Source of CagriSema

{{Infobox compound | name = CagriSema | subtitle = Investigational combination | Components = [[Cagrilintide]] and [[Semaglutide]] | Form = Fixed-ratio co-formulation, single injection | Route = Subcutaneous, weekly | Status = Phase 3; not approved }} {{hatnote|For the components, see [[Cagrilintide]] and [[Semaglutide]].}} {{update|talk=Phase 3 readouts}} '''CagriSema''' is an investigational fixed-ratio combination of the [[Amylin receptor agonist|amylin analogue]] [[Cagrilintide|cagrilintide]] and the [[GLP-1 receptor agonist]] [[Semaglutide|semaglutide]], co-formulated for weekly subcutaneous administration in a single injection. It is not approved for use in any indication.{{r|frias2023cagri}} It differs architecturally from the [[Dual incretin agonist|unimolecular dual agonists]]: rather than one peptide engaging two receptors, CagriSema is two peptides in one syringe. The ratio is therefore set at formulation rather than by chemistry, and the two components retain their own pharmacokinetics — an advantage for design flexibility and a complication for exposure matching.{{r|lau2021}} The rationale is mechanistic complementarity. Amylin and GLP-1 promote satiety through partly separate hindbrain circuits, and the combination has produced greater weight reduction than either component alone in the trials reported to date.{{r|frias2023cagri}} == Rationale == Amylin acts principally at the area postrema through calcitonin-receptor complexes; GLP-1 acts at the area postrema and at hypothalamic [[Arcuate nucleus|arcuate]] circuits through the [[GLP-1 receptor]]. The pathways converge on food intake but are pharmacologically separable, and preclinical work indicated additivity rather than redundancy.{{r|lau2021}} Both components also slow [[Gastric emptying|gastric emptying]], which is where the mechanisms overlap most and where the tolerability cost of combining them is expected to concentrate. The co-formulation approach was chosen over a unimolecular design because no scaffold engages both the [[GLP-1 receptor]] and an amylin receptor — the receptor families are not related in the way the incretin and glucagon receptors are, so the trick that produced [[Tirzepatide|tirzepatide]] is not available here.{{r|frias2023cagri}} == Reported findings == A phase 2 trial in type 2 diabetes reported greater glycated-haemoglobin and weight reduction with the combination than with either component alone at 32 weeks. The phase 3 obesity programme has reported mean weight reduction in the region of 20% at 68 weeks, with the caveat that a substantial proportion of participants did not reach the highest planned doses.{{r|frias2023cagri}} That last point has attracted attention: an efficacy figure obtained when many participants remained on lower doses is not the same as an efficacy figure at the target dose, and the two interpretations of the result — that the ceiling was not reached, or that dose escalation is the practical limit — have different implications. The adverse-effect profile is that of the two components, dominated by gastrointestinal events. Whether combining two agents that both delay gastric emptying is additive for nausea is not directly addressed by the published designs.{{r|lau2021}} == Formulation considerations == A fixed-ratio co-formulation requires that both peptides be stable in the same vehicle at the same pH and concentration for the shelf life of the product. This is a non-trivial constraint: [[Amylin|amylin]] analogues are engineered to resist aggregation but remain more aggregation-prone than acylated incretin analogues, and the buffer that best stabilises one may not best stabilise the other. A specification for a two-component product must accordingly cover both actives and the degradation routes of each.{{r|usp1503,ich_q6b}} The combination also fixes the dose ratio across the whole titration, so a participant intolerant of one component cannot reduce it independently. In practice this means escalation is governed by the less tolerated component. For anyone encountering material sold as "cagrisema" through research-chemical channels, the relevant observation is that a co-formulation is a manufactured product with a defined ratio and a stability programme behind it, not simply two powders in proportion. A vial containing two peptides is characterised by neither component's certificate alone. See [[Certificate of analysis]]. == References == {{reflist}} <ref name="frias2023cagri">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." ''The Lancet'' 402(10403):720–730 (2023). PMID 37364590.</ref> <ref name="lau2021">Lau DCW, Erichsen L, Francisco AM, et al. "Once-weekly cagrilintide for weight management in people with overweight and obesity." ''The Lancet'' 398(10317):2160–2172 (2021). PMID 34798060.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> <ref name="ich_q6b">International Council for Harmonisation, ''Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products'' (1999).</ref> == See also == * [[Cagrilintide]] * [[Semaglutide]] * [[Amylin receptor agonist]] * [[Dual incretin agonist]] * [[Tirzepatide]] {{DEFAULTSORT:CagriSema}} [[Category:Amylin analogues]] [[Category:Peptide drugs]] [[Category:Articles needing updates]] [[Category:Articles describing unapproved compounds]]