Cagrilintide

Mechanism of action

Amylin is a pancreatic hormone that mediates satiety; amylin receptors (AMY) are heterodimers of the calcitonin receptor (CTR) and receptor activity-modifying proteins (RAMPs). Native amylin has a high propensity to form amyloid fibrils, and the approved analogue pramlintide requires three daily injections due to its short half-life; cagrilintide was deliberately designed at Novo Nordisk as a stable, lipidated, long-acting amylin analogue (Kruse et al. 2021). In the pharmacological characterization across 25 endpoints (Fletcher et al. 2021), the substance behaved as a non-selective agonist at AMY receptors and the CTR, with a distinct profile compared with pramlintide and salmon calcitonin. In a phase 1b trial of concomitant administration with semaglutide 2.4 mg (Enebo et al. 2021), exposure was dose-proportional and the terminal half-life was 159 to 195 hours with a median tmax of 24 to 72 hours; semaglutide exposure was unaffected.

State of evidence

The evidence on cagrilintide comprises the molecular development work and receptor pharmacology (Kruse et al. 2021; Fletcher et al. 2021), a phase 1b pharmacokinetic trial of concomitant administration with semaglutide (Enebo et al. 2021), and a placebo- and active-controlled phase 2 dose-finding trial as monotherapy (Lau et al. 2021; NCT03856047, 706 participants randomized, 506 of them to cagrilintide): there, mean weight reductions after 26 weeks ranged from 6.0 to 10.8% depending on dose (0.3 to 4.5 mg weekly) versus 3.0% on placebo, with gastrointestinal events as the most frequent adverse effects. For the combination with semaglutide, a phase 3 trial exists in REDEFINE 1 (Garvey et al., NEJM 2025; 3,417 participants): the combination reached an estimated mean body-weight change of -20.4% at 68 weeks versus -3.0% on placebo (treatment-policy estimand); the trial also carried smaller monotherapy arms of cagrilintide and semaglutide, whose results are not itemized in the abstract. For context, per Novo Nordisk's December 2024 topline announcement, the REDEFINE 1 result (22.7% by the trial-product estimand, 20.4% by the treatment-policy estimand) fell short of the target of about 25% weight reduction the company had previously communicated; the trial also used a flexible dosing protocol under which only 57.3% of CagriSema-treated participants were on the highest dose at 68 weeks. Despite published phase 3 data, cagrilintide holds no marketing authorization as a medicine in any country as of the editorial date, including as a combination. Long-term data beyond the trial durations are lacking; all of the data cited were generated with the pharmaceutical trial material under controlled study conditions and permit no conclusions about the efficacy or safety of research-grade material.

Storage and handling

Lyophilized peptides are generally stored cool, dry, and protected from light; for long-term storage, the literature describes temperatures of 2 to 8 °C or below. After reconstitution, peptide solutions are typically kept refrigerated and used within a few days; repeated freeze-thaw cycles are considered unfavorable. No substance-specific stability data for research-grade cagrilintide have been published.

Questions about the research

What is cagrilintide studied for in research?

Cagrilintide is studied primarily in research on body-weight regulation, building on the role of the amylin pathway in satiety. Published work includes a phase 2 dose-finding trial as monotherapy and trials of the combination with semaglutide, including the phase 3 REDEFINE 1 trial. Beyond that, the substance serves as a pharmacological tool for mechanistic research into amylin and calcitonin receptor signaling and its contribution to appetite regulation.

Is cagrilintide approved as a medicine?

No. As of the editorial date, cagrilintide holds no marketing authorization as a medicine in any country, neither as monotherapy nor as the combination with semaglutide (CagriSema); published data extend up to and including phase 3. All clinical data were generated with the pharmaceutical trial material under controlled conditions and cannot be transferred to unregulated research material.

Sources

1. Kruse et al., J Med Chem 2021DOI: 10.1021/acs.jmedchem.1c00565PMID: 34288673
2. Fletcher et al., J Pharmacol Exp Ther 2021DOI: 10.1124/jpet.121.000567PMID: 33727283
3. Enebo et al., Lancet 2021 (Phase 1b, PK mit Semaglutid)DOI: 10.1016/S0140-6736(21)00845-XPMID: 33894838
4. Lau et al., Lancet 2021 (Phase 2, Monotherapie)DOI: 10.1016/S0140-6736(21)01751-7PMID: 34798060
5. Garvey et al., NEJM 2025 (REDEFINE 1, Phase 3)DOI: 10.1056/NEJMoa2502081PMID: 40544433
6. Novo Nordisk, Topline-Mitteilung REDEFINE 1 (20. Dezember 2024)