KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats

Andreassen, Kim Vietz; Larsen, Anna Thorsø; Sonne, Nina; Mohamed, K.E.; Karsdal, Morten A.; Henriksen, Kim

doi:10.1016/j.molmet.2021.101282

Cited by 22 publications

(26 citation statements)

References 32 publications

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“…Most recently, the acylated form of KBP-066A, a long-acting dual amylin, and calcitonin receptor agonist, has shown increased potency and efficacy to the non-acylated form in rats showing promise for this molecule as both anti-obesity, anti-hypertensive anti-diabetic agent [ 180 ].…”

Section: Treatment Of Obesity To Control Hypertensionmentioning

confidence: 99%

Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control

Meouchy

Wahoud

Allam

et al. 2022

IJMS

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The World Health Organization (WHO) refers to obesity as abnormal or excessive fat accumulation that presents a health risk. Obesity was first designated as a disease in 2012 and since then the cost and the burden of the disease have witnessed a worrisome increase. Obesity and hypertension are closely interrelated as abdominal obesity interferes with the endocrine and immune systems and carries a greater risk for insulin resistance, diabetes, hypertension, and cardiovascular disease. Many factors are at the interplay between obesity and hypertension. They include hemodynamic alterations, oxidative stress, renal injury, hyperinsulinemia, and insulin resistance, sleep apnea syndrome and the leptin-melanocortin pathway. Genetics, epigenetics, and mitochondrial factors also play a major role. The measurement of blood pressure in obese patients requires an adapted cuff and the search for other secondary causes is necessary at higher thresholds than the general population. Lifestyle modifications such as diet and exercise are often not enough to control obesity, and so far, bariatric surgery constitutes the most reliable method to achieve weight loss. Nonetheless, the emergence of new agents such as Semaglutide and Tirzepatide offers promising alternatives. Finally, several molecular pathways are actively being explored, and they should significantly extend the treatment options available.

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Section: Treatment Of Obesity To Control Hypertensionmentioning

confidence: 99%

Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control

Meouchy

Wahoud

Allam

et al. 2022

IJMS

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“…Sequences of all peptides are shown in Table 1 . All peptides activate the amylin and calcitonin receptor [ 9 , 11 , 16 ] with similar potency. Small potency differences can be compensated in vivo by increasing the dose.…”

Section: Methodsmentioning

confidence: 99%

“…KBP-042 was dissolved in mannitol (5%, pH 4), while all other peptides were dissolved in saline (0.9%) for s.c. injection or continuous infusion. The dose ranges chosen for KBP-042, KBP-088, −088A, and −066A, were based on previous studies [ 7 , 9 , 14 , 16 , 23 ]. A higher drug dose was used in ZDF rat studies when using Alzet osmotic pumps, as these studies were carried out while the rats were still young and in a progressive growth phase.…”

Section: Methodsmentioning

confidence: 99%

“…The first designed DACRAs, termed KBPs, were originally developed for once-daily administration and displayed an acute dose-dependent and prolonged action of 24–48 h food suppression, despite a pharmacokinetic (PK) profile peaking 10–20 min post s.c. injection and with total clearance after 2 h [ 9 , 14 , 15 ]. Recently, long-acting KBPs (termed KBP-As) developed for once-weekly administration in humans have been published [ 16 ]. The extended half-life of the peptides results from their conjugation to an acylation that binds to serum albumin, thereby allowing a slow release and clearance.…”

Section: Introductionmentioning

confidence: 99%

“…The extended half-life of the peptides results from their conjugation to an acylation that binds to serum albumin, thereby allowing a slow release and clearance. Hence, KBP-As display a different PK and pharmacodynamic (PD) profile compared to non-acylated KBPs [ 16 ]. Whether the PD effects of KBP and KBP-A can be modulated by alternative exposure profiles is largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy

et al. 2022

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Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague–Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.

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Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects

Rubinić,

Kurtov,

Likić

2024

Pharmacology Res & Perspec

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Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti‐obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide‐based and small molecule‐based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti‐obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O‐acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite‐reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half‐life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti‐obesity therapies.

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KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats

Cited by 22 publications

References 32 publications

Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control

Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control

The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy

Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects

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