Peerless Peptides

Cagrilintide

37-amino-acid long-acting amylin analog (DACRA), investigational

Cagrilintide (development codes AM833 / NN9838) is a synthetic 37-amino-acid long-acting amylin analog from the Novo Nordisk discovery program. The molecule is engineered on the human-amylin backbone first developed in the 2005 FDA-approved short-acting amylin analog (CAS 196078-30-5), with three additional substitutions (N14E, V17R, Y37P) plus N-terminal Lys1 acylation through a γ-L-Glu spacer to a C20 eicosanedioic diacid for albumin-mediated extended plasma residency. The molecule is classified as a DACRA (dual amylin and calcitonin receptor agonist) and is not a GLP-1 family member. Cagrilintide has never been approved by the FDA as a standalone product.

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Biochemical Profile

CAS Number
1415456-99-3
Molecular Formula
C194H312N54O59S2
Molecular Weight
~4409 g/mol (average)
Purity
≥98% (HPLC-UV (220 nm) with confirmatory LC-MS disulfide and lipidation isoform deconvolution)
PubChem CID
167312356
Amino Acid Sequence
37-amino-acid amylin analog (human-amylin backbone with Pro25/Pro28/Pro29 anti-aggregation substitutions plus N14E/V17R/Y37P substitutions; Cys2-Cys7 disulfide; Lys1 acylation via γGlu to C20 eicosanedioic diacid)

Receptor Targets and Signaling Pathway Context

Cagrilintide is a long-acting amylin analog engineered by the Novo Nordisk discovery program. The discovery paper (Kruse et al., 2021) documents three substitutions layered on the human-amylin backbone first deployed in the 2005 FDA-approved short-acting amylin analog (CAS 196078-30-5): an N14E plus V17R pair that forms an intramolecular ionic salt bridge (the ionic lock) stabilizing the N-terminal α-helix, and a Y37P substitution that rigidifies the C-terminal calcitonin-receptor-engagement region[1]. The molecule retains the single Cys2-Cys7 disulfide that is the amylin-family signature and inherits the Pro25/Pro28/Pro29 substitutions originally transferred from rat amylin onto the human-amylin backbone to disrupt the FGAILSS amyloid core. N-terminal Lys1 is acylated through a γ-L-Glu spacer to a C20 eicosanedioic diacid lipidation arm.

The molecule belongs to the calcitonin gene family of peptides, not the proglucagon family. Cagrilintide is therefore not a GLP-1 receptor agonist and is mechanistically distinct from the GLP-1 mono-agonist, GLP-1/GIP dual-agonist, and GLP-1/GIP/glucagon triagonist classes. The amylin pharmacology involves three heterodimeric amylin receptors: AMY1 (calcitonin receptor + RAMP1), AMY2 (CTR + RAMP2), and AMY3 (CTR + RAMP3), plus cross-reactivity at the bare calcitonin receptor[2]. The McLatchie et al. (1998) foundational RAMP paper organizes the calcitonin-family receptor pharmacology[3]. Cao et al. (2025) published cryo-EM structures across all four receptor complexes (AMY1R, AMY2R, AMY3R, and CTR alone), characterizing the structural basis of the amylin/calcitonin receptor system[2].

The molecule's DACRA (dual amylin and calcitonin receptor agonist) classification reflects that calcitonin-receptor engagement contributes a substantial fraction of the food-intake effect observed in preclinical models, distinct from the amylin-receptor-mediated fraction. The amylin-receptor selectivity panels published in the cagrilintide literature are thinner than the GLP-1R equivalent literature; differential tissue expression of AMY1, AMY2, and AMY3 has not been fully characterized in the published record, and calcitonin-receptor and broader CALCR-superfamily cross-reactivity under chronic exposure has not been formally adjudicated.

The lipidation arm produces reversible non-covalent binding to plasma human serum albumin at the fatty-acid pockets, with reported affinity in the micromolar range and a published subcutaneous plasma half-life of approximately 159 to 195 hours (about 6.6 to 8.1 days) in pharmacokinetic studies of the cagrilintide molecule. The pharmacokinetic profile supports once-weekly subcutaneous administration regimens in the published clinical-trial literature[4].

The receptor-binding profile of cagrilintide has not been characterized in human tissue under chronic exposure. Published clinical data on the molecule derive from the Lau et al. (2021) Phase 2 monotherapy dose-finding study[4] and from the combination-product CagriSema clinical program described in Section 6 of the research applications below.

Research Applications

Amylin and Calcitonin Receptor Pharmacology Research

The amylin / calcitonin receptor system comprises three heterodimeric amylin receptors (AMY1 = CTR + RAMP1, AMY2 = CTR + RAMP2, AMY3 = CTR + RAMP3) plus the bare calcitonin receptor (CTR). The Cao et al. (2025) cryo-EM study published in Nature Communications resolved structures across all four receptor complexes engaged by cagrilintide and related amylin-family ligands, characterizing the structural basis of amylin pharmacology at the receptor level[2].

Cagrilintide is classified as a DACRA — dual amylin and calcitonin receptor agonist — because its calcitonin-receptor engagement contributes a substantial component of the food-intake reduction observed in preclinical rodent models, in addition to the amylin-receptor-mediated component. The McLatchie et al. (1998) foundational paper in Nature establishing the receptor-activity-modifying-protein (RAMP) framework is the organizing reference for calcitonin-family receptor pharmacology research generally[3].

Published cagrilintide selectivity panels are thinner than the equivalent GLP-1R literature for the GLP-1 receptor agonist class. Calcitonin-receptor and broader CALCR-superfamily cross-reactivity under chronic exposure has not been formally adjudicated in the peer-reviewed literature, and differential tissue expression of the three amylin-receptor heterodimers has not been fully characterized.

Amylin Discovery and IAPP Biology Research

Native human amylin is a 37-amino-acid peptide encoded by the IAPP gene on chromosome 12. It is co-secreted with insulin from pancreatic β-cells at approximately a 1:100 molar ratio. The peptide is amyloidogenic and forms islet amyloid deposits associated with β-cell loss in type 2 diabetes. The amyloid deposits had been described pathologically since 1901, but the peptide was not sequenced for 85 years.

Two research groups independently isolated and sequenced the molecule in 1986-1987: Cooper, Reid, and Willis at the Oxford MRC unit (publishing in PNAS in 1987 and naming the peptide amylin)[5], and Westermark and colleagues in Sweden (publishing concurrently in PNAS in 1987 and naming the peptide islet amyloid polypeptide, IAPP)[6]. Both designations remain in current use; amylin dominates clinical pharmacology literature and IAPP dominates pathology literature.

Amylin Pharmaceuticals was founded in San Diego in 1987 around this discovery and developed the synthetic short-acting amylin analog from which the cagrilintide backbone is descended. The synthetic design used the rat-amylin scaffold (which does not aggregate due to natural Pro25/Pro28/Pro29 substitutions) transferred onto the human-amylin sequence. The short-acting amylin analog received FDA approval on March 16, 2005 as a mealtime-insulin adjunct, with peak revenue of approximately $103.9 million in 2011. Amylin Pharmaceuticals was acquired by Bristol-Myers Squibb in August 2012 for $5.3 billion, with concurrent AstraZeneca participation in a $3.4 billion joint venture arrangement.

Long-Acting Peptide Engineering Research

Cagrilintide is a research model for the lipidation strategy applied to a non-GLP-1-family peptide hormone. The discovery work by Kruse et al. (2021) reports four engineering decisions layered on the human-amylin backbone: an E14-R17 ionic-lock salt bridge for N-terminal α-helix stabilization; retention of the Pro25/Pro28/Pro29 anti-aggregation substitutions inherited from the rat-amylin scaffold; a Y37P substitution for C-terminal calcitonin-receptor potency; and N-terminal Lys1 acylation through a γ-L-Glu spacer to a C20 eicosanedioic diacid lipidation arm for albumin-mediated extended plasma residency[1].

The lipidation architecture is simpler than that used in the GLP-1 class. Cagrilintide does not use an AEEA polyethylene-glycol spacer in the connector; the γGlu directly links the Lys1 ε-amine to the C20 diacid. The resulting molecule binds reversibly to plasma human serum albumin at the fatty-acid binding pockets with K_d in the micromolar range, producing a subcutaneous half-life of approximately 159 to 195 hours (6.6 to 8.1 days)[4].

The synthesis of the 37-mer presents distinctive challenges relative to short-peptide research-grade syntheses. Orthogonal Lys1 protection (typically Fmoc-Lys(ivDde) or Fmoc-Lys(Mtt)) is required for selective ε-amine acylation. The β-prone C-terminal stretch (residues 25 through 37) requires pseudoproline or Hmb mitigations. Multiple asparagine residues at positions 3, 21-22, 31, and 35 are aspartimide hotspots. Sequential γGlu and C20 diacid couplings follow Lys1 ivDde deprotection. The Cys2-Cys7 disulfide is formed by controlled air oxidation in dilute aqueous solution after global TFA cleavage with thiol-free scavenger.

Stability and Aggregation Research

Cagrilintide carries the distinctive stability vector of the amylin family: even with the engineered Pro25/Pro28/Pro29 substitutions and the E14-R17 ionic lock that mitigate native amylin's amyloidogenic tendency, the molecule retains residual β-sheet propensity. Freeze-thaw cycling and high-concentration storage are reported to drive oligomerization under conditions that would not aggregate GLP-class peptides. The amylin-family aggregation vector is not shared with GLP-1, GIP, or glucagon receptor agonists.

Four additional degradation pathways have been characterized for the amylin-family long-acting analog class. Disulfide reduction (yielding a +2 Da gain corresponding to two Cys-SH) abolishes receptor agonism. Disulfide scrambling, sulfenic acid intermediates, and over-oxidation to sulfonic acid (yielding +16, +32, and +48 Da species respectively) reduce or eliminate activity. Lipidation-arm hydrolysis (the dominant degradation pathway shared with the GLP-class) generates des-C20 and des-γGlu species. Asparagine deamidation at multiple sites contributes +1 Da modifications, and aspartimide hotspots produce α/β-aspartate regioisomers.

Two compounded failure modes both pass single-wavelength 220 nm HPLC purity testing at ≥98% and pass coarse total-mass ESI-MS analysis: a reduced, scrambled, or over-oxidized disulfide isoform (Δ +2, +16, +32, or +48 Da), and a des-lipidated or des-γGlu peptide. Per-batch LC-MS deconvolution of both disulfide isoforms and lipidation isoforms is the analytical layer required to characterize these failure modes; the disulfide-integrity test layer is not required for the GLP-1, GIP, and glucagon receptor agonist class. Lyophilized cagrilintide at -20°C in dry, dark conditions is reported as stable for greater than 24 months in vendor literature; the reconstituted form is more fragile than GLP-class peptides because of the combined disulfide vulnerability and the amyloid-aggregation risk, and single-use aliquot strategies are commonly applied in laboratory practice.

Short-Acting Amylin Analog Precedent

The cagrilintide molecule is engineered on the same human-amylin backbone deployed in the short-acting amylin analog (CAS 196078-30-5) that received FDA approval on March 16, 2005 as a mealtime-insulin adjunct in type 1 and type 2 diabetes under NDA 21-332. The short-acting analog precedent is informative for cagrilintide research framing: it validated the underlying amylin biology in human clinical pharmacology while documenting the specific commercial frictions that the cagrilintide design was engineered to address.

The short-acting amylin analog peaked at approximately $103.9 million in revenue in 2011, with three documented operational frictions: thrice-daily mealtime subcutaneous injection (incompatible with mixing into the same syringe as mealtime insulin); the requirement to coordinate dosing precisely with mealtime insulin administration; and a narrow adjunct-only labeled indication restricted to insulin-using diabetes populations. Phase 3 nausea on titration was reported at approximately 28% to 48%. The short-acting amylin analog manufacturer subsequently discontinued the US-marketed injectable formulation. Amylin Pharmaceuticals was acquired by Bristol-Myers Squibb in August 2012 for $5.3 billion plus concurrent AstraZeneca participation in a $3.4 billion joint venture arrangement; BMS exited the alliance in February 2014 and AstraZeneca took sole ownership.

The cagrilintide molecule was engineered to address three of these operational frictions: the C20 diacid lipidation enables once-weekly rather than thrice-daily dosing; the co-formulation product strategy with the long-acting GLP-1 receptor agonist semaglutide (the CagriSema development program) simplifies coordination with insulin in the diabetes setting; and the broader obesity indication is no longer restricted to insulin-using populations. The biological tolerability ceiling is preserved in the cagrilintide Phase 2 monotherapy data: reported nausea was approximately 20% to 30% across the dose-finding range, lower than the short-acting analog Phase 3 record but not eliminated[4]. The once-weekly half-life also makes acute insulin retitration in insulin-using populations more difficult rather than easier, because dose adjustments cannot be made on a mealtime timescale.

Replication and Clinical Status

The cagrilintide PubMed corpus is small (approximately 60 to 110 indexed papers) and originates predominantly from Novo Nordisk corporate authorship. The discovery program traces to the Kruse et al. (2021) sole discovery paper in the Journal of Medicinal Chemistry[1]. The Lau et al. (2021) Phase 2 monotherapy dose-finding study in the Lancet reported approximately 10.8% weight loss at the top 4.5 mg dose at 26 weeks, compared with 3.0% on placebo and 9.0% on a long-acting GLP-1 receptor agonist active comparator[4]. The standalone cagrilintide effect is modest in the published monotherapy literature.

The commercial development program for cagrilintide is co-formulation with semaglutide as CagriSema. The Phase 1b combination study (Enebo et al., 2021) reported preliminary weight-loss observations[7], and Phase 2 dose-finding for the combination (Frias et al., 2023) followed[8]. The Phase 3 REDEFINE program is the principal published evidence base on the combination product. REDEFINE-1 (NCT05567796, n=3,417, 68-week non-diabetic obesity trial) reported -22.7% body weight on-treatment and -20.4% on the treatment-policy estimand, compared with -3.0% on placebo[9]. The reported combination effect was greater than semaglutide alone (-16.1%) and greater than cagrilintide alone (-11.8%). REDEFINE-1 did not meet the sponsor's prospectively-stated 25% target, and the sponsor's share price reportedly declined approximately 7 to 20 percent on the December 20, 2024 announcement. REDEFINE-2 (NCT05394519, n=1,206, 68-week type 2 diabetes trial) reported -13.7% body weight reduction[10]. REDEFINE-4 (NCT06131437, n=809, 84-week open-label head-to-head versus the dual GIP/GLP-1 receptor agonist at the 15 mg dose) reported -23.0% body weight with the combination product and did not meet the prospectively-stated noninferiority bound versus the comparator. REDEFINE-3 (NCT05669755) is an ongoing cardiovascular outcomes trial with approximately 7,000 participants and a 4.5-year event-driven design.

The regulatory status as of May 2026: cagrilintide is investigational and not FDA-approved as a standalone product; the CagriSema co-formulation NDA was submitted on December 18, 2025, and standard 10-month review puts likely FDA action at approximately mid-October 2026. Cagrilintide does not qualify for compounding under 503A or 503B pathways: the molecule is not on the 503A bulks list, has not been nominated, has no FDA-approved drug-product reference, and has no shortage-list pathway. The September 9, 2025 FDA warning letter to the compounding entity GLP-1 Solution stated explicitly that retatrutide and cagrilintide cannot be used in compounding under federal law. The Alabama Board of Medical Examiners issued specific warning letters on cagrilintide compounding. The April 1, 2026 federal indictment of physician Charles Watkins named cagrilintide individually alongside other long-acting peptide hormone analogs and other unapproved substances; this is reported as the first federal indictment to name the molecule before any FDA approval. Cagrilintide is not scheduled by the Drug Enforcement Administration. The World Anti-Doping Agency does not name cagrilintide by molecule but the substance falls under S0 (Non-Approved Substances) as a default class assignment.

Reconstitution & Storage

Recommended Diluent
Bacteriostatic water (0.9% benzyl alcohol)
Storage (lyophilized)
-20°C, dry, dark, >24 months
Storage (reconstituted)
2-8°C, single-use aliquots preferred given amylin-family aggregation risk
Shelf Life
>24 months lyophilized at -20°C

Research References

  1. [1] Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183-11194. PMID:34288673
  2. [2] Cao J, Belousoff MJ, Liang YL, et al. Structural insight into selectivity of amylin and calcitonin receptor agonists. Nat Commun. 2025;16(1):3275. PMID:40204768
  3. [3] McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 1998;393(6683):333-339. PMID:9620797
  4. [4] Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398(10317):2160-2172. PMID:34798060
  5. [5] 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:3317417
  6. [6] Westermark P, Wernstedt C, Wilander E, Hayden DW, O'Brien TD, Johnson KH. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA. 1987;84(11):3881-3885. PMID:3035556
  7. [7] Enebo LB, Berthelsen KK, Kankam M, 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(10286):1736-1748. PMID:33894838
  8. [8] Frias JP, Deenadayalan S, Erichsen L, 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
  9. [9] Garvey WT, Birkenfeld AL, Davies M, et al. Cagrilintide plus semaglutide for the treatment of obesity (REDEFINE 1). N Engl J Med. 2025;392(24):2284-2295. PMID:40544433
  10. [10] Davies M, Aroda V, Birkenfeld AL, et al. Cagrilintide plus semaglutide in type 2 diabetes and overweight or obesity (REDEFINE 2). N Engl J Med. 2025;392(24):2272-2283. PMID:40544432
  11. [11] Novo Nordisk. REDEFINE 3 (NCT05669755): A research study to investigate how well CagriSema works compared to placebo in people with cardiovascular disease and type 2 diabetes or obesity. ClinicalTrials.gov Identifier: NCT05669755. Phase 3 cardiovascular outcomes trial, n≈7,000, event-driven 4.5-year design; ongoing (verified 2026-05-19).
  12. [12] Novo Nordisk. REDEFINE 4 (NCT06131437): Head-to-head 84-week open-label trial of CagriSema versus a dual GIP/GLP-1 receptor agonist 15 mg in adults with overweight or obesity. ClinicalTrials.gov Identifier: NCT06131437. Phase 3, n=809; primary readout reported failure to meet prospective noninferiority bound (verified 2026-05-19).
  13. [13] Cooper GJS, Day AJ, Willis AC, Roberts AN, Reid KBM, Leighton B. Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. Biochim Biophys Acta. 1989;1014(3):247-258. PMID:2690955
  14. [14] Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev. 2015;67(3):564-600. PMID:26071095
  15. [15] U.S. Food and Drug Administration. Warning Letter to GLP-1 Solution, September 9, 2025. The letter states that retatrutide and cagrilintide cannot be used in compounding under federal law. FDA Enforcement Reports archive (verified 2026-05-19).
  16. [16] U.S. Department of Justice. Indictment of Charles Watkins, MD, et al. Filed April 1, 2026. The indictment names cagrilintide individually alongside several other long-acting peptide hormone analogs and other unapproved substances; reported as the first federal indictment to name cagrilintide before any FDA approval (verified 2026-05-19).
  17. [17] Boyle CN, Lutz TA, Le Foll C. Amylin – its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol Metab. 2018;8:203-210. PMID:29203236
  18. [18] Mathiesen DS, Bagger JI, Knop FK. Long-acting amylin analogues for the management of obesity. Curr Opin Endocrinol Diabetes Obes. 2022;29(2):183-190. PMID:35034031

Scientific Journal Author

Thomas Kruse, PhD

Novo Nordisk A/S, Research Chemistry, Måløv, Denmark (originating discovery program)

Landmark Publications

  • Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183-11194. (PMID 34288673)
  • Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a phase 2 trial. Lancet. 2021;398(10317):2160-2172. (PMID 34798060)
  • Enebo LB, Berthelsen KK, Kankam M, et al. Concomitant administration of cagrilintide with semaglutide 2.4 mg: a phase 1b trial. Lancet. 2021;397(10286):1736-1748. (PMID 33894838)

Dr. Kruse is independently cited here as the corresponding author on the originating cagrilintide discovery publication at Novo Nordisk Research Chemistry. There is no affiliation or commercial relationship between Dr. Kruse, Novo Nordisk A/S, and Peerless Peptides. Peerless Peptides is not affiliated with the originating discovery program and does not sell any FDA-approved drug product.

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