Setmelanotide

Imcivree, RM-493, BIM-22493

Metabolic & weight

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Setmelanotide is an approved prescription medicine for specific rare genetic forms of obesity, not a research-only compound and not a general weight-loss drug. This page explains the published science. Use outside a prescription, or in people without a confirmed genetic diagnosis, has no evidence of benefit and carries the risks discussed below.

Summary

Class: Synthetic cyclic 8-amino-acid peptide, melanocortin-4 receptor (MC4R) agonist; structurally related to α-MSH and the melanotans but ~20-fold selective for MC4R over MC3R
Mechanism: Re-activates the MC4R appetite pathway in the hypothalamus that is broken downstream of leptin in POMC, PCSK1, LEPR and Bardet-Biedl syndrome obesity, reducing hunger and body weight
Routes studied: Subcutaneous once daily (approved); phase 1 IV/SC in general obesity
Dose range reported: Approved: adults and children ≥12 years — 2 mg SC daily for 2 weeks, then 3 mg daily if tolerated; 6–<12 years — 1 mg daily, titrated to 2 then 3 mg; 2–<6 years — 0.5 mg daily, titrated to 1 then 2 mg †. Early general-obesity trials: 0.01–1 mg/day infusions. Community use: anecdotal and inappropriate
Half-life: ~11 h
Storage: Unopened vials: refrigerate 2–8 °C in the carton. After first use: refrigerate or keep at room temperature for up to 30 days, then discard
Regulatory status: Approved medicine (US 2020/2022, EU 2021/2022, UK; others †)

Doses are as reported in studies or by the community — never recommendations.

1What it is

Setmelanotide is the first medicine that treats obesity by fixing a specific broken signal rather than by acting on general appetite physiology. In a small number of people, mutations in the POMC, PCSK1 or LEPR genes, or Bardet-Biedl syndrome, disrupt the pathway by which leptin tells the brain that energy stores are full. The final step of that pathway is the MC4R receptor, and in these conditions it is intact but never switched on. Setmelanotide switches it on directly. Earlier MC4R failed because they also raised blood pressure; setmelanotide was engineered to avoid that, though it keeps enough activity at the skin receptor MC1R to darken skin and hair. It was developed by Rhythm Pharmaceuticals and approved by the FDA in November 2020.

2How it's thought to work

Normal physiology. leptin → POMC neurons in the arcuate nucleus → α-MSH → MC4R neurons in the paraventricular nucleus → reduced hunger, increased energy expenditure.

Genetic obesity. POMC or PCSK1 deficiency means no α-MSH is made; LEPR deficiency means POMC neurons never hear leptin; in Bardet-Biedl syndrome, ciliary defects stop the signal reaching MC4R neurons. In every case the MC4R receptor itself still works.

Setmelanotide. binds MC4R directly, bypassing the upstream defect. Hunger scores fall within days; weight follows over months.

Side-effect biology. residual MC1R activity causes hyperpigmentation; MC4R activity in spinal and brainstem circuits explains spontaneous erections and sexual arousal effects; MC4R-mediated effects on mood are being monitored.

An MC4R-selective agonist acting in the hypothalamus. It sits downstream of the leptin signal, so it still works where that pathway is broken further up — which is why it is approved for specific genetic obesity syndromes rather than for obesity generally.Schematic — not to scale

3What the research shows

POMC/PCSK1 and LEPR deficiency obesity

Proof of concept in two adults with POMC deficiency produced 51 kg and 20.5 kg weight loss over about a year (Kühnen 2016, NEJM). Pivotal single-arm phase 3 trials with an 8-week placebo-controlled withdrawal period: 80% (8/10) of POMC/PCSK1 participants and 45% (5/11) of LEPR participants achieved ≥10% weight loss at one year, with large reductions in hunger scores; weight returned during blinded placebo withdrawal (Clément 2020, Lancet Diabetes Endocrinol). Hunger is the most responsive outcome; weight loss continues at a slower pace in extension studies. [1][3]

Bardet-Biedl syndrome

Phase 3 trial (n=38 including Alström syndrome; 14-week placebo-controlled period then open label): about one-third of BBS participants aged ≥12 achieved ≥10% weight loss at 52 weeks, with mean BMI reduction of ~8–9% and reduced hunger (Haqq 2022, Lancet Diabetes Endocrinol). Approved for BBS in 2022. [4]

Graded B/A

Acquired hypothalamic obesity

In an open-label phase 2 trial in 18 people with obesity after hypothalamic injury (tumours, surgery), mean BMI fell ~15% over 16 weeks (Roth 2024, Lancet Diabetes Endocrinol). Phase 3 (TRANSCEND) reported positive top-line results in 2025 †. Not yet approved for this. [5]

Graded B/A (weak)

Heterozygous MC4R-pathway variants and general obesity

Responses in heterozygous carriers are smaller and variable; in people with common obesity and no pathway defect, early-phase trials showed only modest weight loss and the programme was not pursued (Collet 2017, Mol Metab, and company reports). [6]

4Reported side effects and interactions

Literature-reported

Common (literature; pooled trials). injection-site reactions (~96%), skin hyperpigmentation (~78%; darkening of skin, moles, hair, usually reversible), nausea (~56%), headache, diarrhoea, abdominal pain, back pain, fatigue, vomiting, depression (~26%), upper respiratory infection, spontaneous penile erections (~23% of males), sexual adverse reactions in females, disturbance in sexual arousal.

Serious / warnings. depression and suicidal ideation (monitor; consider stopping if symptoms emerge); disturbance in sexual arousal and prolonged erections (seek care for erections lasting >4 h); hyperpigmentation masking melanoma, so a full skin examination before and periodically during treatment is recommended. Benzyl alcohol preservative is a concern in very young children and neonates. No cardiovascular signal (blood pressure and heart rate unchanged in trials), unlike earlier MC4R .

Community-reported

essentially none; this is a prescription product for a tiny population.

Theoretical. unknown effects in pregnancy; risk of mistaken use in common obesity, where benefit is minimal.

Interactions. no formal studies; not metabolised by CYP enzymes, so pharmacokinetic interactions are unlikely. Additive sexual side effects with PDE5 inhibitors or bremelanotide are plausible.

Markers researchers commonly monitor

Per label and trial protocols:

Marker	Why it's watched
Body weight, BMI (BMI-Z in children) and hunger scores	the primary outcomes; the label advises stopping if there is no meaningful response after ~12–16 weeks at the maximum dose.
Full skin examination	baseline and periodic, because hyperpigmentation can disguise melanoma or change the appearance of moles.
Depression and suicidality screening	at baseline and at each visit.
Blood pressure and heart rate	unchanged in trials, but the class history justifies tracking.
HbA1c, fasting glucose, lipid panel	metabolic outcomes that follow weight loss.
Growth velocity (children)	monitored in paediatric use.
Genetic confirmation	not a monitoring marker, but the single most important prerequisite: without a confirmed pathway variant or BBS diagnosis, the evidence does not apply.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as a 10 mg/mL multi-dose solution; no . Doses are drawn with a 1 mL insulin-type syringe: 0.5 mg = 0.05 mL, 1 mg = 0.1 mL, 2 mg = 0.2 mL, 3 mg = 0.3 mL. Injected subcutaneously in the abdomen, thigh or arm at the start of the day, rotating sites. Small volumes make syringe-reading errors the main risk.

Open in calculator, pre-loaded →

6Commonly studied alongside

α-MSH (the natural ligand, this batch), Melanotan II and bremelanotide/PT-141 (non-selective melanocortin agonists; bremelanotide is approved for hypoactive sexual desire disorder), afamelanotide (MC1R-selective, for erythropoietic protoporphyria), GLP-1 agonists (semaglutide, tirzepatide — compared in discussions of obesity treatment, not combined in trials), metreleptin (for leptin deficiency, a different step in the same pathway).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Imcivree) for chronic weight management in obesity due to POMC, PCSK1 or LEPR deficiency (2020; age ≥2 since 2024) and Bardet-Biedl syndrome (2022). Not approved for common obesity or heterozygous variants
European Union	EMA-authorised (Imcivree) for POMC/PCSK1/LEPR deficiency (2021) and Bardet-Biedl syndrome (2022), age ≥6 †
United Kingdom	MHRA-licensed; NHS access via NICE for BBS and the genetic deficiencies †
Australia	TGA registration status †
South Africa	Not registered †
Sport	Not specifically listed by WADA as of review date †

8Open questions

Which heterozygous or "variant of uncertain significance" patients benefit, if any.
Long-term safety of chronic MC4R activation, especially mood and pigmentation changes over decades.
Whether hypothalamic obesity will become an approved indication, which would broaden the eligible population considerably.

9References

1Kühnen P et al. (2016). Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. PubMed · DOI
2Clément K et al. (2018). MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. PubMed · DOI
3Clément K et al. (2020). 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. PubMed
4Haqq AM et al. (2022). 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. PubMed
5Roth CL et al. (2024). Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. PubMed
6Collet TH et al. (2017). Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol Metab. PubMed · DOI
7Imcivree prescribing information (US) and SmPC (EU), current versions. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

26 Oct 2026Profile published — awaiting medical review

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