Setmelanotide

Setmelanotide is a synthetic cyclic eight-amino-acid melanocortin 4 receptor (MC4R) agonist. It is FDA-approved as Imcivree (2020) for chronic weight management in certain rare genetic forms of obesity affecting the leptin-melanocortin pathway.

Last reviewed 2026-10-25 by the PeptideWiki editorial team. Editorial policy.

Overview

Setmelanotide is a melanocortin 4 receptor agonist designed to restore signaling in a hypothalamic pathway that regulates appetite and energy balance. In this pathway, leptin acts on neurons that produce pro-opiomelanocortin (POMC), whose processed products, including α-MSH, activate MC4R to reduce food intake. Genetic defects in POMC, in the processing enzyme PCSK1 or in the leptin receptor disrupt this signal upstream of MC4R and cause severe early-onset obesity with intense hunger.

Setmelanotide was developed to bypass such upstream defects by activating MC4R directly. Earlier MC4R agonists had been limited by effects on blood pressure and heart rate, and setmelanotide was selected in part for a more favorable profile in this respect. It is marketed as Imcivree and was approved by the FDA in 2020 for certain genetic obesities. It is not a general obesity treatment, and its approved uses depend on confirmed genetic or syndromic diagnoses.

Structure

Setmelanotide is a cyclic octapeptide, Ac-Arg-c[Cys-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2, in which a disulfide bond between the two cysteines closes a seven-residue ring. It carries an N-terminal acetyl group and a C-terminal amide. The ring contains the His-D-Phe-Arg-Trp sequence, the core melanocortin pharmacophore, with D-phenylalanine contributing to potency and stability. Correct disulfide formation is essential to its structure; the reduced linear form has a mass two daltons higher. Research material is usually supplied as an acetate or TFA salt.

Mechanism

Setmelanotide activates MC4R, a Gs-coupled receptor expressed on neurons in the paraventricular nucleus of the hypothalamus and elsewhere in the brain. In the leptin-melanocortin pathway, MC4R activation reduces food intake and increases energy expenditure. When this pathway is interrupted upstream, as in POMC, PCSK1 or leptin receptor deficiency, a direct MC4R agonist can partly restore downstream signaling. Setmelanotide also has activity at other melanocortin receptors, including MC1R, which accounts for skin hyperpigmentation observed in clinical studies.

Research

POMC, PCSK1 and leptin receptor deficiency

Pivotal open-label phase 3 trials enrolled people with obesity due to biallelic variants in POMC, PCSK1 or the leptin receptor gene, evaluating the proportion of participants achieving clinically meaningful weight loss and changes in hunger scores. These trials, which included withdrawal periods to assess response, supported the 2020 FDA approval. The populations were very small because these conditions are rare, and the design reflected the difficulty of conducting conventional placebo-controlled trials in ultra-rare diseases.

Bardet-Biedl syndrome and other indications

Setmelanotide has been studied in Bardet-Biedl syndrome, a genetic ciliopathy associated with obesity and disordered hunger signaling, and its approved labeling was later expanded to include this condition; check the current label for details. Further studies have examined other genetic and acquired disorders affecting the melanocortin pathway, such as hypothalamic obesity. Indications other than those on the current label remain investigational.

Cardiovascular and pigmentation effects

Development of earlier MC4R agonists was hindered by increases in blood pressure and heart rate. Clinical studies of setmelanotide reported that such effects were not prominent at the exposures studied, a key factor in its selection. Hyperpigmentation of skin and darkening of nevi are commonly reported, consistent with MC1R activation. Long-term safety continues to be monitored in extension studies and post-marketing surveillance. Other reported effects in trials included injection-site reactions and nausea.

Precision approach to obesity

Setmelanotide is often cited as an example of genotype-directed therapy for obesity, since response depends on where in the pathway the defect lies. People with obesity unrelated to these pathway defects were not the target population of the pivotal trials. The program has also stimulated genetic screening studies to identify individuals with rare variants affecting melanocortin signaling. Response varies between conditions.

Regulatory status

Setmelanotide is FDA-approved as Imcivree (2020) for chronic weight management in patients with certain genetic forms of obesity, initially obesity due to POMC, PCSK1 or leptin receptor deficiency confirmed by genetic testing; the label has since been expanded, so check current labeling for the full list of indications and age limits. It is not approved for general obesity. Approvals in other jurisdictions should be checked locally. For sport, check the current WADA Prohibited List.

Status changes often. See the regulatory tracker for dated updates.

Quality and identity testing

A certificate of analysis should confirm identity by mass spectrometry, with the observed mass matching the expected mass shown on this page for the disulfide-bridged, acetylated and amidated peptide, and report HPLC purity with the chromatogram. The most important compound-specific checks are complete disulfide formation, since the reduced form is 2 Da heavier, and absence of disulfide-linked dimers or oligomers. The HPLC method should resolve diastereomers at the D-Ala and D-Phe positions. Tryptophan oxidation products should be reported, and the counter-ion and net peptide content stated.

For a walkthrough of each section of a certificate, see how to read a COA.

Storage and stability

Store lyophilized setmelanotide sealed at -20 °C or colder, protected from light and moisture, and let vials reach room temperature before opening. The disulfide bridge can undergo exchange or reduction under some conditions, so avoid reducing agents and high pH in buffers. The tryptophan residue is light- and oxidation-sensitive. Prepare solutions for lab use in sterile buffer, keep them refrigerated for short-term work, aliquot for longer storage at -20 °C or below, and avoid repeated freeze-thaw cycles.

Download the Setmelanotide data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.

Latest research

Frequently asked questions

Related compounds

• PT-141 (bremelanotide)

  PT-141, or bremelanotide, is a cyclic heptapeptide melanocortin receptor agonist derived from melanotan II. It was FDA-approved in 2019 as Vyleesi for hypoactive sexual desire disorder in premenopausal women.

• Afamelanotide

  Afamelanotide is a synthetic 13-amino-acid analogue of α-melanocyte-stimulating hormone, [Nle4, D-Phe7]-α-MSH, that activates the melanocortin 1 receptor. It is FDA-approved as Scenesse (2019) for erythropoietic protoporphyria.

• Melanotan II

  Melanotan II is a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone that activates several melanocortin receptors. It is not approved as a medicine anywhere, and regulators have warned about unlicensed tanning products.

• Semaglutide

  Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is FDA-approved for type 2 diabetes (Ozempic, Rybelsus) and chronic weight management (Wegovy).

References

1. PubMed: all indexed literature on Setmelanotide
2. ClinicalTrials.gov: registered studies mentioning Setmelanotide