Setmelanotide
/ Synthetic melanocortin-4 receptor (MC4R) selective agonist; cyclic 8-residue peptideALIAS · Imcivree (trade) · RM-493 · BIM-22493
Terms in this page you can click for a plain-English popup: , , , , , , , .
Tier 1. Setmelanotide is a synthetic cyclic 8-residue selective melanocortin-4 receptor (MC4R) agonist. FDA-approved 2020 for chronic weight management in genetic obesity due to confirmed bi-allelic POMC, PCSK1, or LEPR deficiency in adults and paediatric patients aged 6 and older, based on the Clement and colleagues Phase 3 trials (Lancet Diabetes Endocrinology 2020). 2022 indication expansion to Bardet-Biedl syndrome (Haqq and colleagues, Lancet Diabetes Endocrinology 2022).
Setmelanotide is a synthetic cyclic 8-residue analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that selectively agonises the melanocortin-4 receptor (MC4R) on hypothalamic neurons of the leptin-melanocortin pathway. In rare genetic obesity syndromes caused by upstream loss-of-function mutations in POMC, PCSK1, LEPR, or PCSK9 (or downstream defects affecting MC4R signalling integrity, as in Bardet-Biedl syndrome), the leptin-melanocortin satiety circuit is functionally disrupted. Direct downstream MC4R agonism with setmelanotide bypasses the upstream lesion and restores satiety-regulating signalling, producing weight reduction in these specific genetic populations. The mechanism does not address common polygenic obesity, where MC4R signalling is intact.
Tier 1. The Clement and colleagues Phase 3 program (Lancet Diabetes Endocrinology 2020) randomised participants with confirmed bi-allelic POMC or LEPR deficiency to setmelanotide and reported clinically significant weight loss and reduction in hunger scores in this orphan population. The Haqq and colleagues Phase 3 trial (Lancet Diabetes Endocrinology 2022) demonstrated similar benefit in Bardet-Biedl syndrome, supporting the indication expansion. Trials are necessarily small (single-digit to low-double-digit participants per genetic subtype) due to the rarity of these conditions.
Skin hyperpigmentation is the most common adverse event and reflects on-target MC1R cross-reactivity (alpha-MSH is the endogenous skin melanin signal). Injection-site reactions, nausea, and dose-dependent vivid dreams have been reported. Spontaneous penile erections in male participants reflect MC4R-mediated central effects on sexual function. Long-term safety in paediatric populations is under post-marketing surveillance.
Regulatory status
- FDA status:
- FDA-approved
- Compounding:
- Not eligible for compounding (approved, not in shortage)
Setmelanotide is the textbook example of mechanism-targeted orphan obesity therapy: highly specific to a rare genetic patient population, with substantial weight-loss effect in that population and no expected utility in common polygenic obesity. The price ($60,000+ annual list) and the complexity of genetic confirmation of eligibility limit access. Vendor research-chemical 'setmelanotide' is not pharmaceutically equivalent to Imcivree and should not be considered for use in genetic obesity diagnosis or management without prescribed medical care.