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 medicinal analogue pramlintide is short-acting; 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 subcutaneous cagrilintide coadministered with semaglutide (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. A 180-hour model reference is representative of that reported range, not a separately measured mean or a universal value for research material.
State of evidence
The evidence on cagrilintide includes molecular development and receptor pharmacology (Kruse et al., 2021; Fletcher et al., 2021), a phase 1b pharmacokinetic trial of coadministration with semaglutide (Enebo et al., 2021), and a placebo- and active-controlled phase 2 monotherapy trial (Lau et al., 2021; NCT03856047). The phase 2 trial randomized 706 participants, including 506 to cagrilintide; mean weight reductions after 26 weeks ranged from 6.0 to 10.8% across the studied groups, versus 3.0% with placebo. Gastrointestinal events were the most frequent adverse effects. The phase 3a REDEFINE 1 trial (Garvey et al., NEJM 2025) randomized 3,417 adults without diabetes to CagriSema, semaglutide, cagrilintide or placebo for 68 weeks. The cagrilintide-alone arm contained 302 participants. The coprimary endpoints, however, compared CagriSema with placebo: estimated mean body-weight changes of -20.4% and -3.0%, respectively, refer to that combination comparison under the treatment-policy estimand, not to cagrilintide alone. This establishes published late-stage evidence while requiring separate interpretation of monotherapy and combination findings. The study duration, population and trial formulation limit extrapolation; the trial report establishes neither authorization nor efficacy or safety of a particular research product.
Questions about the research
- What is cagrilintide studied for in research?
- Cagrilintide is studied primarily in body-weight regulation through the amylin pathway. Published work includes a phase 2 monotherapy trial and phase 3a REDEFINE 1, which included both cagrilintide alone and CagriSema, its combination with semaglutide. The main REDEFINE 1 comparisons concern the combination versus placebo and are not estimates of cagrilintide-alone efficacy. Mechanistic work also examines amylin and calcitonin receptor signaling.
- Is cagrilintide approved as a medicine?
- The cited scientific reports describe clinical development, including a 302-participant cagrilintide monotherapy arm in phase 3a REDEFINE 1. They are not product authorization records. The coprimary results concern CagriSema versus placebo and cannot be presented as cagrilintide-alone effects. Clinical trial data do not establish the identity, quality, efficacy or safety of research material.
Sources
- Kruse et al., J Med Chem 2021DOI: 10.1021/acs.jmedchem.1c00565PMID: 34288673
- Fletcher et al., J Pharmacol Exp Ther 2021DOI: 10.1124/jpet.121.000567PMID: 33727283
- Enebo et al., Lancet 2021 (phase 1b, pharmacokinetics with semaglutide)DOI: 10.1016/S0140-6736(21)00845-XPMID: 33894838
- Lau et al., Lancet 2021 (phase 2, monotherapy)DOI: 10.1016/S0140-6736(21)01751-7PMID: 34798060
- Garvey et al., NEJM 2025 (REDEFINE 1, Phase 3)DOI: 10.1056/NEJMoa2502081PMID: 40544433
- Novo Nordisk, REDEFINE 1 topline announcement (20 December 2024)
