Cagrilintide

Overview

Cagrilintide is a synthetic, long-acting analogue of amylin, a hormone the pancreas co-secretes with insulin after a meal. Amylin acts complementarily to insulin: it suppresses glucagon, slows gastric emptying and reduces appetite via the central nervous system.

What makes cagrilintide interesting alongside the GLP class is that it uses a different route: the amylin and calcitonin receptors rather than the incretin receptors. Engaging two complementary satiety routes at once is the idea behind the combination with semaglutide, called CagriSema in the research.

Cagrilintide (development code AM833 / NN0174-0833) is not approved as a standalone agent. At Peptalis, strictly research use only: in-vitro, not for human or animal use.

Mechanism of action

Cagrilintide mimics amylin and acts on the amylin and calcitonin receptors: a satiety route parallel to GLP-1/GIP.

Amylin/calcitonin receptor engagement

• Amylin is co-secreted with insulin and acts as a satiety signal: it slows gastric emptying, suppresses post-meal glucagon and acts on brain regions (particularly the brainstem) regulating hunger and satiety.
• This is not the incretin route of GLP-1/GIP but a parallel route. That is why cagrilintide is combined with a GLP-1 agent.

Long-acting pharmacokinetics

• The lipidation (C20 fatty-acid tail) and the cyclized structure extend the duration to weekly dosing, where native amylin and pramlintide are short-acting (Kruse 2021).
• Exactly how the amylin and incretin routes reinforce each other on co-administration is an active area of research.

Research findings

• Preclinical: optimised as a long-acting amylin analogue (analogue 23), suited to weekly dosing (Kruse 2021)
• Phase 1b: cagrilintide + semaglutide 2.4 mg, safety/PK-PD and rationale for CagriSema (Enebo 2021)
• Phase 2 monotherapy (up to 4.5 mg/week): dose-dependent weight reductions vs liraglutide/placebo (Lau 2021)
• Phase 3 REDEFINE 1 (CagriSema, n=2,108): mean weight change −20.4% vs −3.0% placebo over 68 weeks (Garvey 2025)

Preclinical evidence

• In the series that led to cagrilintide, amylin analogues were optimised for receptor potency, solubility and duration; cagrilintide (analogue 23) emerged as a long-acting amylin analogue suited to weekly dosing (Kruse 2021).

Human studies

• Phase 1b (Enebo 2021): concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg, assessing safety, tolerability and PK/PD of the combination; provided the rationale for CagriSema.
• Phase 2 (Lau 2021): multicentre, randomized, double-blind, placebo- and active-controlled dose-finding study of once-weekly cagrilintide (up to 4.5 mg) vs liraglutide 3.0 mg and placebo; dose-dependent weight reductions.
• Phase 3 REDEFINE 1 (Garvey 2025): in the CagriSema arm (n=2,108) the mean weight change at 68 weeks was −20.4% vs −3.0% placebo. REDEFINE 2 (Davies 2025) studied the combination in type 2 diabetes.

Research context

This profile describes what has been done and found in research. Regulatory and clinical facts are facts about the respective trials and authorities, not claims about a Peptalis product; the compound is for in-vitro laboratory research only (RUO).

Open questions

• Most human evidence concerns the combination with semaglutide (CagriSema), not cagrilintide as a standalone agent; the monotherapy is mainly studied in phase 2.
• The dossier derives predominantly from a single development tradition (Novo Nordisk), without broad independent replication. Hence conservatively dot 4, not dot 5.
• How much of the CagriSema effect comes from the amylin component and how the amylin and incretin routes reinforce each other is still open.

Research outlook

For research into amylin/calcitonin receptor pharmacology and the interplay of satiety routes, cagrilintide is a well-characterized, current model system.

The standalone contribution of cagrilintide (apart from semaglutide) remains largely to be mapped.

Scientific interest

Broadens the metabolic domain beyond the incretin axis to the amylin axis.

Complementary satiety route, hence the combination with semaglutide (CagriSema).

Rapidly built human dossier up to phase 3.

Specifications

References

1. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial · Lau DCW, et al. · Lancet · 2021
2. 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 · Enebo LB, et al. · Lancet · 2021
3. Development of Cagrilintide, a Long-Acting Amylin Analogue · Kruse T, et al. · J Med Chem · 2021
4. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity · Garvey WT, et al. · N Engl J Med · 2025

Availability

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