Setmelanotide (Imcivree)
A melanocortin-4 receptor (MC4R) agonist licensed for obesity driven by specific rare genetic defects in the leptin-melanocortin pathway (POMC, PCSK1, LEPR deficiency, and Bardet-Biedl syndrome). Administered as a daily subcutaneous injection, it restores appetite-suppressing signalling in patients whose obesity has a defined monogenic cause.
01 Overview
Setmelanotide is a cyclic peptide analogue of α-MSH that selectively activates MC4R, a key node in the hypothalamic circuit controlling hunger and energy expenditure. In people with loss-of-function upstream of MC4R, this restores the satiety signal that is otherwise absent, producing meaningful weight loss and reduced hunger.
Its approval rests on relatively small trials in rare, well-defined genetic populations, so while the evidence within those indications is solid, the total human experience is modest compared with mainstream obesity drugs. It is not indicated for common polygenic obesity.
02 Mechanism
Selective agonist at the melanocortin-4 receptor, restoring downstream satiety and energy-expenditure signalling in leptin-melanocortin pathway deficiencies.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Maintenance (adults) | 2–3 mg/day | SubQ | Titrated up to 3 mg once daily; lower in children. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Weight loss in monogenic obesityProduces clinically meaningful weight reduction in POMC/LEPR deficiency and BBS. | ~10% or more body weight in responders | Clinical | |
| Reduced hungerRestores satiety signalling, lowering the intense hyperphagia typical of these disorders. | Marked drop in hunger scores | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Skin hyperpigmentationDarkening of skin and moles from off-target MC1R activity. | Mild | Very common | Clinical | |
| Injection-site reactionsRedness, itching or bruising at the daily injection site. | Mild | Very common | Clinical | |
| Nausea and spontaneous penile erectionNausea, vomiting and, in males, spontaneous erections from melanocortin activity. | Mild | Common | Clinical |