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Setmelanotide

From PeptidePlaza, the free peptide reference · Entry #036 · Metabolic · Hand-curated entry · Editorial standards

Research warning. Research chemical — not for human consumption. Melanocortin agonism drives melanogenesis: full dermatological examination and naevus monitoring are mandatory in any protocol. Depression and suicidal ideation have been reported; patients with hypothalamic damage require endocrine monitoring for adrenal and sodium disturbance.

Setmelanotide (also known as Imcivree, RM-493, BIM-22493) is a metabolic research peptide. A cyclic octapeptide that restores signalling in a broken melanocortin pathway. The only obesity drug that treats a specific genetic lesion rather than appetite in general.

Setmelanotide is a cyclic, MC4R-selective melanocortin receptor agonist — the therapeutic counterpart to the promiscuous melanocortin agonists such as Melanotan II. The MC4R pathway is the final common route by which leptin signalling suppresses appetite; when it is disrupted by rare genetic defects (POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome) or by structural hypothalamic damage, patients develop severe, early-onset hyperphagic obesity that does not respond to conventional treatment. Setmelanotide re-establishes downstream MC4R signalling. It was FDA-approved in 2020 for obesity due to POMC, PCSK1 or LEPR deficiency, extended to Bardet-Biedl syndrome in 2022, to patients as young as 2 years, and in March 2026 to acquired hypothalamic obesity in patients aged 4 and older — the TRANSCEND phase 3 trial reported a mean BMI change of −16.4% versus +2.4% on placebo. Its selectivity for MC4R over MC1R is incomplete, so hyperpigmentation and darkening of naevi occur commonly; sexual adverse events (spontaneous erections in males, sexual arousal changes in females) follow from melanocortin pharmacology, and depression and suicidal ideation have been reported across indications.

1 Mechanism of action

Selective agonist at the melanocortin-4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus, restoring the anorexigenic signalling that is normally driven by α-MSH derived from POMC. Bypasses upstream defects in leptin, LEPR, POMC or PCSK1 by acting directly at the receptor.

Primary targets: MC4R (primary) · MC1R (partial, off-target) · MC3R (weak)

2 Reported effects

Effects below are those reported in the published literature cited on this page. They are not claims of clinical benefit and not medical advice.

2.1 Reported benefits

  • Effective in genetic obesity syndromes that resist every other intervention
  • Substantial reduction in hyperphagia — hunger scores fall alongside weight
  • Mean BMI reduction of 16.4% vs +2.4% placebo in acquired hypothalamic obesity (TRANSCEND)
  • FDA-approved with defined paediatric indications from age 2
  • Targets a specific molecular lesion rather than suppressing appetite generically

2.2 Side effects

  • Skin hyperpigmentation and darkening of naevi (very common, MC1R-mediated)
  • Injection site reactions
  • Nausea, vomiting, diarrhoea
  • Spontaneous penile erections in males; sexual arousal changes in females
  • Depression and suicidal ideation (monitoring required)
  • Acute adrenal insufficiency in hypothalamic obesity patients with secondary adrenal insufficiency (5%)
  • Sodium imbalance in patients with central diabetes insipidus

3 Chemical and physical properties

CAS number920014-72-8
Molar mass1117.3 g/mol
Purity (typical)>98%
Half-life~11–13 hours (SC injection; once-daily dosing)
Storage−20 °C, lyophilised powder, desiccated
SolubilitySterile water / bacteriostatic water
Receptors / targetsMC4R (primary), MC1R (partial, off-target), MC3R (weak)

3.1 Amino acid sequence

Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2

4 Research dosages

Clinical dosing: 1 mg SC daily initial, titrated to 2–3 mg daily in adults; lower weight-based doses in paediatric patients.

Dosages are reported from published protocols for reference only. Research chemicals are not for human consumption.

5 Research studies (7)

  1. Setmelanotide for Obesity Due to POMC or LEPR Deficiency: Phase 3 Trials
    The Lancet Diabetes & Endocrinology (2020) · RCT · N=21
    Two open-label phase 3 trials in patients with POMC/PCSK1 or LEPR deficiency obesity.
    Key finding: 80% of POMC-deficiency and 45% of LEPR-deficiency participants achieved ≥10% weight loss at ~1 year, with substantial reductions in hunger scores.
  2. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.
    The New England journal of medicine (2026) · RCT
    Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity.
  3. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.
    The lancet. Diabetes & endocrinology (2024) · Preclinical
    Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling.
  4. Setmelanotide: A Melanocortin-4 Receptor Agonist for the Treatment of Severe Obesity Due to Hypothalamic Dysfunction.
    TouchREVIEWS in endocrinology (2024) · Review
    Obesity is a silent global pandemic.
  5. 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.
    The lancet. Diabetes & endocrinology (2022) · RCT
    Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with...
  6. Setmelanotide: A Novel Targeted Treatment for Monogenic Obesity.
    The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians (2022) · Review
    Objective: To review clinical data regarding the newly approved drug setmelanotide, an injectable melanocortin 4 receptor (MC4R) agonist, for chronic weight management in adults and children aged 6 years and...
  7. Setmelanotide: First Approval.
    Drugs (2021) · Review
    Setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase...

6 Safety and risk profile

6.1 Regulatory status

Setmelanotide is currently classified as FDA approved. Approval applies to specific clinical indications and dosing; research-grade material is not the approved product.

Safety score: 66/100 — moderate concern. Derived from clinical data volume, known risks and regulatory status.

6.2 Contraindications

Conditions and populations in which use is contraindicated:

  • Pregnancy or lactation
  • History of significant depression or suicidal ideation (relative)
  • Untreated secondary adrenal insufficiency
  • Melanoma or extensive atypical naevi (relative)
  • Known hypersensitivity to melanocortin agonists

6.3 Drug interactions

Drug or classInteractionRisk
Other melanocortin agonists (Melanotan I/II, PT-141)Additive melanocortin receptor activation — compounded pigmentation and cardiovascular effects.High
Glucocorticoid replacement therapyRapid weight loss and hypothalamic pathology may change corticosteroid requirements; adrenal crisis reported.High
AntidepressantsNo pharmacokinetic interaction established, but psychiatric monitoring is warranted given reported mood effects.Moderate

6.4 Long-term risks

  • Progressive hyperpigmentation with continued exposure
  • Unclear long-term dermatological risk from chronic melanocortin stimulation
  • Psychiatric adverse events with prolonged use
  • Weight regain on discontinuation, as the underlying genetic defect persists

6.5 Research best practices

  • Store refrigerated at 2–8 °C; protect from light
  • Baseline and periodic full-body dermatological examination
  • Screen for depression before and during use
  • In hypothalamic obesity, verify adrenal and sodium status before initiation
Safety data disclaimer. Safety assessments are based on published literature and are for educational reference only. Clinical evidence varies significantly between peptides. Always consult primary research and current regulatory guidance.

7 Frequently asked questions

How is setmelanotide different from Melanotan II?
Both are melanocortin agonists, but setmelanotide is engineered for MC4R selectivity and clinical use, whereas Melanotan II is a non-selective agonist hitting MC1R (pigmentation), MC3R, MC4R and MC5R roughly indiscriminately. Setmelanotide still produces some MC1R-mediated pigmentation, but it is a controlled, approved drug with defined indications.
Does it work for common obesity?
No. It is indicated for obesity driven by defined melanocortin-pathway defects — POMC/PCSK1/LEPR deficiency, Bardet-Biedl syndrome, and acquired hypothalamic obesity. In polygenic common obesity the pathway is intact, and the drug offers no comparable benefit.
What are the most notable adverse effects?
Skin hyperpigmentation and darkening of existing naevi (MC1R activity), injection site reactions, nausea, and spontaneous penile erections in males. Depression and suicidal ideation have been reported and require monitoring; in acquired hypothalamic obesity with secondary adrenal insufficiency, serious adrenal events occurred in 5% of treated patients.

8 References

  1. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity. PubMed (2026). Miller JL, et al.. View source
  2. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. PubMed (2024). Roth CL, et al.. View source
  3. Setmelanotide: A Melanocortin-4 Receptor Agonist for the Treatment of Severe Obesity Due to Hypothalamic Dysfunction. PubMed (2024). Qamar S, et al.. View source
  4. 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. PubMed (2022). Haqq AM, et al.. View source

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Shares mc1r and mc3r pharmacology

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9 See also

For research reference only. Not medical advice. Peptides may be regulated or restricted in your jurisdiction. Entry validated by the PeptidePlaza Biomedical Research Desk; see editorial standards.