Understanding the PK/PD effects of bi- and trimodal incretin agonists with our quantitative PET imaging
Antaros Medical has extensive experience in both driving imaging science and delivering studies in diabetes, obesity and metabolism. We have developed proprietary positron emission tomography (PET) tracers targeting the glucagon and gastric inhibitory peptide (GIP) receptors, to add to our previously developed PET tracer for the glucagon-like peptide-1 (GLP-1) receptor [1, 2]. These receptors are the target of novel bi- and trimodal peptides developed for the treatment of various metabolic disorders and thus there is a need to understand and quantify the overlapping pharmacology of hitting these targets with the same peptide. We deliver tailored solutions measuring receptor occupancy supporting optimal efficacy of incretin co-agonists through understanding their pharmacokinetic (PK) and pharmacodynamic (PD) effects.
Figure 1. The PET images show, for the first time in human, glucagon expression in the liver (left) and GLP-1 expression in the pancreas (right) in a patient with type 2 diabetes.
In the clinical trial setting
Using our PET methodology in a clinical trial setting of T2D patients, we have shown clear differential target engagement of the bimodal GLP-1/glucagon peptide, as shown in Figure 1 [1]. Quantitative analysis of GLP-1 receptor occupancy in the pancreas (graph to the left above) showed a clear decrease in PET signal from baseline (blue markers) to 3 weeks post up-titration of the GLP-1/glucagon peptide (red markers), indicating a receptor occupancy of around 50%. This data can be used to help set dosing and to provide evidence that the drug is hitting several targets as intended. Similar occupancy data are available for both the glucagon and GIP receptors.
Assessing overlapping pharmacology of multimodal incretin agonists using integrated PET-MRI
It is also possible to combine target engagement and receptor occupancy imaging with specific and overlapping PD imaging, as described in the figure to the left [3, 4]. In most cases this can be integrated into a single examination pre and post treatment using integrated PET/MRI. This allows linking target PK to target specific and overlapping PD effects.
References
1. Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes. Eriksson et.al Sci Rep 2020
2. In vivo PET imaging of the gastric inhibitory polypeptide receptor in pancreas. Eriksson et.al EASD congress 2020
3. Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study. Johansson et.al Radiology 2017
4. Structural and functional imaging of Muscle, Heart, Endocrine Pancreas and Kidneys in Cardiometabolic Drug Development. Book Chapter in “Translational Research Methods in Diabetes, Obesity, and Nonalcoholic Fatty Liver disease: A focus on Early Clinical Drug Development. Springer 2019. O Eriksson, P Hockings, E Johansson, L Johansson and J Kullberg