Cagrilintide: Discovery and Regulatory History

Introduction

Cagrilintide (AM833) is a long-acting acylated amylin analog developed by Novo Nordisk. Its history is inseparable from the broader history of amylin pharmacology, which spans from the initial characterization of the peptide in 1987 through the approval of the first amylin-mimetic drug (pramlintide) in 2005 and into an era of medicinal chemistry innovation aimed at producing a once-weekly amylin analog. This article provides a chronological account of that scientific lineage and the regulatory milestones associated with cagrilintide and its principal clinical combination, CagriSema.

Discovery Period: Amylin Identified (1987)

The peptide hormone that would become the pharmacological target underlying cagrilintide was isolated and characterized in 1987. Cooper and colleagues purified a novel peptide from amyloid-rich pancreatic tissue obtained at autopsy from individuals with type 2 diabetes and published the structure and sequence in the Proceedings of the National Academy of Sciences [1]. The peptide — a 37-amino acid sequence with structural similarity to calcitonin gene-related peptide (CGRP) — was identified as the primary constituent of the islet amyloid deposits previously observed in type 2 diabetes pathology and was named amylin (also referred to as islet amyloid polypeptide, IAPP).

Subsequent work in the early 1990s established that amylin is co-secreted with insulin from pancreatic beta cells in a glucose-dependent manner and signals through receptors in the central nervous system and peripheral tissues. The amyloidogenic tendency of the native human sequence — the same property that made it identifiable in pancreatic deposits — was recognized early as the key structural obstacle for pharmaceutical development, and this recognition directed the search toward modified analogs.

Early Research: Pramlintide and the Rationale for a Long-Acting Analog (1990s–2005)

Initial pharmacological interest in amylin receptor agonism led researchers to examine structurally modified analogs that retained receptor activity without the amyloidogenic tendency of the native human sequence. Investigators identified that rat amylin, which differs from human amylin at three amino acid positions (positions 25, 28, and 29), did not form fibrils under the same conditions and could be formulated for pharmaceutical use [2].

Pramlintide — a synthetic triproline analog of human amylin incorporating the non-amyloidogenic rat-sequence substitutions — was developed by Amylin Pharmaceuticals and received FDA approval in 2005 under the brand name Symlin as an adjunct to mealtime insulin therapy in individuals with type 1 and type 2 diabetes [3]. Pramlintide established proof of pharmacological concept for the amylin receptor agonist class, demonstrating that receptor agonism in this pathway was clinically tractable.

Its plasma half-life of approximately 50 minutes — necessitating administration in conjunction with each meal — provided clear motivation for the next generation of medicinal chemistry work: an amylin analog capable of once-weekly dosing to substantially reduce administration burden.

Development of Cagrilintide: Medicinal Chemistry (2010s)

Novo Nordisk undertook a systematic medicinal chemistry campaign applying the fatty acid acylation strategy — the same approach that had enabled once-weekly dosing for semaglutide — to a new generation of amylin analogs. The campaign evaluated libraries of analogs in which amyloidogenic residues were substituted to enable stable formulation, the peptide backbone was optimized for potent amylin receptor binding, and a fatty acid moiety was attached to enable reversible albumin binding and extended plasma half-life.

The scientific output of this campaign was disclosed in 2021 with the publication of the medicinal chemistry report by Andreassen and colleagues in the Journal of Medicinal Chemistry [4]. That paper described how compound 23 — cagrilintide — emerged from the structure-activity optimization as the first amylin analog demonstrating a pharmacokinetic profile consistent with once-weekly clinical dosing in preclinical models. The compound had been advancing through clinical development under the Novo Nordisk designation AM833 while the medicinal chemistry basis was prepared for publication.

Regulatory Milestones

Phase 1b Trial and First Clinical Publication (2021)

Enebo and colleagues published results of the first clinical pharmacology trial of cagrilintide in The Lancet in May 2021 [5]. The Phase 1b, randomized, controlled trial evaluated cagrilintide at six ascending dose levels in combination with semaglutide 2.4 mg in adults with overweight or obesity. The study reported a tolerability profile and pharmacokinetic data — including a half-life consistent with once-weekly dosing — supporting progression to Phase 2 development. This publication marked the first peer-reviewed disclosure of cagrilintide's human pharmacokinetic and safety profile.

Phase 2 Trial in Type 2 Diabetes (2023)

Frias and colleagues published results of a 32-week, randomized, Phase 2 trial of cagrilintide–semaglutide co-administration in adults with type 2 diabetes in The Lancet in June 2023 [6]. The trial provided the first controlled clinical evidence that combining an amylin receptor agonist with a GLP-1 receptor agonist produced greater effects on body weight and glycemic parameters than either monotherapy arm. These findings informed the design and advancement of the Phase 3 REDEFINE program.

Phase 3 REDEFINE Program and NDA Submission (2025)

REDEFINE 1 and REDEFINE 2 — the pivotal trials for cagrilintide–semaglutide (CagriSema) — were published in the New England Journal of Medicine in June 2025 [7, 8]. REDEFINE 1 enrolled 3,417 adults with overweight or obesity without type 2 diabetes; REDEFINE 2 enrolled 1,206 adults with overweight or obesity and type 2 diabetes; both trials ran for 68 weeks. Phase 3 data for cagrilintide as a monotherapy, presented at scientific meetings in September 2025, reported clinically meaningful body weight reductions relative to placebo, informing Novo Nordisk's decision to initiate the dedicated RENEW Phase 3 monotherapy program [9].

In December 2025, Novo Nordisk submitted a New Drug Application to the FDA for once-weekly CagriSema for chronic weight management in adults [10] — the first regulatory filing for a fixed-dose combination of a GLP-1 receptor agonist and an amylin receptor agonist in the United States.

Current Research Landscape

As of mid-2026, cagrilintide is under active investigation across multiple programs: the RENEW Phase 3 monotherapy program; subsidiary REDEFINE trials in specific populations including East Asian adults and individuals on basal insulin; and investigational studies examining effects on bone metabolism (ClinicalTrials.gov NCT07010432).

The structural pharmacology of cagrilintide's receptor interactions was characterized at high resolution in a 2025 Nature Communications study [11], and receptor biology investigations published in eBioMedicine in 2025 identified the RAMP1- and RAMP3-containing receptor subtypes as principal mediators of the compound's in vivo body weight pharmacology in preclinical models [12]. These mechanistic findings are informing ongoing basic science inquiry into the amylin receptor system and the scientific rationale for combining AMY1R/AMY3R agonism with GLP-1 receptor agonism. A range of amylin analog discovery programs at organizations outside Novo Nordisk were additionally reported as active as of 2025, indicating that cagrilintide's clinical development trajectory has catalyzed broader pharmaceutical interest in long-acting amylin pharmacology. The cagrilintide mechanism of action article provides a detailed account of the receptor binding and signaling findings that emerged from these investigations. Research-grade cagrilintide from SpartaLabs is available for preclinical research with full batch documentation.

References

1. Cooper GJS, Willis AC, Clark A, Turner RC, Sim RB, Reid KBM. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA. 1987;84(23):8628–8632. PMID: 3320585.

2. Westermark P, Betsholtz C, Johansson B, Engström U, Wilander E, Johnson KH, et al. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci USA. 1990;87(13):5036–5040. PMID: 2141136. DOI: 10.1073/pnas.87.13.5036

3. US Food and Drug Administration. SYMLIN (pramlintide acetate) injection: NDA 021332 approval. 2005. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021332lbl.pdf

4. 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

5. 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

6. 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

7. 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

8. 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

9. Novo Nordisk. Novo Nordisk presents phase 3 data for next-generation amylin cagrilintide, leading to advancement into dedicated clinical programme. Press release. September 2025. Available at: https://www.globenewswire.com/news-release/2025/09/16/3150597/0/en/novo-nordisk-presents-phase-3-data-for-next-generation-amylin-cagrilintide-leading-to-advancement-into-dedicated-clinical-programme.html

10. Novo Nordisk. Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP-1 and amylin analogues for weight management. Press release. December 2025. Available at: https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916470

11. 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

12. 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