Fixed-dose Amylin/CTR Agonist + GLP-1 Receptor Agonist Combination (Incretin Class)

CagriSema

Also Known As: NN9838, cagrilintide + semaglutide, cagrilintide/semaglutide

CagriSema (development code NN9838) is not a single new chemical entity but a subcutaneous fixed-dose combination of two peptides delivered together in a single once-weekly pen: 2.4 mg cagrilintide (a 37-amino-acid amylin/calcitonin receptor agonist with a C20 fatty-diacid acylation at the N-terminal lysine) and 2.4 mg semaglutide (a 31-amino-acid GLP-1 analogue documented separately at /portfolio/semaglutide). The combination has been evaluated in the Phase 3 REDEFINE 1 and REDEFINE 2 trials (published in NEJM 2025) and in the open-label head-to-head REDEFINE 4 study against tirzepatide 15 mg (February 2026 — primary endpoint not met). Novo Nordisk submitted a U.S. FDA NDA on 18 December 2025; as of May 2026, CagriSema is not approved by any major regulator.

Identity & Chemistry

Skeletal chemical structure of cagrilintide, a 37-amino-acid amylin analogue with an intramolecular Cys²–Cys⁷ disulfide bridge and an N-terminal C20 fatty-diacid acylation that confers a once-weekly half-life. CagriSema is the fixed-dose co-formulation of cagrilintide (shown) plus semaglutide (separate molecule; see semaglutide entry).
Image credit: Boghog, via Wikimedia Commons · CC0 1.0 (Public Domain Dedication)
Amino Acid Sequence
KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH₂ (cagrilintide component; 37-residue pramlintide-derived backbone with Cys²–Cys⁷ disulfide bridge and N-terminal Lys¹ acylation by a C20 fatty di-acid via γGlu linker). The semaglutide component is documented separately at /portfolio/semaglutide.
Molecular Formula
C₁₉₄H₃₁₂N₅₄O₅₉S₂ (cagrilintide) + C₁₈₇H₂₉₁N₄₅O₅₉ (semaglutide)
Molecular Weight
~4433.95 Da (cagrilintide) + 4113.64 Da (semaglutide); fixed-dose 2.4 mg / 2.4 mg co-formulation
CAS Number
1415456-99-3 (cagrilintide) / 910463-68-2 (semaglutide)
PubChem CID
171397054
DrugBank ID
DB18887
IUPAC Name
Cagrilintide: full IUPAC name omitted due to peptide-nomenclature length (see PubChem CID 171397054). Semaglutide systematic name available at PubChem CID 56843331. CagriSema is a fixed-dose combination, not a single chemical entity.
Solubility
Both components are water-soluble. The clinical product is supplied as a buffered ready-to-inject pen; research-grade single components are typically reconstituted in bacteriostatic water, sterile water, or 0.9% NaCl. Cagrilintide acetate is soluble at ~10 mg/mL in aqueous buffer for laboratory use.
Storage
Lyophilised single components: −20 °C, protected from light. Reconstituted solutions: short-term storage at 2–8 °C. The clinical product is refrigerated per the sponsor-supplied prescribing information.

Mechanism of Action

CagriSema couples dual amylin/calcitonin receptor agonism (via cagrilintide) with GLP-1 receptor agonism (via semaglutide), engaging two complementary central and peripheral satiety pathways at once.

The pharmacological rationale for combining the two classes rests on the observation that GLP-1 and amylin receptor agonism act on partially distinct hindbrain and hypothalamic circuits that nevertheless converge on appetite suppression and reduced energy intake. The Phase 2 trial in T2D (Frías et al., Lancet 2023) reported a 32-week body-weight change of −15.6% with CagriSema versus −5.1% with semaglutide alone and −8.1% with cagrilintide alone. In the Phase 3 REDEFINE 1 trial (Garvey et al., NEJM 2025), the 68-week mean body-weight reduction was −20.4% with CagriSema versus −14.9% with semaglutide 2.4 mg, −11.5% with cagrilintide 2.4 mg, and −3.0% with placebo (treatment-policy estimand). These data quantify the additive benefit of dual-pathway engagement in obesity without diabetes. Structural-pharmacology elucidation of cagrilintide binding to calcitonin and amylin receptors was published by Cao et al. (Nat Commun 2025). The ~7-day half-life of each component is achieved by non-covalent serum-albumin binding through the C20 di-acid acylation (cagrilintide) and the C18 di-acid acylation (semaglutide), respectively.

Molecular Targets

  • Amylin receptors AMY1R, AMY2R, AMY3R (heterodimers of the calcitonin receptor with RAMP1/2/3) — cagrilintide component
  • Calcitonin receptor (CTR) — directly engaged by cagrilintide
  • Glucagon-like peptide-1 receptor (GLP-1R), a class-B1 GPCR — semaglutide component
  • Human serum albumin — non-covalent binding by both components via their fatty-diacid side chains (C20 in cagrilintide, C18 in semaglutide)

Signaling Pathways

  • GLP-1R (semaglutide): Gαs → adenylyl cyclase → cAMP → glucose-dependent insulin secretion, glucagon suppression, slowed gastric emptying, central hypothalamic satiety signalling
  • AMYR/CTR (cagrilintide): Gαs and Gαq coupling depending on RAMP partner → action on the area postrema and nucleus tractus solitarius → suppression of meal size and post-prandial glucagon
  • Albumin-mediated half-life extension (~7 days) via C20 (cagrilintide) and C18 (semaglutide) acylation — supports once-weekly dosing
  • Convergent appetite suppression at the hindbrain and hypothalamic level with additive effects on body weight

Research Applications

CagriSema has been studied in an extensive Phase 1b / 2 / 3 programme in obesity (with and without T2D) and in an open-label head-to-head trial against tirzepatide. A cardiovascular outcomes trial (REDEFINE 3) and a paediatric programme are ongoing.

Obesity without T2D (REDEFINE 1, 68 weeks, 4-arm: CagriSema vs cagrilintide vs semaglutide vs placebo, n=3,417)

Phase III

Studies report a mean body-weight reduction of −20.4% with CagriSema vs −14.9% with semaglutide 2.4 mg, −11.5% with cagrilintide 2.4 mg, and −3.0% with placebo (treatment-policy estimand); 40.4% of CagriSema participants reached ≥25% weight loss.

— Garvey et al., NEJM 2025;393(7):635–647 (REDEFINE 1)

Obesity with type 2 diabetes (REDEFINE 2, 68 weeks, 3:1 randomisation vs placebo, n=1,206)

Phase III

Studies report a mean body-weight reduction of −13.7% with CagriSema vs −3.4% with placebo and an HbA1c reduction of −2.0 percentage points vs −0.1 percentage points; 80.7% of CagriSema participants reached HbA1c ≤6.5% vs 12.2% on placebo.

— Davies et al., NEJM 2025;393(7):648–659 (REDEFINE 2)

Head-to-head vs tirzepatide 15 mg (REDEFINE 4, 84 weeks, open-label, n=809)

Phase III

Studies report −23.0% body-weight reduction with CagriSema vs −25.5% with tirzepatide 15 mg (on-treatment estimand). The trial did not meet its primary non-inferiority endpoint.

— Novo Nordisk A/S, press release 23 February 2026

Type 2 diabetes (Phase 2, Frías et al., 32 weeks)

Phase II

Studies report an HbA1c reduction of −2.2% with CagriSema vs −1.8% with semaglutide and −0.9% with cagrilintide, and a body-weight change of −15.6% vs −5.1% vs −8.1% respectively.

— Frías et al., Lancet 2023;402(10403):720–730

Safety, tolerability, PK/PD (Phase 1b, Enebo et al., n=96)

Phase I

The multiple-ascending-dose study established acceptable safety and tolerability of cagrilintide co-administered with semaglutide 2.4 mg and supported progression to Phase 2/3.

— Enebo et al., Lancet 2021;397(10286):1736–1748

Clinical Status

Regulatory Status
Investigational. A New Drug Application was submitted to the U.S. FDA on 18 December 2025 for adults with obesity, or overweight with weight-related comorbidities; an FDA decision is expected during 2026. As of May 2026 CagriSema is not approved in any major jurisdiction.
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Highest Trial Phase
Phase III (multiple completed pivotal trials; CV outcomes trial REDEFINE 3 ongoing)
Sponsor
Novo Nordisk A/S

Key Clinical Trials

  • REDEFINE 1: CagriSema vs cagrilintide vs semaglutide vs placebo in adults with overweight/obesity (n=3,417, 68 weeks)
    Phase 3
    NCT05567796
  • REDEFINE 2: CagriSema vs placebo in adults with overweight/obesity and type 2 diabetes (n=1,206, 68 weeks)
    Phase 3
    NCT05394519
  • REDEFINE 3: CagriSema cardiovascular outcomes trial (3-point MACE) in obesity with established CV disease (n≈7,000, event-driven)
    Phase 3
    NCT05669755
  • REDEFINE 4: open-label head-to-head CagriSema vs tirzepatide 15 mg in adults with obesity and ≥1 comorbidity (n=809, 84 weeks)
    Phase 3
    NCT05669728
  • REIMAGINE 2: CagriSema HbA1c and weight outcomes in adults with type 2 diabetes
    Phase 3
    NCT05996848
  • Phase 1b multiple-ascending-dose study of cagrilintide co-administered with semaglutide 2.4 mg in adults with overweight/obesity (n=96)
    Phase 1
    NCT04982575

Safety Profile

Observed in research settings

Across the Phase 1b / 2 / 3 programmes the safety profile observed in research settings has been broadly consistent with the GLP-1 receptor agonist class: predominantly mild-to-moderate gastrointestinal events that diminish over time. No new safety signals beyond the established incretin-class profile have been reported.

Adverse Events Reported in Studies

  • Nausea
  • Vomiting
  • Diarrhoea
  • Constipation
  • Abdominal pain / dyspepsia
  • Decreased appetite
  • Any GI adverse event: 79.6% on CagriSema vs 39.9% on placebo in REDEFINE 1; 72.5% in REDEFINE 2

Serious Adverse Events

  • Acute pancreatitis — monitored as a GLP-1 class signal
  • Gallbladder disease (cholelithiasis, cholecystitis) — class-level risk
  • Hypersensitivity reactions including anaphylaxis and angioedema
  • Thyroid C-cell tumours — rodent-model GLP-1 class signal; human relevance unknown
  • Acute kidney injury secondary to dehydration from severe GI symptoms

References

  1. Garvey WT, Blüher M, Osorto Contreras CK, et al.; REDEFINE 1 Study Group Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). N Engl J Med 2025;393(7):635–647. 2025 .

    DOI: 10.1056/NEJMoa2502081 PMID: 40544433 View Source

  2. Davies MJ, Bajaj HS, Broholm C, et al.; REDEFINE 2 Study Group Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). N Engl J Med 2025;393(7):648–659. 2025 .

    DOI: 10.1056/NEJMoa2502082 PMID: 40544432 View Source

  3. Frías 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. 2023 .

    DOI: 10.1016/S0140-6736(23)01163-7 PMID: 37364590 View Source

  4. 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. 2021 .

    DOI: 10.1016/S0140-6736(21)00845-X PMID: 33894838 View Source

  5. Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem 2021;64(15):11183–11194. 2021 .

    DOI: 10.1021/acs.jmedchem.1c00565 View Source

  6. Cao J, Belousoff MJ, Liang Y-L, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nat Commun 2025;16:3389. 2025 .

    DOI: 10.1038/s41467-025-58680-y PMID: 40204768 View Source

  7. Novo Nordisk A/S Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP-1 and amylin analogues for weight management. Company announcement, 18 December 2025. 2025 .

    View Source

  8. Novo Nordisk A/S CagriSema demonstrated 23% weight loss in an open-label head-to-head REDEFINE 4 trial in people with obesity; the primary endpoint was not achieved. Company announcement, 23 February 2026. 2026 .

    View Source

Frequently Asked Questions

What is CagriSema?
CagriSema (development code NN9838) is an investigational, fixed-dose, once-weekly subcutaneous combination of two peptides: cagrilintide (a long-acting amylin/calcitonin receptor agonist) and semaglutide (a long-acting GLP-1 receptor agonist), each at 2.4 mg per dose. It is being developed by Novo Nordisk for weight management.
How does CagriSema differ from semaglutide alone?
Semaglutide acts only at the GLP-1 receptor. CagriSema adds cagrilintide, which acts at amylin and calcitonin receptors — a second, complementary appetite-regulating pathway. In Phase 3 REDEFINE 1, the combination produced −20.4% mean weight loss versus −14.9% with semaglutide 2.4 mg alone at 68 weeks (treatment-policy estimand).
How does CagriSema compare with tirzepatide?
In the open-label head-to-head REDEFINE 4 trial (February 2026), CagriSema produced −23.0% weight loss versus −25.5% with tirzepatide 15 mg at 84 weeks (on-treatment estimand). The trial did not meet its primary non-inferiority endpoint.
Is CagriSema approved by regulatory agencies?
No. CagriSema is investigational. Novo Nordisk filed an NDA with the U.S. FDA on 18 December 2025; FDA review is expected during 2026. As of May 2026 it is not approved by FDA, EMA, or any other major regulator.
What weight loss has been observed in the REDEFINE trials?
REDEFINE 1 (obesity without T2D): −20.4% at 68 weeks (treatment policy); 40.4% of participants reached ≥25% weight loss. REDEFINE 2 (obesity + T2D): −13.7% at 68 weeks. REDEFINE 4 (vs tirzepatide): −23.0% at 84 weeks (on-treatment).
What main adverse events have been reported in studies?
The most frequent adverse events have been gastrointestinal (nausea, vomiting, diarrhoea, constipation, abdominal pain) and predominantly mild-to-moderate. In REDEFINE 1, GI events occurred in 79.6% of CagriSema participants versus 39.9% on placebo and decreased in frequency over the treatment period.

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