Cagrilintide 5mg*10vials

▎Cagrilintide Structure

▎Cagrilintide Research

What is the origin of Cagrilintide?

Cagrilintide—an amylin analog：

Amylin is a hormone secreted by pancreatic islet β cells. Under physiological conditions, it collaborates with insulin and possesses a multitude of significant physiological functions.

Firstly, amylin plays a pivotal role in inducing satiety and reducing food intake. Its mechanism of action predominantly involves activating the receptors in the Area Postrema at the base of the fourth ventricle. The neural signals are transmitted to the forebrain via the Nucleus of the Solitary Tract. Simultaneously, they can also be conveyed to the Lateral Hypothalamic Area and other hypothalamic nuclear groups through the Lateral Parabrachial Nucleus. Amylin has the ability to stimulate the satiety center of the organism and inhibit food intake in animals^[1].

Amylin is capable of regulating glucose homeostasis, which is achieved by inhibiting the secretion of both insulin and glucagon^[2]. This function contributes significantly to maintaining the stability of blood glucose levels and holds great importance for the treatment of diseases such as diabetes.

Moreover, amylin exerts its effects by influencing the release of neurotransmitters. For instance, it inhibits the release of dopamine in the hypothalamus of rats, while having a relatively minor impact on norepinephrine and serotonin^[3]. In the context of glucose homeostasis, amylin maintains blood glucose stability by suppressing the secretion of insulin and glucagon. Its mechanisms include directly acting on pancreatic islet α cells and indirectly regulating glucagon secretion through neural signal transduction in the hypothalamus. In patients with diabetes, the destruction of β cells not only leads to insulin deficiency but also results in a decrease in the secretion of both C-peptide and amylin. Amylin is evidently involved in the regulation of glucose homeostasis by inhibiting gastric emptying and postprandial hepatic glucose production, ultimately reducing postprandial blood glucose fluctuations ^[4]. Additionally, amylin can delay gastric emptying, inhibit gastrointestinal peristalsis through the central nervous system, and prolong the residence time of food in the gastrointestinal tract, thereby preventing a rapid increase in blood glucose.

Nevertheless, amylin has a relatively short half-life, which restricts its clinical application. Research indicates that the existing amylin analog, pramlintide, as an adjuvant drug for the treatment of diabetes, requires administration three times a day. This not only causes inconvenience to patients but also reduces their compliance ^[5]. To address the issue of the short half-life of natural amylin, Cagrilintide has been developed as a long-acting analog. The development of Cagrilintide is grounded in a profound understanding of the physiological functions of natural amylin. It aims to simulate the mechanism of action of amylin while enhancing the stability and long-acting properties of the drug to meet the requirements of clinical treatment.

The Potential and Pharmacological Properties of Cagrilintide

Cagrilintide is a novel long-acting amylin analogue with significant potential, demonstrating remarkable effects in the treatment of obesity and diabetes. It is lipidated and possesses stable long-acting characteristics^[5]. Amylin is a hormone co-released by pancreatic β cells along with insulin, which induces satiety by acting on the homeostatic and hedonic regions of the brain. As an analogue of amylin, Cagrilintide can mimic this effect, inducing satiety and thus aiding in weight control. Moreover, Cagrilintide is a dual amylin and calcitonin receptor agonist, derived from the amylin backbone, endowing it with a unique mechanism of action in metabolic regulation.

The Progress of Clinical Studies on Cagrilintide

In clinical trials, Cagrilintide has yielded promising results in inducing weight loss. For instance, in a multicenter, randomized, double-blind, placebo-controlled, and active-controlled phase 2 dose-finding trial, participants treated with Cagrilintide showed more pronounced weight loss compared to those receiving the placebo. The mean percentage of weight reduction from baseline for all doses of Cagrilintide (0.3 - 4.5 mg) was higher (6.0% - 10.8%) than that of the placebo group (3.0%). The weight reduction in the group treated with 4.5 mg of Cagrilintide was also greater than that in the group treated with 3.0 mg of liraglutide (10.8% vs. 9.0%). These results suggest that Cagrilintide can be an effective option for weight management^[6].

Cagrilintide and the GLP-1 receptor agonist semaglutide possess distinct yet interrelated mechanisms of action. Semaglutid exerts its effects by acting on the GLP-1 receptors in the hypothalamus, which leads to a reduction in appetite, an increase in insulin secretion, and a delay in gastric emptying. Conversely, Cagrilintide further suppresses appetite by activating the amylin receptors. The combined administration of these two agents elicits a superimposed effect on appetite through multiple mechanisms, significantly enhancing the weight loss efficacy^[7]. Given the intricate nature of obesity, combination therapy targeting multiple pathophysiological endpoints represents a rational and efficacious strategy.

Moreover, Cagrilintide has also demonstrated promising blood glucose control capabilities in patients with type 2 diabetes. Clinical investigations have indicated that Cagrilintide exhibits favorable stability and efficacy in the management of both obesity and type 2 diabetes. For instance, in a clinical trial involving patients with type 2 diabetes, the combination of Cagrilintide and the GLP-1 receptor agonist semaglutide manifested remarkable blood glucose control and weight loss effects. This suggests that Cagrilintide maintains a high level of stability in clinical practice and is capable of exerting sustained therapeutic effects. In another clinical trial, Cagrilintide, whether administered alone or in combination with semaglutide, demonstrated good tolerability and safety ^[8]. This further validates the stability of Cagrilintide, as in clinical applications, the stability of a drug is intricately associated with its tolerability and safety.

Finally, in clinical trials, the treatment with cagrilintide has been well tolerated. In the phase 2 dose-finding trial, the rates of permanent treatment discontinuation were comparable across various treatment groups, predominantly attributable to adverse events. Nevertheless, the most prevalent adverse events were gastrointestinal disorders and injection site reactions, with the majority being mild to moderate in severity. In a randomized, controlled phase 1b trial, the concurrent treatment with cagrilintide and 2.4 mg of semaglutide also demonstrated good tolerability and an acceptable safety profile^[9]. Larger-scale and longer-duration trials are warranted in the future to comprehensively evaluate the effectiveness and safety of this combination therapy.

Structural Model of Cagrinlintide

Source:PubMed^[5]

The Significance of Using Cagrilintide

The emergence of Cagrilintide has brought new hope to the treatment of obesity and type 2 diabetes. Despite the increasing severity of the global obesity problem, the currently approved options for pharmaceutical treatment remain limited. As a novel long-acting amylin analogue, Cagrilintide provides a new therapeutic option for obese patients, especially those who have poor responses to lifestyle interventions and are not suitable for bariatric surgery. It achieves weight management through a unique mechanism of action, offering new ideas and methods for the treatment of obesity, and it may exhibit better efficacy and safety compared to traditional anti-obesity drugs ^[7]. Moreover, the successful case of the combination of Cagrilintide and semaglutide (CagriSema) demonstrates that combination therapy targeting multiple pathophysiological targets is an effective strategy for enhancing the treatment response in obesity^[8]. This multi-target treatment model not only provides a new paradigm for the management of obesity but also brings significant metabolic improvements to patients with type 2 diabetes.

In conclusion, as a novel long-acting amylin analogue, Cagrilintide has remarkable potential for weight loss and blood glucose control. It activates the satiety signaling pathway by mimicking the action of amylin and regulates metabolism as a dual receptor agonist. Clinical trials have shown that Cagrilintide, either used alone or in combination with semaglutide, can significantly reduce body weight and is well tolerated. Additionally, it has also demonstrated good blood glucose control capabilities in patients with type 2 diabetes, providing a new choice for the treatment of obesity and diabetes and filling the gap in existing treatment regimens, especially for those patients with poor responses to lifestyle interventions and who are not suitable for surgery. Its multi-target treatment strategy offers new insights for the management of metabolic diseases.

About The Author

The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.

Scientific Journal Author

Dr. D. C. W. Lau is a professor at the Cumming School of Medicine, University of Calgary, Canada. His research interests cover endocrinology and metabolism, general and internal medicine, cardiovascular system and cardiology, public health, environmental and occupational health, as well as oncology. He also holds positions with Alberta Health Services (AHS) and Obesity Canada and works at the Julia McFarlane Diabetes Research Centre. Dr. Lau has extensive experience in the fields of diabetes and obesity research, with his work published in academic journals such as the Canadian Journal of Diabetes. Dr. D. C. W. is listed in the reference of citation [6].

▎Relevant Citations

[1] Hansen KE, Murali S, Chaves IZ, Suen G, Ney DM. Glycomacropeptide Impacts Amylin-Mediated Satiety, Postprandial Markers of Glucose Homeostasis, and the Fecal Microbiome in Obese Postmenopausal Women. J NUTR 2023; 153(7): 1915-29. DOI:10.1016/j.tjnut.2023.03.014.

[2] Ling W, Huang Y, Qiao Y, Zhang X, Zhao H. Human Amylin: From Pathology to Physiology and Pharmacology. CURR PROTEIN PEPT SC 2019; 20(9): 944-57. DOI:10.2174/1389203720666190328111833.

[3] Brunetti L, Recinella L, Orlando G, Michelotto B, Di Nisio C, Vacca M. Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus. EUR J PHARMACOL 2002; 454(2-3): 189-92. DOI:10.1016/S0014-2999(02)02552 9.

[4] Gedulin BR, Jodka CM, Herrmann K, Young AA. Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regulatory Peptides 2006; 137(3): 121-7. DOI:10.1016/j.regpep.2006.06.004.

[5] Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J MED CHEM 2021; 64(15): 11183-94. DOI:10.1021/acs.jmedchem.1c00565.

[6] Lau DCW, Erichsen L, Francisco AM, et al. 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. LANCET 2021; 398(10317): 2160-72. DOI:10.1016/S0140-6736(21)01751-7.

[7] D'Ascanio AM, Mullally JA, Frishman WH. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity. CARDIOL REV 2024; 32(1): 83-90. DOI:10.1097/CRD.0000000000000513.

[8] Frias 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. LANCET 2023; 402(10403): 720-30. DOI:10.1016/S0140-6736(23)01163-7.

[9] Enebo LB, Berthelsen KK, Kankam M, et al. 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. LANCET 2021; 397(10286): 1736-48. DOI:10.1016/S0140-6736(21)00845-X.

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