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Peptide drug (FDA approved)Human trialsFDA approved

Setmelanotide

Setmelanotide

Last reviewed October 27, 2026 · 17 sources · Written for general readers · Compare with another compound →

The bottom line

Setmelanotide is an FDA approved drug sold as Imcivree, but only for rare causes of obesity: certain gene defects, Bardet-Biedl syndrome, and obesity after damage to the hypothalamus. In those groups it caused large weight loss and less hunger. A large 2026 trial in people carrying only one faulty gene copy missed its main goal, and in ordinary obesity only tiny, weeks long studies exist. Skin darkening is very common, and the label warns about depression and sexual side effects.

Where the evidence stands

What it is

Setmelanotide is a small ring shaped peptide of 8 amino acids. It is built as a copy of alpha MSH (alpha melanocyte stimulating hormone), a natural hormone.[1]

It is sold as Imcivree by Rhythm Pharmaceuticals. It is approved only for rare causes of obesity: acquired hypothalamic obesity (obesity caused by damage to the hypothalamus, a brain area that helps control hunger) in people 4 and older; Bardet-Biedl syndrome, a rare inherited condition, in people 2 and older; and confirmed genetic deficiency of POMC, PCSK1 or LEPR in people 2 and older.[1]

It is not approved for common obesity or for obesity linked to other genetic syndromes.[1] It is given as a daily shot under the skin. The label lists the formula of the free base as C49H68N18O9S2, and FDA's substance registry lists its CAS number as 920014-72-8.[1][2]

Early research papers call it RM-493 or BIM-22493.[3][4] A 2026 review of obesity in young children noted it is the only FDA approved obesity drug for children under 12, and only for these rare conditions.[5]

Name
Setmelanotide (Setmelanotide)
Other names
Imcivree, RM-493, BIM-22493
Type
Peptide drug (FDA approved)
CAS number
920014-72-8
Formula
C49H68N18O9S2
Molecular weight
About 1117.3 g/mol

What it does in the body

Setmelanotide copies alpha MSH, a natural hormone that switches on MC4 receptors in the hypothalamus, part of the brain that controls hunger, fullness and energy use. In the rare conditions it treats, the signals that should switch on MC4R are broken, and the drug switches the receptor on directly.[1]

This is the biology, area by area. A change measured in the body, like a higher blood level, does not always mean a person feels a benefit. The claims check below covers that.

Brain, hunger and fat

Well established

By switching on MC4R in the hypothalamus, it lowers food intake.[1] In a placebo controlled trial of 120 people with hypothalamic obesity, BMI fell 16.5 percent over 52 weeks versus a 3.3 percent rise on placebo, and hunger scores fell more on the drug.[6] In POMC and LEPR deficiency, hunger scores fell about 27 and 44 percent over about a year.[7]

Energy use

Measured in people

In 12 adults with ordinary obesity kept in a sealed room that measures calorie burn, 72 hours on the drug raised resting calorie burn by about 6.4 percent, about 111 calories a day, and shifted the body toward burning a bit more fat.[3] This was one tiny, very short study.

Skin and hair

Well established

It also switches on MC1 receptors on skin pigment cells, which builds up melanin and darkens skin.[1] Skin darkening was seen in 58 percent on the drug versus 10 percent on placebo in the hypothalamic obesity trial, and moles can darken or new ones appear.[1]

Sexual function

Measured in people

The label lists disturbed sexual arousal, including spontaneous erections in males, as a side effect.[1] In a short study of adults, about 13 percent reported unwanted erections.[8] It has never been tested as a treatment for low sexual desire.

Heart and blood vessels

Measured in people

Older drugs aimed at MC4R raised blood pressure. In obese monkeys treated for 8 weeks, setmelanotide did not raise heart rate or blood pressure.[4] In 49 adults with common obesity treated for up to 28 days, heart rate and blood pressure also did not rise.[8]

Blood sugar, fats and metabolic health

Measured in people

In obese monkeys it improved how the body handled sugar.[4] In a 2026 follow up analysis of 18 people with POMC or LEPR deficiency treated for about a year, a combined score of metabolic syndrome risk dropped, more so in people who lost more weight and in POMC than in LEPR deficiency.[9]

How it works

Setmelanotide switches on the MC4 receptor (MC4R). MC4 receptors in the brain help regulate hunger, fullness and energy use.[1]

  • In the rare conditions it treats, the signal chain that should switch on MC4R is broken. The label says lab and animal evidence suggests the drug can restore activity in this pathway, which lowers food intake.[1]
  • In a small study of 12 adults with obesity, 72 hours of the drug raised calories burned at rest by about 6.4 percent, or about 111 calories a day, compared with placebo.[3]
  • It is about 20 times less active at the related MC3 and MC1 receptors.[1]
  • MC1 receptors sit on pigment cells in the skin. Switching them on builds up melanin, which explains why skin darkening is a common side effect.[1]

The receptor target is clear. How much it helps people whose MC4 pathway works normally is not established.

What the research shows

We keep animal and human evidence apart. A result in animals is a reason to study something in people, not proof that it works in people.

Animal and lab studies

Monkey study showed weight loss without a rise in blood pressure

  • In obese rhesus monkeys treated for 8 weeks, body weight fell about 13.5 percent. Food intake dropped about 35 percent at first, then partly recovered.[4]
  • The same monkeys handled sugar better, and their heart rate and blood pressure did not rise. Older drugs of this type had raised blood pressure.[4]
  • A 26 week study in specially bred mice found no cancer from setmelanotide.[1]

Limit: Approval rests on human trials, so animal data matter mostly for safety.

Human studies

Strong results in rare conditions, little data in common obesity

  • First report, 2016: two patients with POMC deficiency, a rare gene defect that causes extreme hunger, got daily shots under the skin. One lost about 51 kg over 42 weeks and the other about 20.5 kg over 12 weeks.[11]
  • POMC and LEPR deficiency, phase 3: 21 people aged 6 and older got daily shots for about a year in open trials without a placebo group. 8 of 10 with POMC deficiency and 5 of 11 with LEPR deficiency lost at least 10 percent of body weight. Every POMC patient had injection site reactions and skin darkening, and 5 had nausea. No serious drug related side effects were reported.[7][10]
  • Bardet-Biedl syndrome, phase 3: 38 people were randomly given the drug or placebo for 14 weeks, then everyone got the drug. After 52 weeks, about 32 percent of those 12 and older with Bardet-Biedl syndrome lost at least 10 percent of body weight. Skin darkening (61 percent) and redness at the shot site (48 percent) were most common.[16] Across the FDA review, BMI fell 7.9 percent on average in 44 people.[12]
  • Young children: 12 children aged 2 to 5 with these rare conditions were treated for a year. BMI fell about 18 percent on average, more in POMC or LEPR deficiency (about 26 percent) than in Bardet-Biedl syndrome (about 10 percent). All side effects were mild or moderate.[13]
  • Hypothalamic obesity, phase 2: 18 patients aged 6 to 40 were treated for 16 weeks without a placebo group. 16 of 18 cut BMI by at least 5 percent, the average drop was 15 percent, and nausea (61 percent), vomiting (33 percent) and skin darkening (33 percent) were common.[14]
  • Hypothalamic obesity, phase 3, 2026: 120 people aged 4 to 66 were randomly given daily shots of the drug or placebo for 52 weeks. BMI fell 16.5 percent on the drug and rose 3.3 percent on placebo, and hunger scores fell more on the drug.[6]
  • In that trial, side effects were reported by everyone on the drug and 90 percent on placebo. Serious side effects occurred in 28 percent on the drug versus 8 percent on placebo. Skin darkening, nausea, vomiting and headache were most common.[6]
  • Single faulty gene copy, EMANATE, 2026: 295 people carrying one faulty copy of POMC, PCSK1, LEPR, SRC1 or SH2B1 were randomly given the drug or placebo for 52 weeks. None of the four gene groups met the main goal; the extra BMI drop over placebo was only about 2 to 4 percent and not statistically reliable. No new safety problems were seen.[15]
  • Common obesity: 49 adults got the drug or placebo as a constant drip under the skin for 14 or 28 days. In the 28 day group, the drug group lost about 4 kg more, with no rise in heart rate or blood pressure. Tanning (56 percent), headache (33 percent), skin spots (18 percent), nausea (15 percent) and unwanted erections (13 percent) were the most common complaints.[8]
  • Energy use: in 12 adults with obesity, 72 hours of the drug raised resting calorie burn by about 6.4 percent versus placebo.[3]
  • Across the approved uses, depression was reported in 26 percent of people in the gene deficiency trials.[1]

Limit: Most trials in the approved conditions were small and several had no placebo group because these conditions are rare. Studies in common obesity lasted only weeks, and the larger trial in single gene copy carriers failed.

Claims check

The most common claims about this compound, and what studies actually found. Verdicts rate the evidence, not whether you should use it.

Causes major weight loss in rare genetic obesity

Shown in people

In two 1 year studies of people with POMC, PCSK1 or LEPR deficiency, 80 percent of the POMC or PCSK1 group and 46 percent of the LEPR group lost at least 10 percent of their body weight. Only 21 people were assessed, and there was no placebo group.[10][7] In an earlier report, two patients with POMC deficiency lost about 51 kg and 20.5 kg.[11] In 44 people with Bardet-Biedl syndrome, BMI fell 7.9 percent on average after 52 weeks.[12] In 12 children aged 2 to 5, BMI fell about 18 percent over a year.[13]

Reverses obesity after brain tumors or brain injury

Shown in people

In a placebo controlled trial of 120 people aged 4 to 66 with obesity after hypothalamic damage, BMI fell 16.5 percent after 52 weeks on the drug, while it rose 3.3 percent on placebo.[6] An earlier 16 week open trial of 18 patients found an average BMI drop of 15 percent.[14] FDA approved this use in 2026.[1]

Works for ordinary obesity

Mixed results

Only short, small studies exist. In a 2017 report, 49 adults with common obesity got the drug or placebo as a constant drip under the skin for 14 or 28 days, and in the 28 day group those on the drug lost about 4 kg more than those on placebo.[8] The label says it is not for common obesity, and no long trial in common obesity has been published.[1] A 52 week placebo controlled trial in 295 people carrying a single faulty copy of one of several obesity genes missed its main goal in all four gene groups in 2026.[15]

Shuts down hunger

Shown in people

In the hypothalamic obesity trial, hunger scores in people 12 and older fell about 2.7 points on a 0 to 10 scale on the drug, versus about 1.5 points on placebo.[6] In the gene deficiency studies, average hunger scores fell about 27 percent in POMC deficiency and 44 percent in LEPR deficiency, but the drop varied a lot between patients.[7] In young children, 91 percent of caregivers reported less hunger.[13]

Speeds up metabolism

Mixed results

One crossover study kept 12 adults with obesity in a sealed room that measures calorie burn. After 72 hours on the drug, resting calorie burn was about 6.4 percent higher than on placebo, about 111 calories a day, and the body burned a bit more fat. The effect of a meal or exercise on calorie burn did not change.[3] This was one tiny, very short study.

Improves blood sugar and heart risk markers

Mixed results

In a follow up analysis of 18 patients with POMC or LEPR deficiency treated for about a year, a combined metabolic syndrome risk score improved, mostly in those who lost more weight.[9] This came from trials without a placebo group, and no trial has tested heart attacks or diabetes outcomes.

Gives you a tan

Shown in people

Skin darkening is one of its most common side effects. It was seen in 58 percent of people on the drug versus 10 percent on placebo in the hypothalamic obesity trial, and in 63 to 83 percent in other trials.[1] In the 2017 short term study, about 56 percent reported tanning.[8] The label warns that moles can darken and new ones can appear, so skin checks are required.[1]

Boosts libido and erections

Not tested

No study has tested it as a sex drive treatment. Unwanted sexual effects are a known side effect: the label lists disturbed sexual arousal, including spontaneous erections in males.[1] In the 2017 study, about 13 percent reported unwanted erections.[8]

Known risks and side effects

  • Skin darkening and moles. Skin darkening affected 58 percent versus 10 percent on placebo in one trial and up to 83 percent in others. Moles can darken and new ones can appear, so the label calls for full body skin exams.[1]
  • Depression and suicidal thoughts. The label warns about depression and suicidal thinking. Depression was reported in 26 percent of people in the gene deficiency trials.[1]
  • Sexual side effects. It can disturb sexual arousal, including spontaneous erections in males. About 13 percent reported unwanted erections in a short study.[1][8]
  • Nausea, vomiting and serious events. Nausea affected 61 percent and vomiting 33 percent in a 16 week trial.[14] In the 2026 hypothalamic obesity trial, serious side effects were more frequent on the drug (28 percent) than on placebo (8 percent).[6]
  • Hormone and salt problems in hypothalamic obesity. In people with acquired hypothalamic obesity, the label warns about sudden adrenal insufficiency and about sodium imbalance in those with central diabetes insipidus.[1] Anything sold online under this name is not the approved product and has not been checked by FDA.

Regulatory status

Today: Imcivree is FDA approved for three rare causes of obesity, most recently acquired hypothalamic obesity in March 2026. It is not approved for common obesity.[1] In March 2026 its maker reported that the EMANATE trial in single gene copy carriers failed.[15] WADA's 2026 Prohibited List does not name it.[17]

  1. FDA approved Imcivree for obesity due to POMC, PCSK1 or LEPR deficiency in people 6 and older.[10]
  2. FDA approved Imcivree for obesity due to Bardet-Biedl syndrome in people 6 and older.[12]
  3. Label revised to add acquired hypothalamic obesity in people 4 and older. By then the other uses covered people 2 and older.[1]
  4. Rhythm reported that all four groups in the EMANATE phase 3 trial missed the main goal.[15]
  5. Results of the phase 3 hypothalamic obesity trial were published in the New England Journal of Medicine.[6]

Sources

  1. Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) injection: prescribing information. Revised 03/2026. FDA label
  2. U.S. Food and Drug Administration, Global Substance Registration System. Setmelanotide (UNII N7T15V1FUY): codes. FDA GSRS
  3. Chen KY, Muniyappa R, Abel BS, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100(4):1639-1645. PMID 25675384
  4. Kievit P, Halem H, Marks DL, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62(2):490-497. PMID 23048186
  5. Fox CK, Armstrong SC, Kelly AS. Obesity in children aged 2 to 12 years: a review. JAMA. Published online October 21, 2026. PMID 42905688
  6. Miller JL, van Santen HM, Phillips SA, et al. Setmelanotide for the treatment of acquired hypothalamic obesity. N Engl J Med. 2026;395(2):138-150. PMID 42418774
  7. Clément K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID 33137293
  8. Collet TH, Dubern B, Mokrosinski J, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-1329. PMID 29031731
  9. Wabitsch M, Farooqi IS, Chung WK, et al. Impact of setmelanotide on metabolic syndrome risk in patients with proopiomelanocortin or leptin receptor deficiencies. J Clin Endocrinol Metab. Published online October 19, 2026. PMID 42895739
  10. U.S. Food and Drug Administration. FDA approves first treatment for weight management for people with certain rare genetic conditions. November 27, 2020. FDA
  11. Kühnen P, Clément K, Wiegand S, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375(3):240-246. PMID 27468060
  12. U.S. Food and Drug Administration. FDA approves treatment for weight management in patients with Bardet-Biedl Syndrome aged 6 or older. June 16, 2022. FDA
  13. Argente J, Verge CF, Okorie U, et al. Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial. Lancet Diabetes Endocrinol. 2025;13(1):29-37. PMID 39549719
  14. Roth CL, Scimia C, Shoemaker AH, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. 2024;12(6):380-389. PMID 38697184
  15. Rhythm Pharmaceuticals, Inc. Rhythm Pharmaceuticals announces topline results from Phase 3 EMANATE trial. Press release, Form 8-K Exhibit 99.1, U.S. Securities and Exchange Commission. March 16, 2026. SEC filing
  16. Haqq AM, Chung WK, Dollfus H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859-868. PMID 36356613
  17. World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. September 2025. WADA Prohibited List 2026
Medical disclaimer

This page is educational information only. It is not medical advice and does not replace care from a licensed medical provider. Do not use this page to decide whether to take any substance. Talk to a licensed medical provider first.

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