Cagrilintide: experimental once-weekly weight-loss drug (AM833)
A lab-engineered copy of amylin, the natural fullness hormone from the pancreas; tells the brain to eat less and slows digestion; experimental, not yet an approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Cagrilintide (also known as AM833 and NN9838) is an experimental weight-loss drug that mimics amylin — a natural hormone released from the pancreas after eating that helps signal fullness and slows how quickly food leaves the stomach. Unlike pramlintide, an older amylin analogue approved in 2005 that requires multiple daily injections, cagrilintide is engineered for once-weekly dosing. Novo Nordisk developed it primarily as the amylin half of a fixed-dose combination with semaglutide, known as CagriSema, rather than as a standalone medicine. As of early 2026, neither cagrilintide nor CagriSema is approved by the FDA or EMA; both remain investigational.
The stored sequence (KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY, 37 amino acids) represents the backbone; the active drug additionally carries a C18 fatty diacid group attached via acylation that enables albumin binding and extends the half-life to roughly one week — this modification is not visible in the raw sequence.
History
Cagrilintide grew out of Novo Nordisk's long-running interest in the amylin pathway. Pramlintide (brand name Symlin) had demonstrated the clinical potential of amylin agonism when the FDA approved it in 2005 as an insulin adjunct for diabetes, but its requirement for multiple daily injections limited real-world uptake. Novo engineers set out to redesign the molecule for once-weekly administration by adding a fatty-acid chain — the same albumin-binding strategy already used in semaglutide. The resulting compound, internally designated AM833 (later NN9838), was characterised in a medicinal chemistry program published in the Journal of Medicinal Chemistry (Lau and colleagues, J Med Chem, 2021). A Phase 2 dose-finding trial reported in The Lancet in 2021 (Lau and colleagues) established the 2.4 mg weekly dose as the candidate for further development based on weight-loss signal and tolerability. The programme's strategic direction then shifted decisively toward the fixed-dose combination: the Phase 3 REDEFINE programme (REDEFINE 1 in adults with obesity without type 2 diabetes; REDEFINE 2 in adults with obesity and type 2 diabetes) reported results in 2024–2025 and became the primary evidence base for the combination. Regulatory filings for CagriSema are anticipated following those readouts; a standalone regulatory pathway for cagrilintide has not been pursued.
What it does
Cagrilintide activates amylin receptors in brainstem regions that regulate appetite, reducing hunger and slowing gastric emptying. When combined with semaglutide — which works through a different appetite-regulating pathway (GLP-1 receptors) — the two signals act in parallel on distinct brain circuits. The goal of the combination is greater weight reduction than either agent alone can produce. In human trials, this complementary mechanism has translated into meaningfully higher weight loss with CagriSema than with semaglutide by itself, though the combination also produces more gastrointestinal side effects than semaglutide alone.
Evidence
- Human: A Phase 2 dose-finding trial in adults with overweight or obesity (no diabetes) showed approximately 10% body weight reduction at the 2.4 mg weekly monotherapy dose over 26 weeks (Lau and colleagues, The Lancet, 2021). The Phase 3 REDEFINE programme subsequently evaluated CagriSema (cagrilintide 2.4 mg plus semaglutide 2.4 mg weekly): REDEFINE 1 (obesity without type 2 diabetes) and REDEFINE 2 (obesity with type 2 diabetes) reported approximately 20–23% mean weight reduction with CagriSema versus approximately 15% with semaglutide alone. These combination results do not isolate cagrilintide's individual contribution. A Phase 1b trial established the pharmacokinetics and tolerability of co-administering cagrilintide with semaglutide 2.4 mg. An earlier Phase 2 trial in adults with type 2 diabetes evaluated the combination and reported both weight and glycaemic outcomes. A thorough QT study in healthy participants found no clinically relevant QTc prolongation with cagrilintide.
- Animal: Preclinical studies in rodents characterised AMY1 and AMY3 as the primary receptor targets mediating cagrilintide's effects on energy balance and weight, and a dorsal vagal complex atlas study mapped neural mediators of the effect. A 2025 Nature Metabolism study (Jacobsen and colleagues) examined how CagriSema drives weight loss in rats by reducing energy intake while preserving energy expenditure.
- In vitro: Structural and dynamic characterisation of cagrilintide binding to calcitonin and amylin receptors has been published, providing mechanistic detail on receptor engagement geometry.
Known effects
- Body weight reduction (monotherapy) — Phase 2 RCT; approximately 10% at 2.4 mg weekly over 26 weeks in adults with overweight or obesity
- Body weight reduction (combination with semaglutide) — Phase 3 RCTs; approximately 20–23% with CagriSema versus approximately 15% with semaglutide alone in the REDEFINE programme
- Gastric emptying delay — Pharmacological; both amylin and GLP-1 agonism slow gastric motility; combined effect described in the literature as potentially magnifying motility symptoms
- Postprandial glucagon suppression — Mechanistic; consistent with amylin pharmacology (Madsbad and colleagues, Expert Opinion on Investigational Drugs, 2025)
- Appetite and satiety signalling — Mechanistic/preclinical; mediated through brainstem amylin receptors
Safety signals
GI adverse events — nausea, vomiting, diarrhoea, constipation — are common with cagrilintide, particularly during dose titration, and are more frequent with the CagriSema combination than with semaglutide monotherapy; trial discontinuation rates due to GI events in CagriSema arms were higher than in semaglutide arms in the REDEFINE programme. Injection-site reactions are consistent with the subcutaneous amylin analogue class. The thorough QT study found no clinically relevant QTc prolongation (Lau and colleagues, The Lancet, 2021; peptidelist data). Because CagriSema contains semaglutide, it inherits the GLP-1 class-level signal of thyroid C-cell tumours observed in rodents at supratherapeutic doses — the clinical relevance to humans is not established, but the caution applies to the combination product. No dedicated cardiovascular outcomes trial (CVOT) for cagrilintide or CagriSema has reported results; cardiovascular safety beyond the approximately 68–72 week Phase 3 trial duration is not established.
Regulatory status
- US (FDA): Investigational — not approved as of early 2026, neither as monotherapy nor as part of CagriSema. Novo Nordisk has indicated intent to file for CagriSema approval based on REDEFINE programme results; a standalone monotherapy filing is not in the near-term regulatory pathway.
- EU (EMA): Not approved as of early 2026; regulatory submissions expected to follow Phase 3 data.
- Other jurisdictions (MHRA, TGA, Health Canada, PMDA): Not approved as of early 2026.
- WADA: Amylin analogues are not specifically named on the WADA Prohibited List per available sources; general anti-doping provisions may still apply in specific competitive contexts.
- Controlled substance status (US): Not a controlled substance.
- Compounding: Compounded cagrilintide has appeared in some wellness clinic and research-chemical channels, but no FDA-approved reference standard exists; this is outside any authorised use.
Mechanism
Cagrilintide acts as a non-selective agonist at amylin receptors — specifically AMY1 and AMY3, which are heterodimeric complexes formed by the calcitonin receptor (CTR) paired with receptor activity-modifying protein 1 (RAMP1) or RAMP3, respectively. These receptor complexes are concentrated in brainstem satiety centres including the area postrema and nucleus tractus solitarius, and in the dorsal vagal complex. Activation promotes satiety signalling, reduces voluntary caloric intake, decelerates gastric emptying, and suppresses postprandial glucagon secretion (Madsbad and colleagues, Expert Opinion on Investigational Drugs, 2025).
The acylation of cagrilintide with a C18 fatty diacid group enables reversible non-covalent binding to circulating albumin, extending the plasma half-life to approximately one week and enabling once-weekly subcutaneous dosing — a pharmacokinetic approach analogous to that used for semaglutide. The molecule was built using human amylin as the structural starting point with design inputs from salmon calcitonin, which exhibits an unusually long receptor off-rate (Lau and colleagues, J Med Chem, 2021).
When combined with semaglutide, the GLP-1 receptor agonism and amylin receptor agonism engage distinct hypothalamic and brainstem circuits in a complementary rather than simply additive fashion. Preclinical evidence supports this parallel pathway engagement as the mechanistic basis for the greater weight reduction observed with CagriSema compared with either agent alone (Jacobsen and colleagues, Nature Metabolism, 2025).
Structural studies characterising cagrilintide's binding geometry and conformational dynamics at calcitonin and amylin receptors have been published. Preclinical work has specifically identified AMY1 and AMY3 as the primary targets mediating its effects on energy balance in rodent models.
Open questions
- Cardiovascular outcomes: No dedicated CVOT for cagrilintide or CagriSema has reported results. Semaglutide has the SELECT cardiovascular outcomes trial; the corresponding data gap for the combination will be critical for prescribing context if CagriSema is approved.
- Monotherapy regulatory path: Novo Nordisk is not pursuing standalone regulatory approval for cagrilintide. Whether it could serve specific subgroups — for example, patients who cannot tolerate GLP-1 agonists — has not been evaluated in a Phase 3 monotherapy setting.
- Long-term safety: Phase 3 REDEFINE trials ran approximately 68–72 weeks. Data on three to five or more years of continuous use, including bone, renal, and long-term tolerability endpoints, are not yet available.
- Discontinuation and weight regain: Class-level GLP-1 discontinuation data consistently show substantial weight regain within 12–18 months of stopping. CagriSema-specific discontinuation trial data are limited; whether the dual-pathway pharmacology affects the regain trajectory relative to semaglutide alone is unknown.
- Responder biology: A meaningful minority of participants in GLP-1 and amylin analogue obesity trials do not achieve clinically significant weight loss. Predictors of response to cagrilintide or CagriSema are not characterised.
- Head-to-head versus tirzepatide: No direct head-to-head comparison between CagriSema and tirzepatide has been reported; current cross-trial comparisons involve differing populations, titration schedules, and follow-up durations.
- Independent replication: The Phase 3 REDEFINE results originate from the Novo Nordisk development programme; independent replication in non-sponsor trials has not yet been published.
Related peptides
- Semaglutide — GLP-1 receptor agonist; the combination partner in CagriSema; provides the GLP-1 pathway alongside cagrilintide's amylin pathway
- Pramlintide — earlier FDA-approved amylin analogue (2005, as insulin adjunct for diabetes); requires multiple daily injections, in contrast to cagrilintide's once-weekly design; not yet a separate platform card
- Tirzepatide — dual GIP/GLP-1 receptor agonist; the primary clinical comparator for CagriSema in terms of weight-loss magnitude; not yet a separate platform card
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does cagrilintide stop the body from lowering its calorie-burning rate when a person loses weight?
Most diets and weight-loss drugs work less well over time because the body adapts by burning fewer calories. If cagrilintide blocks that adaptation, the drug could keep working longer and more effectively, a major advance for the millions of people who regain weight after initial success.
Could cagrilintide, by activating the same receptor that calcitonin uses, also slow bone loss in people losing weight rapidly?
Rapid weight loss can weaken bones. If cagrilintide shields bone at the same time it reduces body weight, that would make the CagriSema combination safer for older women already at fracture risk, a large share of the intended patient population.
Could the fatty-acid coating that gives cagrilintide its once-weekly profile be applied to related peptides to create new long-acting drugs targeting different receptor subtypes?
If the albumin-binding approach transfers to related peptides, drug developers could build an entirely new set of once-weekly medicines that target specific tissues, such as bone or liver, without the central nervous system side effects seen with brain-active compounds.
Could cagrilintide produce meaningful weight loss in patients with slow stomach emptying, a group for whom semaglutide-type drugs are often unsafe?
Millions of people with obesity also have gastroparesis, a condition that makes current weight-loss drugs dangerous. If cagrilintide works safely in this group, it would be the first pharmacological option for a population with no good alternatives today.
Does cagrilintide primarily engage a two-protein amylin receptor complex in the brain rather than the simpler calcitonin receptor alone?
If true, it would clarify why the drug suppresses appetite so powerfully, help predict which patients benefit most, and flag potential side effects related to blood vessel regulation. This could guide safer dosing in the CagriSema combination.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.87417072057724 | boltz-2 |
| ranking score | 0.8246027827262878 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10997,
sequence = {KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}