Setmelanotide
A daily injection that activates the melanocortin-4 receptor, approved for obesity caused by rare genetic defects and by hypothalamic damage
Setmelanotide activates the melanocortin-4 (MC4) receptor, part of the brain pathway that regulates body weight. Sold as Imcivree, it is approved in the US for obesity due to Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency, and for acquired hypothalamic obesity.
What is it?
The MC4 receptor belongs to the leptin-melanocortin pathway, which helps regulate body weight, and rare variants in genes along that pathway cause severe obesity from early childhood. Setmelanotide activates the receptor directly. In cells it is markedly more potent at the MC4 receptor than the body's own ligand, alpha-MSH, and in a 28-day phase 1b study people with defects upstream of the receptor, in the POMC gene, lost more weight than those whose MC4 receptor itself was impaired; mice lacking the receptor did not respond at all. That is why its use is restricted to specific diagnoses rather than common obesity.
Its approvals rest on small trials in rare conditions. In phase 3 trials for POMC and LEPR deficiency, 8 of 10 and 5 of 11 participants lost at least 10% of body weight at about a year; in Bardet-Biedl syndrome, 32.3% of patients aged 12 or older did after 52 weeks. In acquired hypothalamic obesity, after a tumour, lesion or injury of the hypothalamus, the 120-person TRANSCEND trial found BMI fell 16.5% on setmelanotide and rose 3.3% on placebo over 52 weeks.
Later analyses add context rather than new randomised data. In 22 evaluable Bardet-Biedl patients, a metabolic-syndrome severity score fell by 0.34 over 52 weeks, more in those who reached the weight-loss thresholds. A 2026 indirect comparison against a matched registry cohort found 58.6% of treated Bardet-Biedl patients met the primary weight endpoint against 6.9% of untreated controls (71.4% against 10.7% in children). Quality-of-life scores improved by about 11 to 12 points after a year in the Bardet-Biedl phase 3 trial, with clinically meaningful gains in most of those impaired at the start. In children aged 2 to 5, the VENTURE trial found BMI fell 18% on average at a year.
The label sets doses by age and diagnosis. Hypothalamic obesity starts at 0.5 mg once daily for two weeks; Bardet-Biedl syndrome and POMC, PCSK1 or LEPR deficiency start at 2 mg from age 12, 1 mg from 6 to 11 and 0.5 mg from 2 to 5, with a maintenance dose of 3 mg once daily from age 6 for all indications. Given under the skin, it peaks at a median of 8 hours, has an effective half-life of about 11 hours, reaches steady state within two days and accumulates by about 30% over 12 weeks.
Skin darkening is its signature side effect, reported in 61% of the Bardet-Biedl trial, alongside injection-site reactions, nausea and vomiting. The label's warnings go further: spontaneous erections in males and sexual adverse reactions in females, with emergency care for an erection lasting over four hours; depression and suicidal ideation; serious hypersensitivity reactions including anaphylaxis; darkening of existing moles and new moles, so skin examinations are advised; and, in hypothalamic obesity, acute adrenal insufficiency (serious in 5% of treated patients with secondary adrenal insufficiency against none on placebo) and sodium imbalance in those with central diabetes insipidus.
Mechanism of Action
Setmelanotide activates the MC4 receptor in the leptin-melanocortin pathway, restoring a signal that genetic defects or hypothalamic damage interrupt.
MC4 receptor activation
More potent than the natural ligand alpha-MSH in cells; mice lacking the receptor did not respond.
Upstream defects respond best
People with POMC defects lost more weight than those with impaired MC4 receptors in the phase 1b study.
Pigmentation
Skin darkening, darkening of existing moles and new moles are common and listed in the label's warnings.
Once-daily kinetics
Peaks at about 8 hours, effective half-life about 11 hours, steady state within two days (label).
Published Research
The studies behind setmelanotide, read from their PubMed abstracts: mechanism, the phase 2 and 3 trials in each rare indication, children, and later analyses.
MC4R deficiency: cells, mice and a phase 1b study
Setmelanotide was more potent than alpha-MSH at MC4R; in a 28-day phase 1b study, obese MC4R variant carriers lost weight, and people with POMC defects lost significantly more than MC4R-deficient patients or obese controls.
TRANSCEND: acquired hypothalamic obesity, 120 people
Ages 4 to 66, 1.5 to 3.0 mg daily or placebo for 52 weeks after dose escalation. BMI changed -16.5% against +3.3%, and hunger fell more. Serious adverse events: 28% against 8%; skin darkening, nausea, vomiting and headache were commonest.
Hypothalamic obesity, phase 2: 18 patients
Titrated to 3.0 mg daily for 16 weeks: 16 of 18 reached at least a 5% fall in BMI, mean -15%. Nausea (61%), vomiting and skin darkening (33% each) were frequent.
POMC and LEPR deficiency, phase 3: 21 people
At about one year, 8 of 10 with POMC deficiency and 5 of 11 with LEPR deficiency had lost at least 10% of body weight; hunger scores fell 27% and 44%. Injection-site reactions affected everyone.
Bardet-Biedl and Alström syndromes: 38 patients
After 14 placebo-controlled weeks and 52 weeks of treatment, 32.3% of Bardet-Biedl patients aged 12 or older lost at least 10%; Alström results were inconclusive. Skin darkening affected 61%.
VENTURE: children aged 2 to 5, 12 patients
Starting at 0.5 mg daily and rising by weight, BMI fell 18% on average at 52 weeks: 26% with POMC or LEPR deficiency, 10% with Bardet-Biedl syndrome. All adverse events were mild or moderate.
Metabolic syndrome score in Bardet-Biedl
In 22 evaluable patients, the metabolic syndrome severity score fell by 0.34 at week 52, by 0.64 in those meeting weight-loss thresholds against a rise of 0.08 in those who did not.
Bardet-Biedl against a matched registry
An indirect comparison found 58.6% of treated patients met the primary weight endpoint at 52 weeks against 6.9% of matched registry controls (71.4% against 10.7% in children).
Quality of life after one year
In the Bardet-Biedl phase 3 trial, PedsQL scores rose by 11.2 in children and IWQOL-Lite by 12.0 in adults, with meaningful gains in all impaired children and 62.5% of impaired adults.
Dosing Data
Imcivree is injected under the skin once daily, starting low and increasing to maintenance by age and diagnosis.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trials above and the Imcivree prescribing information (Rhythm Pharmaceuticals; DailyMed set 70c3ccf7, version 14, effective April 1, 2026).
Contraindications & Cautions
From the label and the trials.
Legal Status
Setmelanotide is approved in the US as Imcivree.
Frequently Asked Questions
?What is setmelanotide?
A peptide that activates the MC4 receptor in the brain's weight-regulating pathway, given as a daily injection and sold as Imcivree.
?Who is it approved for?
In the US, obesity from Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency from age 2, and acquired hypothalamic obesity from age 4.
?How much weight do people lose?
In acquired hypothalamic obesity, BMI fell 16.5% against a 3.3% rise on placebo over 52 weeks; in POMC deficiency, 8 of 10 lost at least 10% in a year.
?What are the side effects?
Skin darkening, injection-site reactions, nausea, vomiting and headache.
?What dose is used?
It starts low (0.5 to 2 mg once daily for two weeks, by age and diagnosis) and is usually maintained at 3 mg once daily from age 6 (label).
?Why doesn't it work for ordinary obesity?
Its approvals cover specific defects in the leptin-melanocortin pathway; a mechanistic study found the most weight loss when the defect was upstream of the MC4 receptor.
?What are the label's main warnings?
Sexual adverse reactions including prolonged erections, depression and suicidal thoughts, serious allergic reactions, mole changes, and adrenal and sodium problems in hypothalamic obesity.
References
- [fda] FDA. Drugs@FDA (openFDA): IMCIVREE (setmelanotide), NDA 213793, prescription. Read September 30, 2026.
- [fda] Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) injection, US prescribing information: sections 1, 2 and 12.3. DailyMed version 14, effective April 1, 2026. Read September 30, 2026.
- [pubmed] Collet TH, et al. "Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency." Mol Metab, 2017;6(10):1321-1329. PMID: 29031731.
- [pubmed] Miller JL, et al. "Setmelanotide for the Treatment of Acquired Hypothalamic Obesity." N Engl J Med, 2026;395(2):138-150. PMID: 42418774.
- [pubmed] Roth CL, 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.
- [pubmed] Clément K, 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.
- [pubmed] Haqq AM, 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.
- [pubmed] Argente J, 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.
- [pubmed] Haqq AM, et al. "Impact of Setmelanotide on Metabolic Syndrome Risk in Patients With Bardet-Biedl Syndrome." J Clin Endocrinol Metab, 2025;110(10):e3271-e3282. PMID: 39919037.
- [pubmed] Argente J, et al. "Setmelanotide in Bardet-Biedl Syndrome: A 52-Week Comparison of Phase 3 Trial Participants With a Matched Registry Cohort." Obesity (Silver Spring), 2026;34(3):579-587. PMID: 41703984.
- [pubmed] Forsythe E, et al. "Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results." Orphanet J Rare Dis, 2023;18(1):12. PMID: 36647077.
Sources & Citations
Studies were read from their PubMed records (October 6, 2026); the label and Drugs@FDA are listed below with their read dates.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.