Setmelanotide
MC4R agonist
Also Imcivree, RM-493, RM493, BIM-22493, Setmelanotide injection
- Evidence
- BSome human evidence
- FDA status
- FDA approvedas of 2026-10-26
- Route
- Injection
- Studies cited
- 3 human0 animal or cell
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Setmelanotide is the drug that treats obesity caused by a broken appetite switch in the brain, in people whose hunger never turns off.
Studies say
In rare genetic and brain-injury forms of obesity, setmelanotide produces large sustained weight loss in trials ranging from 10 to 142 patients, with skin darkening and nausea as the trade-offs; it has not been tested as a treatment for ordinary obesity.
Why grade B. The original approvals rested on two open-label single-arm trials of 10 and 11 patients in which most lost more than a tenth of their weight, which is strong for diseases this rare but is not randomized evidence. The Bardet-Biedl approval added a placebo-controlled phase, and the 2026 hypothalamic obesity approval rests on TRANSCEND, a randomized placebo-controlled trial of 142 patients, the largest to date. One true RCT plus small single-arm trials in rare genetic conditions is B. 123
FDA. Setmelanotide is FDA-approved as Imcivree for chronic weight management in patients aged 2 and older with obesity due to POMC, PCSK1 or LEPR deficiency (first approved November 2020), Bardet-Biedl syndrome (2022), and, since March 19, 2026, acquired hypothalamic obesity in patients aged 4 and older. It is not approved for common obesity. 23
Written from 3 cited sources. Fact-checked 2026-10-27: 16 claims checked, 2 corrected. Last refreshed 2026-10-27. Not physician reviewed.
Evidence checklist
- Randomised controlled trial TRANSCEND placebo-controlled; BBS placebo phaseyes
- Human study over 100 people TRANSCEND 142; others 10 to 21yes
- More than one research group Sponsor-run trialsno
- Clinical outcomes, not surrogate markers Weight and hunger scores, not complicationsno
- Human safety data beyond case reports Trial and label data; skin and mood warningsyes
Drawn from the cited studies below. A dash means the sources give no information.
What it is
Setmelanotide is a cyclic eight-amino-acid peptide that activates the melanocortin-4 receptor (MC4R), a brain receptor at the center of the pathway that tells the body it has eaten enough. It was developed by Rhythm Pharmaceuticals and is given as a daily subcutaneous injection. 12
It is approved only for obesity with a specific cause. POMC, PCSK1 and LEPR deficiencies are rare inherited defects in the chain of signals that leads from the fat hormone leptin to MC4R; people with them are severely obese from infancy and constantly hungry. Bardet-Biedl syndrome is a genetic disorder that also disrupts this pathway. Acquired hypothalamic obesity follows damage to the hypothalamus, usually from a brain tumor such as craniopharyngioma or its surgery, and causes relentless weight gain that diet does not touch. 123
How it works
Leptin from fat tissue signals the hypothalamus that energy stores are adequate. Neurons there respond by making POMC, cutting it (using the PCSK1 enzyme) into alpha-MSH, which activates MC4R on downstream neurons to reduce hunger and raise energy expenditure. A defect anywhere along that chain leaves MC4R silent and hunger unchecked. Setmelanotide bypasses the broken steps by stimulating MC4R directly. Earlier MC4R agonists raised blood pressure and heart rate; setmelanotide was designed to avoid that, and the trials bore it out. Because it also weakly activates MC1R, the receptor that controls pigment, it darkens skin, moles and hair. 12
What human research shows
The trials behind the first approval were two open-label phase 3 studies: 10 patients with POMC or PCSK1 deficiency and 11 with LEPR deficiency, treated for about a year. Eight of 10 in the POMC group and 5 of 11 in the LEPR group lost at least 10 percent of their body weight, and in the patients assessed the most-hunger score fell by 27 percent in the POMC trial and 44 percent in the LEPR trial. A blinded withdrawal period, in which patients were switched to placebo for a few weeks, showed weight and hunger returning, which supported a drug effect despite the lack of a parallel control group. 1
The Bardet-Biedl approval drew on a trial with a 14-week placebo-controlled phase followed by open-label treatment, summarized in the label. The 2026 hypothalamic obesity approval rested on TRANSCEND, which randomized 142 patients 2:1 to setmelanotide or placebo for 52 weeks. BMI fell by a mean of 15.8 percent on setmelanotide and rose 2.6 percent on placebo. The label now carries all three indications. 23
| Study | Model | Finding |
|---|---|---|
| POMC and LEPR deficiency phase 3 trials | Humans, n=10 and n=11, open-label single-arm with blinded withdrawal, about 1 year | 80 percent of POMC-deficient and 45 percent of LEPR-deficient patients lost at least 10 percent of body weight; most-hunger scores fell 27 and 44 percent. 1 |
| TRANSCEND (acquired hypothalamic obesity) | Humans, n=142, randomized 2:1, double-blind, placebo-controlled, 52 weeks | BMI fell 15.8 percent on setmelanotide versus a 2.6 percent rise on placebo. 3 |
| Imcivree prescribing information | FDA label, 2026 revision | Summarizes the Bardet-Biedl placebo-controlled data and the adverse reaction profile across indications. 2 |
Safety
Skin hyperpigmentation is the signature side effect, occurring in most patients, along with darkening of existing moles and new ones; the label advises full-body skin checks because dark lesions are harder to monitor. Nausea, vomiting, injection site reactions and headache are common. Spontaneous erections in males and changes in sexual arousal are reported, a class effect shared with bremelanotide. The label warns of depression and suicidal thoughts, with monitoring recommended. In hypothalamic obesity patients who also have central diabetes insipidus, sodium imbalances occurred, and acute adrenal insufficiency was reported in that population. Trials involve small numbers treated for one to a few years, so rare harms and lifelong effects are not known. 123
Questions for your clinician
- Does my type of obesity have a confirmed genetic or hypothalamic cause?
- Is there any controlled trial for ordinary obesity?
- How would my skin and mood be monitored?
Questions people ask
Who can be prescribed setmelanotide?
Patients aged 2 and older with obesity caused by genetically confirmed POMC, PCSK1 or LEPR deficiency or by Bardet-Biedl syndrome, and patients aged 4 and older with obesity caused by hypothalamic damage. Variants classed as benign or likely benign do not qualify; variants of uncertain significance do. It is not approved for obesity without one of these causes. 2
Does setmelanotide work for ordinary obesity?
It has not been shown to. All of setmelanotide's trials and approvals are in conditions where the leptin-melanocortin pathway is broken upstream of the receptor, and the label limits use to those conditions. 12
Why does it darken skin?
Setmelanotide also activates MC1R, the receptor on pigment cells that alpha-MSH normally uses to trigger tanning. Most patients develop darker skin and moles within weeks; the label recommends skin examinations because new or changing dark lesions are harder to assess. 12
How is it related to PT-141 and melanotan?
All are melanocortin receptor agonists derived from alpha-MSH. Melanotan II hits several melanocortin receptors and causes tanning, nausea and erections; bremelanotide (PT-141) was refined from it for sexual desire; setmelanotide was refined for selective MC4R activation to control appetite. The shared ancestry explains the overlapping side effects. 1
Citations
- Clément 2020, Lancet Diabetes Endocrinol: setmelanotide in POMC and LEPR deficiency obesity, two open-label phase 3 trials doi.org
- Imcivree (setmelanotide) prescribing information, FDA, 2026 accessdata.fda.gov
- Contemporary Pediatrics, March 2026: FDA approves setmelanotide for acquired hypothalamic obesity (TRANSCEND results) contemporarypediatrics.com