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Study · Animal study (in vivo) · mouse · 2022

12 results

BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy.

Zimmermann T, Thomas L, Baader-Pagler T, Haebel P, Simon E, Reindl W, Bajrami B, Rist W, Uphues I, Drucker DJ, Klein H, Santhanam R, Hamprecht D, Neubauer H, Augustin R

Molecular metabolism7 Nov 2022Cited by 115 (Europe PMC)

PMID36356832 (opens in a new tab)PMCIDPMC9679702 (opens in a new tab)DOI10.1016/j.molmet.2022.101633 (opens in a new tab)PepBankPUB-36356832
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Summary

ObjectiveObesity 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.MethodsBI 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.ResultsBI 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.ConclusionsBI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

12 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In mice, pharmacological doses of BI 456906 gave greater bodyweight reductions than maximally effective doses of the GLP-1R agonist semaglutide.

    In plain wordsIn mice, BI 456906 lowered body weight more than the best doses of semaglutide.

    Peptide
    Survodutide
    Outcome
    DecreaseBody weight reduction in mice versus semaglutide
    Study

    mousen: not reported in source

    mice
    Comparator
    Semaglutide (maximally effective doses)
    Outcome group
    Body weight · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide.
    1 context sentence
    Summary · context
    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.
  2. 02AnimalAnimal study (in vivo)Mechanism

    In mice, the greater efficacy of BI 456906 was the consequence of increased energy expenditure.

    In plain wordsIn mice, BI 456906 raised energy use, which helped explain its stronger weight loss.

    Peptide
    Survodutide
    Outcome
    IncreaseEnergy expenditure
    Study

    mousen: not reported in source

    mice
    Outcome group
    Energy expenditure and thermogenesis · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake.
    1 context sentence
    Summary · context
    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.
  3. 03AnimalAnimal study (in vivo)Efficacy outcome

    In mice, the greater efficacy of BI 456906 was the consequence of reduced food intake.

    In plain wordsIn mice, BI 456906 reduced food intake, which helped explain its stronger weight loss.

    Peptide
    Survodutide
    Outcome
    DecreaseFood intake
    Study

    mousen: not reported in source

    mice
    Outcome group
    Appetite and food intake · Metabolic and weight
    Studied dose
    Dose not stated

    Source sentences

    Summary
    BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake.
    1 context sentence
    Summary · context
    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.
  4. 04AnimalAnimal study (in vivo)Mechanism

    In mice, glucose tolerance tests demonstrated in vivo engagement of the GLP-1R by BI 456906.

    In plain wordsIn mice, a glucose tolerance test showed that BI 456906 acts on the GLP-1 receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGLP-1R engagement: glucose tolerance
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  5. 05AnimalAnimal study (in vivo)Mechanism

    In mice, food intake tests demonstrated in vivo engagement of the GLP-1R by BI 456906.

    In plain wordsIn mice, a food intake test showed that BI 456906 acts on the GLP-1 receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGLP-1R engagement: food intake test
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  6. 06AnimalAnimal study (in vivo)Mechanism

    In mice, gastric emptying tests demonstrated in vivo engagement of the GLP-1R by BI 456906.

    In plain wordsIn mice, a stomach emptying test showed that BI 456906 acts on the GLP-1 receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGLP-1R engagement: gastric emptying
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Gastrointestinal
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  7. 07AnimalAnimal study (in vivo)Mechanism

    In mice, liver nicotinamide N-methyltransferase mRNA expression demonstrated in vivo engagement of the GCGR by BI 456906.

    In plain wordsIn mice, a liver gene marker showed that BI 456906 acts on the glucagon receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGCGR engagement: liver nicotinamide N-methyltransferase mRNA expression
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Liver
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  8. 08AnimalAnimal study (in vivo)Mechanism

    In mice, circulating amino acids demonstrated in vivo engagement of the GCGR by BI 456906.

    In plain wordsIn mice, blood amino acid levels showed that BI 456906 acts on the glucagon receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGCGR engagement: circulating amino acids
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  9. 09AnimalAnimal study (in vivo)Mechanism

    In mice, circulating fibroblast growth factor-21 demonstrated in vivo engagement of the GCGR by BI 456906.

    In plain wordsIn mice, blood FGF21 levels showed that BI 456906 acts on the glucagon receptor.

    Peptide
    Survodutide
    Outcome
    Direction not reportedGCGR engagement: circulating fibroblast growth factor-21
    Study

    mousen: not reported in source

    mice
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  10. 10AnimalAnimal study (in vivo)Mechanism

    Studies in GLP-1R knockout and transgenic reporter mice supported dual activity of BI 456906 at the GLP-1R and GCGR.

    In plain wordsIn genetically modified mice, results supported that BI 456906 acts on both the GLP-1 and glucagon receptors.

    Peptide
    Survodutide
    Outcome
    Direction not reportedDual activity at GLP-1R and GCGR in GLP-1R knockout and transgenic reporter mice
    Study

    mousen: not reported in source

    GLP-1R knockout and transgenic reporter mice
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  11. 11LabEx vivo tissueMechanism

    An ex vivo bioactivity assay supported dual activity of BI 456906 at the GLP-1R and GCGR.

    In plain wordsIn lab tests on tissue samples, results supported that BI 456906 acts on both the GLP-1 and glucagon receptors.

    Peptide
    Survodutide
    Outcome
    Direction not reportedDual activity at GLP-1R and GCGR in an ex vivo bioactivity assay
    Study

    n: not reported in source

    ex vivo bioactivity assay
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    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.
    1 context sentence
    Summary · context
    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.
  12. 12LabIn vitro (cells)Activity measurement

    In cell-based in vitro assays, BI 456906 was characterized as a potent glucagon receptor and GLP-1 receptor dual agonist.

    In plain wordsIn lab tests with cells, BI 456906 was a strong activator of the glucagon receptor and the GLP-1 receptor.

    Peptide
    Survodutide
    Outcome
    Not applicableFunctional agonism at GCGR and GLP-1R in cell-based assays
    Study

    n: not reported in source

    cell-based in vitro assays
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.
    2 context sentences
    Summary · context
    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.
    Summary · context
    BI 456906 was characterized using cell-based in vitro assays to determine functional agonism.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Versions 3 to 38Current

    28 Oct 2026, 02:04 UTC

    The same notice was added 36 times, first on 9 Oct 2026, 19:08 UTC. The status did not change between them.

    Study results updated

  2. Version 2

    9 Oct 2026, 03:06 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:06 UTC

    First added · source update from Europe PMC

Subjects

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