colleagues published results of a randomized, controlled, multiple-ascending dose Phase 1b trial in The Lancet in May 2021 [4]. The trial enrolled adults with overweight or obesity without diabetes at a single US site and evaluated cagrilintide across six escalating dose levels in combination with semaglutide 2.4 mg, compared to semaglutide plus placebo. The study reported that the combination was generally well tolerated across all tested cagrilintide dose levels, with the majority of adverse events being gastrointestinal in nature and graded as mild or moderate in severity. Pharmacokinetic data demonstrated a plasma half-life consistent with once-weekly dosing. The authors described the tolerability and pharmacokinetic profile as supporting further clinical development.

Phase 2 Clinical Trial: Co-Administration with Semaglutide in Type 2 Diabetes (2023)

Frias and colleagues published results of a randomized, double-blind, active-controlled Phase 2 trial in The Lancet in June 2023 [5]. The 32-week trial enrolled adults with type 2 diabetes and body mass index ≥27 kg/m² from 17 sites in the United States. Participants were assigned to once-weekly CagriSema (cagrilintide 2.4 mg co-administered with semaglutide 2.4 mg), semaglutide monotherapy, or cagrilintide monotherapy. The trial reported that participants in the CagriSema arm achieved greater reductions in both body weight and glycated hemoglobin (HbA1c) compared to either monotherapy arm. The most frequently reported adverse events across all arms were gastrointestinal. The authors concluded that the pharmacodynamic data supported advancement of the combination into Phase 3 clinical evaluation.

Phase 3 REDEFINE 1: Co-Administration in Adults with Overweight or Obesity (2025)

Aronne and colleagues published the REDEFINE 1 trial in the New England Journal of Medicine in June 2025 [6]. This was a Phase 3, randomized, double-blind, 68-week trial enrolling 3,417 adults with overweight or obesity and at least one weight-related comorbidity, without type 2 diabetes. Participants were assigned to cagrilintide–semaglutide combination, semaglutide monotherapy, cagrilintide monotherapy, or placebo. The estimated mean percent change in body weight from baseline to week 68 was reported as −20.4% in the cagrilintide–semaglutide arm compared to −3.0% in the placebo arm. The cagrilintide monotherapy arm produced an estimated body weight reduction of approximately 11.8% compared to 2.3% with placebo. Cardiometabolic secondary endpoints including systolic blood pressure, waist circumference, and lipid parameters showed directional changes favoring the combination arm. The safety profile in REDEFINE 1 was described as consistent with prior clinical trial experience for the compound class.

Phase 3 REDEFINE 2: Co-Administration in Adults with Type 2 Diabetes (2025)

Davies and colleagues published the REDEFINE 2 trial in the New England Journal of Medicine in June 2025 [7]. This Phase 3 trial enrolled 1,206 adults with overweight or obesity and type 2 diabetes over 68 weeks. The primary and secondary findings in the combination arm were qualitatively consistent with REDEFINE 1. The estimated mean percent change in body weight from baseline to week 68 was approximately −13.7% with cagrilintide–semaglutide compared to −3.1% with placebo. Glycemic endpoints, including HbA1c reduction, were also reported to favor the combination arm relative to placebo.

Active Research Frontiers

The cagrilintide research landscape has expanded substantially since the Phase 3 REDEFINE publications, and several productive directions are under active investigation. Head-to-head comparative studies between cagrilintide and other long-acting amylin analogs in clinical populations represent an emerging area, as additional compounds in this class advance through development. The molecular basis for the additive pharmacological profile observed when cagrilintide is combined with semaglutide is a focus of ongoing basic science inquiry into shared and distinct neural circuit engagement across the amylin and GLP-1 receptor systems. The published clinical trial evidence for semaglutide as a GLP-1 receptor agonist represents a useful reference context for understanding the combination pharmacology evaluated in the REDEFINE program. Research-grade cagrilintide from SpartaLabs is available with batch-level certificates of analysis for preclinical investigation.

Population pharmacokinetic characterization continues to develop, with a published pharmacokinetic study (Kasichayanula et al., 2026) having reported that renal or hepatic impairment does not meaningfully alter cagrilintide's pharmacokinetic profile [8]. Long-term observation data beyond the 68-week REDEFINE window, and the receptor occupancy profile across AMY1R, AMY2R, AMY3R, and CTR in human tissue at clinically relevant concentrations, are areas where additional peer-reviewed publications are anticipated as the clinical program matures.

References

1. Andreassen KV, Feigh M, Hjuler ST, Christoffersen BØ, Damgaard Møller A, Rolin B, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183–11194. DOI: 10.1021/acs.jmedchem.1c00565

2. Deganutti G, Atanasio S, Bhatt DL, Igonet S, Koehl A, Bhattacharya S, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nat Commun. 2025;16:3389. PMID: 40204768. DOI: 10.1038/s41467-025-58680-y

3. Carvas AO, Leuthardt A, Kulka P, Lommi G, Hassan S, Coester B, et al. Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3. eBioMedicine. 2025;105836. PMC12270663. DOI: 10.1016/j.ebiom.2025.105836

4. Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397(10288):1736–1748. PMID: 33894838. DOI: 10.1016/S0140-6736(21)00845-X

5. Frias JP, Erichsen L, Knop FK, Lingvay I, Davies M, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402(10403):720–730. PMID: 37364590. DOI: 10.1016/S0140-6736(23)01163-7

6. Aronne LJ, Horn DB, le Roux CW, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity (REDEFINE 1). N Engl J Med. 2025. DOI: 10.1056/NEJMoa2502081

7. Davies M, et al. Cagrilintide–semaglutide in adults with overweight or obesity and type 2 diabetes (REDEFINE 2). N Engl J Med. 2025;393:648–659. DOI: 10.1056/NEJMoa2502082

8. Kasichayanula S, Boulton DW, et al. Renal or hepatic impairment does not affect pharmacokinetics, safety, or tolerability of subcutaneous cagrilintide. Clin Pharmacokinet. 2026. DOI: 10.1007/s40262-026-01654-0