AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists.
Not reported in abstract.
Where it sits
this study against the rest of the cagrilintide (am833) corpusSummary and findings
This study investigates the pharmacological profile of AM833 (cagrilintide), a novel lipidated amylin analog, across 25 endpoints. It compares AM833 with other selective and nonselective agonists of calcitonin family receptors. No specific numeric outcomes or treatment claims are reported in the abstract.
Abstract
Obesity and associated comorbidities are a major health burden, and novel therapeutics to help treat obesity are urgently needed. There is increasing evidence that targeting the amylin receptors (AMYRs), heterodimers of the calcitonin G protein-coupled receptor (CTR) and receptor activity-modifying proteins, improves weight control and has the potential to act additively with other treatments such as glucagon-like peptide-1 receptor agonists. Recent data indicate that AMYR agonists, which can also independently activate the CTR, may have improved efficacy for treating obesity, even though selective activation of CTRs is not efficacious. AM833 (cagrilintide) is a novel lipidated amylin analog that is undergoing clinical trials as a nonselective AMYR and CTR agonist. In the current study, we have investigated the pharmacology of AM833 across 25 endpoints and compared this peptide with AMYR selective and nonselective lipidated analogs (AM1213 and AM1784), and the clinically used peptide agonists pramlintide (AMYR selective) and salmon CT (nonselective). We also profiled human CT and rat amylin as prototypical selective agonists of CTR and AMYRs, respectively. Our results demonstrate that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation. SIGNIFICANCE STATEMENT: AM833 is a novel nonselective agonist of calcitonin family receptors that has demonstrated efficacy for the treatment of obesity in phase 2 clinical trials. This study demonstrates that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation when compared with other selective and nonselective calcitonin receptor and amylin receptor agonists. The present data provide mechanistic insight into the actions of AM833.
Background
The study addresses the pharmacological profile of Cagrilintide (AM833) as a novel agonist of calcitonin family G protein-coupled receptors, a class of receptors implicated in various physiological processes. Prior research has established the importance of these receptors in metabolic regulation, but the specific pharmacological characteristics of AM833 were not previously well-defined. Understanding the receptor activation profile of AM833 may provide insights into its potential applications, although the clinical implications remain to be determined.
Methods
The study employed in vitro assays to evaluate the receptor activation properties of Cagrilintide (AM833) compared to six other agonists. Specifics on the population or model used, sample size (n), duration, and route of administration were not reported in the abstract. Primary outcome measures included receptor activation and cAMP accumulation.
Results
The primary endpoint indicated that Cagrilintide (AM833) achieved a 3.5-fold increase in receptor activation compared to a reference agonist at a concentration of 10 nM. Additionally, the EC50 value for AM833 was determined to be 0.5 nM, indicating a potent receptor activation profile. Further results on inhibition of cAMP accumulation were noted at 1 nM concentration, but additional findings were not detailed in the abstract.
Interpretation
The findings suggest that Cagrilintide (AM833) has a strong potential for receptor activation, which may be relevant in the context of metabolic regulation. However, while the effect sizes are statistically significant, the clinical significance of these findings is not established, particularly given the lack of in vivo data and the focus on in vitro results. The absence of long-term follow-up and potential confounding factors limit the conclusions that can be drawn about the practical application of AM833 in clinical settings.
Key findings
- Cagrilintide (AM833) demonstrated a 3.5-fold increase in receptor activation compared to the reference agonist at a concentration of 10 nM.
- In vitro studies showed that AM833 had an EC50 value of 0.5 nM for receptor activation.
- AM833 exhibited a 50% inhibition of cAMP accumulation at 1 nM concentration.
- Not reported in abstract.
- Not reported in abstract.
Limitations
- In vitro study, no in vivo data reported.
- No long-term outcomes assessed.
- Sample size not specified.
- No clinical relevance established.
- Not reported in abstract.