Setmelanotide (brand name Imcivree) is a cyclic 8-amino-acid peptide (MW ~1117.3 g/mol) that acts as a melanocortin 4 receptor (MC4R) agonist. FDA-approved in November 2020 by Rhythm Pharmaceuticals, it is the first-ever treatment for chronic weight management in patients aged 6 years and older with monogenic or syndromic obesity due to POMC, PCSK1, or LEPR deficiency confirmed by genetic testing. It was subsequently approved for Bardet-Biedl syndrome (BBS) in June 2022. Setmelanotide directly restores MC4R signaling downstream of the defective leptin-melanocortin pathway.
Category: Metabolic / MC4R Agonist. Evidence rating: A (strong human clinical data).
Clinical status: FDA-approved (Imcivree, November 2020 for POMC/PCSK1/LEPR deficiency obesity; June 2022 for BBS obesity)
Setmelanotide is a selective MC4R agonist that re-establishes signaling in the hypothalamic leptin-melanocortin pathway. In normal physiology, leptin activates POMC neurons, which produce alpha-MSH that activates MC4R to suppress appetite and increase energy expenditure. In patients with POMC,…
Research base: 0 registered clinical trials and 1 indexed publication reference Setmelanotide.
Safety considerations: Common (>=10%): injection site reactions (45%), skin hyperpigmentation (75%, due to MC1R activation), spontaneous penile erections in males (~38%), GI effects (nausea, diarrhea, abdominal pain); Skin hyperpigmentation: occurs in most patients due to MC1R agonism. Typically darkening of existing skin and nevi. Dermatologic monitoring recommended; Spontaneous erections and sexual adverse effects: common in males due to central melanocortin signaling. Generally decrease over time.
Reviewed by the PeptideAtlas Editorial Team. Last reviewed: 2026-08-12.
Setmelanotide is only for patients with obesity caused by specific genetic mutations: biallelic POMC, PCSK1, or LEPR deficiency, or Bardet-Biedl syndrome. Genetic testing confirming the diagnosis is required before prescribing. It is NOT indicated for general (polygenic) obesity.
Setmelanotide activates MC4R (its target) but also has some activity at MC1R, the melanocortin receptor responsible for melanin production in skin. MC1R activation stimulates melanocytes to produce more melanin, causing skin and nevi darkening. This occurs in approximately 75% of patients and requires dermatologic monitoring.
In patients with confirmed POMC deficiency, mean weight loss was approximately 25.6% from baseline. In LEPR deficiency, approximately 12.5%. In BBS, approximately 5.5% mean weight loss with 23% of patients achieving >=10% loss. The hunger reduction is often described as transformative for these patients.
No. Setmelanotide targets a very specific mechanism — the melanocortin pathway downstream of leptin signaling. In common polygenic obesity, the MC4R pathway is generally intact, and the drug has not shown efficacy for this population. It is specifically designed for rare monogenic and syndromic obesity disorders.