Does receptor balance matter? – Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models

Oct 15, 2022Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Comparing how two drugs that target related receptors affect metabolism in animal models

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Abstract

KBP-336 demonstrated superior weight loss and glucose control compared to cagrilintide in obese and diabetic rat models.

Both KBP-336 and cagrilintide activate the amylin and calcitonin receptors in laboratory studies.
KBP-336 exhibited greater potency and a bias towards calcitonin receptor activation.
In high-fat diet rats, both peptides led to significant weight loss in a dose-dependent manner.
KBP-336 outperformed cagrilintide in improving fasting blood glucose, HbA1c levels, and insulin action in diabetic rats.
The differing receptor activation balance between the two peptides may explain their distinct effects on weight and glucose regulation.

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Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and Calcitonin Receptor Agonist (DACRA) derived from an amylin backbone. Another class of long-acting DACRAs exists, namely the KBPs. These are salmon calcitonin-based and have shown preclinical potential; however, how and if they differentiate from amylin-derived molecules remain to be studied. Here, we compare cagrilintide to the DACRA KBP-336 with respect to receptor activation balance in vitro and using metabolic in vivo models. Peptide potencies were assessed using receptor-specific assays in vitro and in vivo. In vivo efficacies on body weight and glucose homeostasis were investigated head-to-head in high-fat diet (HFD) fed obese and T2D (ZDF) rat models. Both peptides activate the amylin and the calcitonin receptor in vitro and in vivo, with KBP-336 being more potent, and showing a CTR bias. KBP-336 and cagrilintide induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP-336 being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved fasting blood glucose, HbA1c levels, and insulin action, with KBP-336 being superior to cagrilintide in improving glucose control. In summary, both KBP-336 and cagrilintide are DACRAs, however with KBP-336 being biased towards the CTR resulting in a different receptor activation balance. Interestingly, KBP-336 showed superior long-term efficacy on both weight loss and glucose control, supporting relevance of the receptor balance, and highlighting KBP-336 as a promising agent for the treatment of obesity and T2D.

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Does receptor balance matter? – Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models

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