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BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy
OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9679702/ https://www.ncbi.nlm.nih.gov/pubmed/36356832 http://dx.doi.org/10.1016/j.molmet.2022.101633 |
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author | Zimmermann, Tina Thomas, Leo Baader-Pagler, Tamara Haebel, Peter Simon, Eric Reindl, Wolfgang Bajrami, Besnik Rist, Wolfgang Uphues, Ingo Drucker, Daniel J. Klein, Holger Santhanam, Rakesh Hamprecht, Dieter Neubauer, Heike Augustin, Robert |
author_facet | Zimmermann, Tina Thomas, Leo Baader-Pagler, Tamara Haebel, Peter Simon, Eric Reindl, Wolfgang Bajrami, Besnik Rist, Wolfgang Uphues, Ingo Drucker, Daniel J. Klein, Holger Santhanam, Rakesh Hamprecht, Dieter Neubauer, Heike Augustin, Robert |
author_sort | Zimmermann, Tina |
collection | PubMed |
description | OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. METHODS: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. RESULTS: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906’s superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. CONCLUSIONS: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake. |
format | Online Article Text |
id | pubmed-9679702 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-96797022022-11-23 BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy Zimmermann, Tina Thomas, Leo Baader-Pagler, Tamara Haebel, Peter Simon, Eric Reindl, Wolfgang Bajrami, Besnik Rist, Wolfgang Uphues, Ingo Drucker, Daniel J. Klein, Holger Santhanam, Rakesh Hamprecht, Dieter Neubauer, Heike Augustin, Robert Mol Metab Original Article OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. METHODS: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. RESULTS: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906’s superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. CONCLUSIONS: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake. Elsevier 2022-11-07 /pmc/articles/PMC9679702/ /pubmed/36356832 http://dx.doi.org/10.1016/j.molmet.2022.101633 Text en © 2022 Boehringer Ingelheim Pharma GmbH & CoKG https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Zimmermann, Tina Thomas, Leo Baader-Pagler, Tamara Haebel, Peter Simon, Eric Reindl, Wolfgang Bajrami, Besnik Rist, Wolfgang Uphues, Ingo Drucker, Daniel J. Klein, Holger Santhanam, Rakesh Hamprecht, Dieter Neubauer, Heike Augustin, Robert BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title | BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title_full | BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title_fullStr | BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title_full_unstemmed | BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title_short | BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy |
title_sort | bi 456906: discovery and preclinical pharmacology of a novel gcgr/glp-1r dual agonist with robust anti-obesity efficacy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9679702/ https://www.ncbi.nlm.nih.gov/pubmed/36356832 http://dx.doi.org/10.1016/j.molmet.2022.101633 |
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