Setmelanotide

Origin and structure

Setmelanotide is a synthetic analogue of alpha-MSH (alpha-melanocyte-stimulating hormone), a 13-amino-acid hormone that signals fullness in the brain and pigment production in the skin. It keeps only eight amino acids, closed into a ring by a sulphur bridge between two cysteines: Ac-Arg-cyclo[Cys-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2. At its centre sits the four-amino-acid core His-D-Phe-Arg-Trp, which it shares with afamelanotide (Melanotan I), melanotan II and bremelanotide (PT-141). Its molecular formula is C49H68N18O9S2 and its molecular weight 1117.3 daltons.

Setmelanotide was developed at the French drug company Ipsen under the code BIM-22493; Rhythm Pharmaceuticals in Boston licensed it from Ipsen, to which it still pays royalties, and developed it further as RM-493. In obese rhesus monkeys, eight weeks of treatment lowered body weight by 13.5% without raising blood pressure or heart rate. In the same monkeys LY2112688, an earlier MC4R agonist that had raised both in human volunteers, did increase them. Rhythm sells setmelanotide as Imcivree, a solution of 10 mg per ml in a 1 ml vial; the EU marketing authorisation is held by its Dutch subsidiary in Amsterdam.

How it works

Body fat releases the hormone leptin, which acts on the leptin receptor (LEPR) of nerve cells in the hypothalamus. These cells make POMC (pro-opiomelanocortin), a precursor protein that enzymes including PCSK1 cut into smaller hormones such as alpha-MSH, and alpha-MSH then switches on MC4R, which damps hunger. When both copies of the POMC, PCSK1 or LEPR gene are faulty, the chain breaks before it reaches MC4R, and severe hunger and obesity begin very early in life, often in infancy. MC4R itself is intact in these patients, so a drug that switches it on can stand in for the alpha-MSH signal that never arrives.

In Bardet-Biedl syndrome, faulty cilia, the small antenna-like structures on cells, are thought to disturb the same pathway. In acquired hypothalamic obesity, damage to the hypothalamus from a tumour, its treatment or another injury is thought to weaken melanocortin signalling. In both cases the link is a working theory rather than a proven mechanism.

Setmelanotide favours MC4R: the FDA label puts its activity at the MC3 and MC1 receptors about 20 times lower, and in the EMA's assessment it did not stimulate MC2R, the receptor for ACTH, the hormone that drives cortisol release. The remaining MC1R activity is enough to darken the skin, because MC1R on pigment cells drives melanin production even without sunlight. The labels attribute the weight loss to lower calorie intake and higher energy expenditure; in a short study in 12 otherwise healthy adults with obesity, setmelanotide raised resting energy expenditure and shifted fuel use towards fat.

After an injection under the skin, blood levels peak after about 8 hours and the effective half-life is about 11 hours, which suits one injection a day. About 39% of a dose leaves the body unchanged in the urine, and exposure is higher when the kidneys work poorly, so the labels give a lower dosing scheme for severe kidney impairment and advise against use in end-stage kidney disease.

Is setmelanotide approved?

Yes, in the EU and the US, and since August 2026 in Japan, but only for a few rare causes of obesity. It is not approved for common obesity: the US label states that it would not be expected to work there.

In the Netherlands Imcivree is a prescription-only medicine through the EU authorisation, held by Rhythm Pharmaceuticals Netherlands B.V. in Amsterdam, and the EU label reserves prescribing for doctors experienced in rare genetic or hypothalamic obesity. Basic health insurance has reimbursed it since 1 October 2022 for POMC, PCSK1 or LEPR deficiency from the age of 6, on conditions: the patient has completed a combined lifestyle intervention, is treated at an expertise centre, and stops if after 6 months on the maintenance dose weight has not stabilised in a growing child or has not fallen by at least 5% in an adult or fully grown adolescent. In 2025 the Zorginstituut advised against reimbursement for Bardet-Biedl syndrome because added value had not been shown, and the minister followed that advice in July 2025. We found no Dutch reimbursement decision for acquired hypothalamic obesity as of October 2026.

We do not sell setmelanotide. Setmelanotide offered online as a research chemical is not Imcivree: it has no marketing authorisation, is not made under a medicines licence and may not be used in people. The approvals below cover Imcivree only.

• EU: authorised on 16 July 2021 for obesity and hunger control in genetically confirmed loss-of-function POMC (including PCSK1) or LEPR deficiency on both gene copies, from the age of 6, as an orphan medicine supported through the EMA's PRIME scheme. Bardet-Biedl syndrome was added on 2 September 2022, children from 2 years on 26 July 2024, and acquired hypothalamic obesity from 4 years on 30 April 2026, after a positive CHMP opinion on 26 March 2026. An application for Alström syndrome, backed by 6 patients, was withdrawn on 22 April 2022 after the EMA's provisional view was that it could not be approved.
• US: approved on 25 November 2020 for chronic weight management in POMC, PCSK1 or LEPR deficiency from the age of 6, with priority review and orphan status; Bardet-Biedl syndrome followed on 16 June 2022, children from 2 years on 20 December 2024 and acquired hypothalamic obesity from 4 years on 19 March 2026. The current US label also accepts gene variants of uncertain significance, where the EU label requires confirmed loss-of-function variants on both gene copies.
• Japan: Rhythm announced on 24 August 2026 that the health ministry had approved Imcivree for acquired hypothalamic obesity, on the basis of TRANSCEND, which included a Japanese cohort.

What the research shows

Because the target diseases are so rare, most setmelanotide trials are small and many have no control group. Only TRANSCEND and the negative EMANATE trial compared it with placebo for a full year; the Bardet-Biedl trial had a 14-week placebo phase and the POMC and LEPR trials a 4-week blinded placebo withdrawal. Rhythm Pharmaceuticals funded the phase 2 and 3 trials. The results:

• First patients (Kühnen et al., 2016): in an investigator-initiated, open-label study in Berlin, two patients with POMC deficiency reported less hunger and lost 51.0 kg after 42 weeks and 20.5 kg after 12 weeks.
• POMC and LEPR deficiency, phase 3 (Clément et al., 2020): two single-arm trials at ten hospitals in Canada, the US, Belgium, France, Germany, the Netherlands and the UK, with 10 participants with POMC or PCSK1 deficiency and 11 with LEPR deficiency, aged 6 and over. After about a year 8 of 10 (80%) and 5 of 11 (45%) had lost at least 10% of their body weight. In those who responded in the first 12 weeks, weight fell by 25.6% and 12.5% on average and hunger scores by 27.1% and 43.7%; during four blinded weeks on placebo they regained 5.5 and 5.0 kg on average. Erasmus MC in Rotterdam was one of the sites.
• Bardet-Biedl syndrome, phase 3 (Haqq et al., 2022): 38 patients aged 6 and over with Bardet-Biedl or Alström syndrome received setmelanotide or placebo for 14 weeks, after which all received setmelanotide for 52 weeks. Of patients with Bardet-Biedl syndrome aged 12 and over, 32.3% lost at least 10% of their body weight after a year; in Alström syndrome the result was inconclusive. In the US label's analysis of the 14-week placebo phase, BMI fell by 4.6% against 0.1% on placebo.
• Young children (VENTURE): 12 children aged 2 to 5 with POMC or LEPR deficiency or Bardet-Biedl syndrome were treated open-label for a year. BMI fell by 18% on average, 26% in POMC or LEPR deficiency and 10% in Bardet-Biedl syndrome, and 10 of the 12 reached a clinically meaningful drop in BMI z-score (EU label). There was no control group.
• Acquired hypothalamic obesity, phase 2 (Roth et al., 2024): 18 patients aged 6 to 40 at five US centres were treated open-label for 16 weeks; 16 (89%) lowered their BMI by at least 5%, and BMI fell by 15% on average.
• TRANSCEND, phase 3 (Miller et al., 2026): 120 people aged 4 to 66 with acquired hypothalamic obesity were randomised 2:1 to setmelanotide or placebo for 52 weeks after dose escalation. BMI changed by −16.5% against +3.3% on placebo, a difference of about 19.8 percentage points, and in those aged 12 and over the weekly maximal hunger score (0 to 10) fell by 2.73 points against 1.45. In all, 83% against 21% reached a clinically meaningful drop in BMI or BMI z-score (EU label). The FDA, analysing all 142 randomised patients including a Japanese cohort, puts the difference at 18.4 points. The Princess Máxima Center in Utrecht was a trial site, and H.M. van Santen of that centre and UMC Utrecht is the paper's second author.
• EMANATE, phase 3 (announced March 2026): four placebo-controlled substudies in 295 people with milder genetic defects, namely one faulty copy of POMC/PCSK1 or LEPR, or variants in SRC1 or SH2B1. None met its primary endpoint, with placebo-adjusted BMI changes of −1.7% to −4.3% after 52 weeks. Rhythm reported better figures for POMC/PCSK1 and SRC1 in post hoc analyses, which do not count as proof.

Side effects and warnings

Across the trials summarised in the EU label, the most frequent side effects were skin darkening (66%), injection-site reactions (45%), nausea (36%), headache (19%) and vomiting (17%). Nausea and vomiting usually came in the first month, were mild and did not lead to stopping. In TRANSCEND, the year-long placebo-controlled trial in hypothalamic obesity, skin darkening affected 58% against 10% on placebo, nausea 55% against 25%, vomiting 38% against 19% and new or darker moles 15% against 6% (FDA label, 142 patients). In the published trial report, serious adverse events occurred in 28% against 8%.

The skin darkening is a direct melanocortin effect through MC1R. It usually starts 2 to 3 weeks into treatment, lasts as long as treatment continues and fades after stopping. Setmelanotide can also darken existing moles and cause new ones, so the EU label asks for a full-body skin examination before and yearly during treatment, and the US label before starting and periodically.

Spontaneous erections were reported by 14% of male patients and more frequent erections by 13%, none lasting longer than 4 hours; both labels tell patients to seek emergency care if one does. Depression has been reported: in the two POMC and LEPR trials (27 patients) the US label lists depression in 26% and suicidal ideation in 11%, and both labels advise considering stopping treatment if suicidal thoughts appear. Serious allergic reactions, including anaphylaxis, have been reported since approval.

Patients with acquired hypothalamic obesity may also lack pituitary hormones. In TRANSCEND serious acute adrenal insufficiency occurred in 5% on setmelanotide and in none on placebo, and in patients with central diabetes insipidus low blood sodium occurred in 6% against 2% and high blood sodium in 5% against 4%. The EU label asks for adrenal function to be checked before starting in patients with a history of hypothalamic or pituitary disease, and for heart rate and blood pressure to be measured at every visit and at least every 6 months; in animal studies rats and minipigs showed raised heart rate and blood pressure, monkeys did not. The vial contains benzyl alcohol as a preservative, which can build up in children under 3. The EU label rules out use in liver impairment and end-stage kidney disease and says treatment should not be started during pregnancy.

Setmelanotide, melanotan and PT-141

All four are synthetic relatives of alpha-MSH built around the same His-D-Phe-Arg-Trp core, but they act on the melanocortin receptors in different proportions. Afamelanotide (Melanotan I) binds mainly MC1R on pigment cells and is authorised as the Scenesse implant for EPP, a rare disorder in which light causes painful skin reactions. Melanotan II and bremelanotide (PT-141) are seven-amino-acid rings that act on several receptors at once; bremelanotide is approved in the US as Vyleesi for low sexual desire in premenopausal women. Setmelanotide was designed to favour MC4R, the receptor that controls hunger.

The overlap shows in the side effects. Setmelanotide still darkens the skin through MC1R, the effect behind the tanning use of melanotan, and it causes spontaneous erections through MC4R, the effect that turned melanotan II into the lead for bremelanotide. The difference lies in what each was tested and approved for: setmelanotide is the only one authorised for weight, and only in rare diseases of the melanocortin pathway, as a daily injection under specialist care.

Frequently asked questions

Does setmelanotide work for ordinary obesity?

There is no evidence that it does, and it is not approved for it. The labels limit it to obesity caused by POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome and acquired hypothalamic obesity, and the US label states that it is not expected to work in general obesity. In the EMANATE trial, 295 people with milder single-gene defects did not lose significantly more BMI than on placebo in any of the four substudies.

Why does setmelanotide make the skin darker?

Besides MC4R it also activates MC1R, the receptor on pigment cells that drives melanin production, even without sunlight. About two thirds of patients get darker skin, usually within 2 to 3 weeks, and it fades after stopping. Moles can darken and new ones can appear, so the labels ask for regular full-body skin checks.

Is Imcivree reimbursed in the Netherlands?

For POMC, PCSK1 or LEPR deficiency from the age of 6, yes, since 1 October 2022 and under conditions: treatment at an expertise centre after a combined lifestyle intervention, and stopping if after 6 months on the maintenance dose weight has not stabilised in a growing child or fallen by at least 5% in an adult. For Bardet-Biedl syndrome, no: in July 2025 the minister followed the Zorginstituut's advice not to reimburse it. We found no Dutch decision yet for acquired hypothalamic obesity.

Does weight come back after stopping setmelanotide?

In the trials it did. In the POMC and LEPR trials, participants who were switched to placebo for four blinded weeks regained 5.5 and 5.0 kg on average and lost weight again when treatment restarted. The EU label states that weight loss and hunger control last only as long as treatment continues without interruption.

Is setmelanotide the same as Melanotan or PT-141?

No. They are related alpha-MSH analogues that share the same core, but they are different molecules. Setmelanotide is an eight-amino-acid ring designed to favour the hunger receptor MC4R, Melanotan I (afamelanotide) mainly targets the pigment receptor MC1R, and melanotan II and PT-141 (bremelanotide) act on several receptors. Only setmelanotide is approved for weight, and only in rare forms of obesity.

Is setmelanotide banned in sport?

It is not named on the 2026 WADA Prohibited List or on the 2027 List that takes effect on 1 January 2027, which the Dutch anti-doping rules follow. Because it is an approved medicine in the EU and the US, it does not fall under class S0, which covers substances with no approval for human use. Athletes who want certainty can ask the Dopingautoriteit.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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