Summary
Setmelanotide is a selective MC4R agonist approved for rare genetic forms of obesity in which the brain’s leptin–melanocortin pathway is broken. In phase 3 trials in people with POMC deficiency, 80% lost at least 10% of body weight over about a year.
Structure
A cyclic octapeptide selective for the melanocortin-4 receptor.
How it works
MC4R in the hypothalamus is the final step in the leptin signalling pathway that tells the brain the body has enough energy stores. Setmelanotide restores signalling downstream of the genetic defect.
Research use cases
Areas where Setmelanotide has been studied. Inclusion here does not mean it works for that purpose.
- POMC, PCSK1 and LEPR deficiency obesity
- Bardet-Biedl syndrome
- Hypothalamic obesity (studied)
What the research found
Phase 3 genetic obesity trials
In single-arm trials, 8 of 10 participants with POMC deficiency and 5 of 11 with LEPR deficiency lost at least 10% of body weight at about one year, with large reductions in hunger scores.1
Safety and open questions
Skin darkening (via MC1R cross-activity), injection-site reactions, nausea, and spontaneous erections in males. Depression and suicidal ideation are labelled warnings.
Regulatory status
FDA-approved (Imcivree, 2020) for obesity due to POMC, PCSK1 or LEPR deficiency, and (2022) Bardet-Biedl syndrome. Prescription only.
Status was accurate when this page was last reviewed on October 26, 2026. Regulations change; check with the relevant authority before relying on it.
Setmelanotide: common questions
Does setmelanotide work for common obesity?
It is approved only for specific genetic causes. Common obesity does not usually involve a broken MC4R pathway, and earlier trials in general obesity were not pursued.
Is Setmelanotide approved for human use?
FDA-approved (Imcivree, 2020) for obesity due to POMC, PCSK1 or LEPR deficiency, and (2022) Bardet-Biedl syndrome. Prescription only.
References
- Clément K, van den Akker E, Argente J, 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. The Lancet Diabetes & Endocrinology.
Links open a PubMed search for the exact title, or the original source where one is given.