Setmelanotide (Imcivree)

Summary

Setmelanotide (Imcivree) is an FDA approved daily injectable melanocortin-4 receptor agonist, a drug that activates a brain receptor controlling hunger, for chronic weight management in people with obesity caused by POMC, PCSK1, or LEPR deficiency, rare gene defects in that hunger pathway (approved November 2020), or Bardet-Biedl syndrome, a rare inherited disorder (June 2022), with the age range extended to 2 years and older in December 2024, and extended in March 2026 to acquired hypothalamic obesity (obesity after damage to the hypothalamus) in patients 4 and older. In phase 3 trials, 80% of POMC deficient and 45% of LEPR deficient patients lost at least 10% of body weight at one year, and about one third of Bardet-Biedl patients did. It is not approved or effective for common obesity, and it is prescription only.

What is Setmelanotide?

Setmelanotide is a cyclic 8 amino acid melanocortin-4 receptor (MC4R) agonist. It is also known as Imcivree, RM-493, BIM-22493, Setmelanotide acetate.

How does it work?

Setmelanotide activates the melanocortin-4 receptor in the hypothalamus, restoring the satiety signal that is lost when upstream leptin to POMC to MC4R signaling is broken by genetic variants. Unlike earlier MC4R agonists it has little effect on blood pressure at approved doses. Activation of MC1R in skin causes darkening of skin and hair.

FDA-approved uses of Setmelanotide

Yes. The Imcivree label covers reducing excess body weight and maintaining the reduction long term in patients 4 and older with acquired hypothalamic obesity (obesity after damage to the brain's hunger control center), and in patients 2 and older with Bardet-Biedl syndrome (a rare inherited disorder) or with POMC, PCSK1, or LEPR deficiency (rare gene defects in the hunger pathway) confirmed by genetic testing showing variants interpreted as pathogenic (disease causing), likely pathogenic, or of uncertain significance. It is not approved for common obesity. [5]

What does the evidence say about Setmelanotide?

Phase 3 evidence in rare genetic obesity. Clement 2020: single arm phase 3 trials in POMC or PCSK1 deficiency (n = 10; 8 of 10 achieved at least 10% weight loss, mean 25.6% loss at 1 year) and LEPR deficiency (n = 11; 5 of 11 achieved at least 10%, mean 12.5% loss), with large reductions in hunger scores. Haqq 2022: randomized placebo controlled phase 3 in Bardet-Biedl and Alstrom syndrome (n = 38 randomized, 14 week placebo period then open label to 52 weeks); at 52 weeks about one third of Bardet-Biedl patients aged 12 and older achieved at least 10% weight loss. Roth 2025: phase 3 in children aged 2 to 5 showed BMI reductions. In the randomized phase 3 TRANSCEND trial in acquired hypothalamic obesity (n = 142), BMI fell 15.8% versus a 2.6% rise on placebo at 52 weeks, a placebo adjusted difference of 18.4% (manufacturer reported). An earlier study in common obesity showed no meaningful effect at tolerable doses.

Human evidence

Kuhnen 2016 (NEJM): two adults with POMC deficiency lost 51 kg over 42 weeks and 20.5 kg over 12 weeks, with normalization of hunger. Clement 2020 (Lancet Diabetes Endocrinol): 80% of POMC deficient participants and 45% of LEPR deficient participants achieved at least 10% weight loss at 1 year; mean hunger score fell by 27% and 44%. Haqq 2022: in Bardet-Biedl syndrome, mean BMI fell about 6% during the 14 week placebo controlled period on setmelanotide versus a small change on placebo, and 32% of patients aged 12 and older lost at least 10% of body weight at 52 weeks. Roth 2025: in children aged 2 to 5 with POMC, PCSK1, LEPR deficiency or Bardet-Biedl syndrome, BMI z scores fell substantially over 52 weeks.

Animal evidence

Rodent and primate studies established that MC4R agonism reduces food intake and body weight and that setmelanotide, unlike earlier compounds, does not raise blood pressure in primates. Animal data guided the human program; the clinically relevant evidence is human.

Key studies

Conditions studied

Is Setmelanotide legal in the United States?

FDA and compounding status

FDA approved product (Imcivree, November 2020 for POMC, PCSK1, and LEPR deficiency obesity; June 2022 for Bardet-Biedl syndrome; December 2024 expansion to ages 2 and older). It is available only by prescription and requires a confirmed genetic diagnosis for coverage. Because an approved product exists and is not in shortage, compounding is not permitted except for a documented patient specific clinical need. Setmelanotide is not on any FDA compounding bulks list. The current label also covers acquired hypothalamic obesity in patients 4 years and older.

WADA status

Not WADA prohibited. Not named on the current prohibited list. Athletes should still confirm against the list in force for their season.

Regulatory timeline

1. Mar 19, 2026FDA

   FDA approves Imcivree (setmelanotide) for acquired hypothalamic obesity

   FDA extended Imcivree to acquired hypothalamic obesity in adults and children 4 years and older, based on the phase 3 TRANSCEND trial.

   Regulatory: FDA approvedSource: Manufacturer press release: FDA approval of Imcivree for acquired hypothalamic obesity (March 19, 2026)
2. Nov 25, 2020FDA

   FDA approves Imcivree (setmelanotide) for rare genetic obesity

   FDA approved setmelanotide injection (Imcivree), an MC4R agonist, for chronic weight management in patients with obesity due to POMC, PCSK1, or LEPR deficiency confirmed by genetic testing.

   Regulatory: FDA approvedSource: Drugs@FDA: Imcivree (setmelanotide) NDA 213793

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Setmelanotide dose on the FDA label

Doses below are quoted from the FDA label for its approved uses, plus the doses used in the pivotal trials where noted. The prescriber sets the dose; PeptideAgent does not recommend doses or protocols.

FDA label (Imcivree, DailyMed; subcutaneous once daily): starting doses are 2 mg daily for 2 weeks in patients 12 and older with Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency, 1 mg daily for 2 weeks at ages 6 to under 12, and 0.5 mg daily for 2 weeks at ages 2 to under 6; acquired hypothalamic obesity starts at 0.5 mg daily for 2 weeks in patients 4 and older. The maintenance dose is 3 mg daily for all indications at ages 6 and older, while younger children use a weight based maintenance dose. The label has separate dosing for renal impairment.

Routes reported

What are the side effects and interactions of Setmelanotide?

Side effects

Interactions

Contraindications

How do people access Setmelanotide legally?

Typical cost: List price is in the hundreds of thousands of USD per year. Patients with a confirmed qualifying genetic diagnosis are usually covered by insurance with manufacturer support programs; out of pocket cost without coverage is prohibitive.

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Frequently asked questions

Decisions about starting, stopping, or combining any treatment belong with a licensed clinician who knows your history.

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Sources

Numbered citations above point to these primary sources. PubMed entries link to the indexed abstract.