What it is
Setmelanotide is an eight-amino-acid peptide closed into a ring. It is sold as Imcivree, approved in the US on 25 November 2020 for obesity with a known, named cause in the brain's hunger pathway. It is one of the smallest approved peptide drugs, at 1,117.3 daltons.
Its template is alpha-melanocyte-stimulating hormone (alpha-MSH), the body's own messenger at a family of five melanocortin receptors. The Imcivree label gives the structure: Ac-Arg-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys-NH₂, with a disulfide bond joining the two cysteines into a ring. Two of the eight are D-amino acids — mirror-image forms that protein-cutting enzymes handle poorly, which is part of why the drug lasts.
How it works
The MC4 receptor sits in the hypothalamus at the end of a chain: fat tissue releases leptin → leptin acts on its receptor (LEPR) → neurons make POMC → the enzyme PCSK1 cuts POMC into alpha-MSH → alpha-MSH switches on MC4 → hunger falls. A broken link anywhere in that chain leaves MC4 under-stimulated and hunger unchecked. Setmelanotide switches on MC4 directly, downstream of the break.
That is why it works only in people with a break. The label names each approved cause: variants in POMC, PCSK1 or LEPR; Bardet-Biedl syndrome, a genetic disorder that disrupts the same signalling; and acquired hypothalamic obesity, after tumours, surgery or injury damage the hypothalamus.
The Imcivree label reports about 20-fold less activity at MC3 and MC1 than at MC4. Less is not none, and MC1 is the receptor pigment cells use to tan.
The evidence
| Trial (Imcivree label) | People | Design | Result reported |
|---|---|---|---|
| Trial 1 — acquired hypothalamic obesity | 142 | Placebo-controlled, 56–60 weeks | BMI −18.4% vs placebo at 52 weeks on the therapeutic dose |
| Trial 2 — Bardet-Biedl syndrome | 44 | 14 weeks placebo-controlled, then 52 weeks open-label | Weight and BMI reduction |
| Trials 3 and 4 — POMC/PCSK1 and LEPR deficiency | small cohorts | One-year open-label, 8-week blinded withdrawal | Weight reduction; no parallel placebo group |
The hypothalamic-obesity trial is the strongest design: randomised, placebo-controlled, and the largest. The genetic-deficiency approvals rest on open-label trials with a withdrawal period instead of a placebo arm — a normal design for conditions with a handful of patients worldwide, and a real limit on how precisely the effect can be measured. Of 191 MEDLINE records naming setmelanotide, 4 are tagged as randomised controlled trials (Europe PMC, 2026-09-28).
Doses on the label
Reported as the Imcivree label states them, not as guidance. Starting doses run two weeks and depend on age and indication: 0.5 mg (acquired hypothalamic obesity from age 4; genetic indications aged 2 to under 6), 1 mg (genetic indications aged 6 to under 12) or 2 mg (genetic indications aged 12 and over). The maintenance dose for patients aged 6 and over is 3 mg once daily. The effective half-life is about 11 hours.
Safety
The label's warnings: disturbance in sexual arousal, including spontaneous penile erections; depression and suicidal ideation; hypersensitivity, including anaphylaxis; skin hyperpigmentation, darkening of existing moles and new moles; and, in acquired hypothalamic obesity, acute adrenal insufficiency and sodium imbalance in patients who also have central diabetes insipidus. In the Bardet-Biedl trial's placebo-controlled weeks, hyperpigmentation was reported in 67% of treated patients against 0% on placebo, and vomiting in 11% against 0%.
Where it stands
FDA application data list one presentation, the 10 mg/mL vial, as a current prescription product, with no generic (2026-09-28). The label was last revised on 1 April 2026. ClinicalTrials.gov holds 27 records with setmelanotide as an intervention.
Related reading
Setmelanotide's relatives are the unapproved tanning peptides Melanotan II and the earlier skin-tanning analogue Melanotan I — also built on alpha-MSH, but acting across the receptor family. For the hormone pathway that the common obesity drugs use instead, see semaglutide, which acts on the GLP-1 receptor rather than MC4.