Development of Cagrilintide, a Long-Acting Amylin Analogue

Kruse, Thomas; Hansen, Jakob Lerche; Dahl, Kirsten; Schäffer, Lauge; Sensfuß, Ulrich; Paar, Christian; Schlein, Morten; Hansen, Ann Maria Kruse; Jeppesen, Claus; Cour, Charlotta Dornonville de la; Clausen, T.; Johansson, E.; Skyggebjerg, Rikke Bjerring; Raun, Kirsten

doi:10.1021/acs.jmedchem.1c00565

Cited by 63 publications

(67 citation statements)

References 42 publications

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“…A combination of pramlintide (360 μg twice daily) and metreleptin (5 mg twice daily) produced substantial (∼12% at week 20 in the responder population) weight loss in people with obesity, with some individuals experiencing 15–20% weight loss [ 119 ]. Cagrilintide is an acylated long-acting non-selective human amylin receptor agonist [ 120 ] that is being evaluated, in combination with semaglutide, for the treatment of obesity. In a 20-week ascending dose-escalation Phase 1B safety and pharmacokinetic analysis, individuals with obesity treated with 4.5 mg of cagrilintide and 2.4 mg of semaglutide once weekly reported a mean weight loss of 17.1%, with gastrointestinal complaints, such as nausea and vomiting being the most common AEs [ 121 ].…”

Section: Glp-1-based Co-agonists and Weight Lossmentioning

confidence: 99%

GLP-1 physiology informs the pharmacotherapy of obesity

Drucker

2022

Molecular Metabolism

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124

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Section: Glp-1-based Co-agonists and Weight Lossmentioning

confidence: 99%

GLP-1 physiology informs the pharmacotherapy of obesity

Drucker

2022

Molecular Metabolism

222

124

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“…Presence of plasma in the assay did not affect receptor balance (1:4, 1:0.2, 1:15, NN1177, NN1151, NN1359, respectively) but did cause a loss of potency. The reduced potency is likely explained by compoundalbumin binding interfering with compound-receptor interaction as has been explained previously for similarly protracted peptides [23,24]. In mouse plasma the apparent reduction for…”

Section: In Vitro Characterizationmentioning

confidence: 62%

Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls

et al. 2022

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During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.

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“…Mass spectrometry was performed at Genscript to confirm the molecular weight of the synthesized peptides. Fluorescein isothiocyanate (FITC)-labeled sCT (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), FITC-labeled AC413 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), and FITC-labeled AC413(6-25) with Y25P mutation were used as peptide probes for peptide binding assay. The extinction coefficient of FITC (63,000 M −1 •cm −1 at 495 nm, pH 7.0) was used to determine the concentration of the FITC-labeled peptide probes.…”

Section: Synthetic Peptidesmentioning

confidence: 99%

“…Background (reaction buffer only) was subtracted for anisotropy calculation. For the SpectraiD5, G factor (0.38 for FITC-sCT(22-32) and 0.41 for FITC-AC413 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and FITC-AC413(6-25) Y25P) was used to correct the instrumental bias for anisotropy calculation. The polarization (mP) of the FITC-peptide probes only (No receptor ECD) was set close to 50 mP.…”

Section: Fluorescence Polarization/anisotropy (Fp) Peptide Binding Assaymentioning

confidence: 99%

“…A rat amylin analog pramlintide was developed and is available in clinics to treat diabetes as co-therapy with insulin [8]. In addition, lots of effort has been focused on developing next-generation peptide drugs targeting AMY receptors as exemplified with dual amylin calcitonin receptor agonists (DACRA) and long-acting amylin/calcitonin receptor agonists [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

Lee

2021

Biomolecules

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The calcitonin and amylin receptors (CTR and AMY receptors) are the drug targets for osteoporosis and diabetes treatment, respectively. Salmon calcitonin (sCT) and pramlintide were developed as peptide drugs that activate these receptors. However, next-generation drugs with improved receptor binding profiles are desirable for more effective pharmacotherapy. The extracellular domain (ECD) of CTR was reported as the critical binding site for the C-terminal half of sCT. For the screening of high-affinity sCT analog fragments, purified CTR ECD was used for fluorescence polarization/anisotropy peptide binding assay. When three mutations (N26D, S29P, and P32HYP) were introduced to the sCT(22–32) fragment, sCT(22–32) affinity for the CTR ECD was increased by 21-fold. CTR was reported to form a complex with receptor activity-modifying protein (RAMP), and the CTR:RAMP complexes function as amylin receptors with increased binding for the peptide hormone amylin. All three types of functional AMY receptor ECDs were prepared and tested for the binding of the mutated sCT(22–32). Interestingly, the mutated sCT(22–32) also retained its high affinity for all three types of the AMY receptor ECDs. In summary, the mutated sCT(22–32) showing high affinity for CTR and AMY receptor ECDs could be considered for developing the next-generation peptide agonists.

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Development of Cagrilintide, a Long-Acting Amylin Analogue

Cited by 63 publications

References 42 publications

GLP-1 physiology informs the pharmacotherapy of obesity

GLP-1 physiology informs the pharmacotherapy of obesity

Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls

Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors

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