Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R and 16 more

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Le Beyec J, Pépin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clément K, Farooqi IS, Van der Ploeg LHT

Molecular metabolism8 Jul 2017Cited by 237 (Europe PMC)

PMID29031731PMCIDPMC5641599DOI10.1016/j.molmet.2017.06.015PepBankPUB-29031731

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Summary

ObjectivePro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.MethodsWe studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.ResultsIn cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.ConclusionsSetmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

7 results from studies that gave the peptide. 3 results from people.

01HumanNon-randomized trialEfficacy outcome
In a 28-day clinical trial, Setmelanotide reduced weight in obese MC4R variant carriers.
In plain wordsIn obese MC4R variant carriers, weight decreased with Setmelanotide in a 28-day clinical trial.
Peptide
Setmelanotide
Outcome
DecreaseWeight loss in MC4R variant carriers
Study
n: not reported in source
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173105
02HumanObservational studyEfficacy outcome
Patients with upstream POMC defects had significantly greater weight loss with Setmelanotide than MC4R deficient patients.
In plain wordsPatients with upstream POMC defects had significantly greater weight loss with Setmelanotide than MC4R deficient patients.
Peptide
Setmelanotide
Outcome
IncreaseWeight loss by POMC versus MC4R deficiency
Study
n: not reported in source
Comparator
MC4R deficient patients
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173106
03HumanObservational studyEfficacy outcome
Patients with upstream POMC defects had significantly greater weight loss with Setmelanotide than obese controls.
In plain wordsPatients with upstream POMC defects had significantly greater weight loss with Setmelanotide than obese controls.
Peptide
Setmelanotide
Outcome
IncreaseWeight loss by POMC defects versus obese controls
Study
n: not reported in source
Comparator
Obese controls
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173107
04AnimalAnimal study (in vivo)Efficacy outcome
Wild-type rodents appeared more sensitive to Setmelanotide than MC4R heterozygous deficient mice.
In plain wordsIn rodents, wild-type animals appeared more sensitive to Setmelanotide than MC4R heterozygous deficient mice.
Peptide
Setmelanotide
Outcome
IncreaseSensitivity to Setmelanotide
Study
rodentn: not reported in source
Wild-type and MC4R heterozygous deficient rodents
Comparator
MC4R heterozygous deficient mice
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173103
05AnimalAnimal study (in vivo)Efficacy outcome
MC4R knockout mice failed to respond to Setmelanotide.
In plain wordsIn mice lacking MC4R, Setmelanotide produced no response.
Peptide
Setmelanotide
Outcome
No significant changeResponse to Setmelanotide
Study
mousen: not reported in source
MC4R knockout mice
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173104
06LabIn vitro (cells)Activity measurement
In cells, Setmelanotide was significantly more potent at MC4R than alpha-melanocyte stimulating hormone.
In plain wordsIn cells, Setmelanotide was significantly more potent at MC4R than alpha-melanocyte stimulating hormone.
Peptide
Setmelanotide
Outcome
IncreaseMC4R agonist potency
Study
n: not reported in source
Cells expressing MC4R
Comparator
Alpha-melanocyte stimulating hormone
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173101
07LabIn vitro (cells)Mechanism
In cells, Setmelanotide disproportionately rescued signaling by a subset of severely impaired MC4R mutants.
In plain wordsIn cells, Setmelanotide disproportionately rescued signaling by a subset of severely impaired MC4R mutants.
Peptide
Setmelanotide
Outcome
IncreaseMutant MC4R signaling rescue
Study
n: not reported in source
Cells expressing severely impaired MC4R mutants
Outcome group
Receptor activity and mechanism · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants.
1 context sentence(design, population, supporting numbers)
Summary · context
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial.
Show in the study text Report a problemFND-2903173102

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

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 ongoing · source ClinicalTrials.gov (opens in a new tab)

RecruitingPhase 4NCT07674290

Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic Obesity

Tom Hühnen = 2001 Jan 2023 to est. 31 Dec 2030

Bardet Biedl Syndrome (BBS) · Bardet Biedl Syndrome · Bardet-Biedl Syndrome (BBS) · Alstrom Syndrome

Trial page ClinicalTrials.govUpdated 29 Jun 2026

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.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:36 UTC
First added · source update from Europe PMC

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