Mechanism of Action
Amylin Receptor Signaling
amylin/" class="wiki-internal-link">Amylin receptors are heterodimers of the calcitonin receptor with receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3). Cagrilintide activates these receptors in the area postrema, nucleus tractus solitarius, and hypothalamic arcuate nucleus, reducing meal size, slowing gastric emptying, and decreasing glucagon secretion during meals. The neurochemical pathways partially overlap with but are distinct from GLP-1 receptor signaling.
Complementary to GLP-1 Action
Combination with semaglutide targets non-overlapping satiety circuits: GLP-1 receptors primarily in arcuate nucleus and vagal afferents, amylin receptors primarily in area postrema and NTS. This complementarity may explain the additive weight loss observed with CagriSema that exceeds either agent alone, suggesting combination incretin-amylin therapy as a superior strategy.
Research Summary
Monotherapy (DOSE program)
Phase 2 CompletePhase 2 dose-finding trial showed 8.0%, 10.8% weight loss at 2.4 mg and 4.5 mg weekly doses respectively over 26 weeks. Dose-dependent response with favorable tolerability. Phase 2b extended to 52 weeks demonstrated maintained weight loss without plateau at highest doses.
CagriSema Combination (Phase 2)
Phase 2 CompleteREDEFINE Phase 2 (n=96): cagrilintide 2.4 mg + semaglutide 2.4 mg achieved 22.7% weight reduction at 68 weeks vs 8.0% cagrilintide alone and 10.6% semaglutide alone. 71% achieved >20% weight loss with CagriSema. These results established the combination as potentially superior to tirzepatide benchmarks.
REDEFINE Phase 3
Active ResearchREDEFINE 1-6 Phase 3 program is enrolling across obesity, T2D, cardiovascular outcomes, and MASH indications. Primary endpoints include weight reduction and cardiovascular events. Results expected 2025-2027 with potential NDA submission to FDA thereafter.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Phase 2 monotherapy reference | 0.3 mg/week escalating monthly to 2.4-4.5 mg target | Weekly | Subcutaneous |
| CagriSema Phase 2 reference | Cagrilintide 2.4 mg + semaglutide 2.4 mg co-administered weekly | Weekly | Subcutaneous |
Not yet approved; protocols are from Phase 2 research. Not for clinical use outside trials.
Interactions
Safety Profile
Tolerability profile favorable in Phase 2. GI side effects (nausea, vomiting) occur but at lower rates than GLP-1 agonists alone, and paradoxically CagriSema GI rates were not additive. Injection site reactions are mild and transient. No serious safety signals identified in Phase 2. Nausea rate for cagrilintide monotherapy approximately 15% vs 10% placebo at 2.4 mg. Phase 3 will provide comprehensive safety characterization for regulatory review.
References
- [1]Enebo LB, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of cagrilintide (AM833). Lancet. 2021;397(10279):1736-1748.
- [2]Lau DCW, et al. Once-weekly cagrilintide plus semaglutide 2.4 mg (CagriSema) in adults with overweight and obesity. Lancet. 2023;402(10403):720-730.