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Setmelanotide

Imcivree

Grade A: Approved and proven

TL;DR: Setmelanotide (Imcivree) is FDA-approved for chronic weight management in patients with obesity arising from specific rare genetic conditions affecting the melanocortin-4 receptor (MC4R) pathway, including POMC deficiency, PCSK1 deficiency, LEPR deficiency, Bardet-Biedl syndrome, and, as of March 2026, acquired hypothalamic obesity in adults and pediatric patients aged 4 years and older. Phase 3 trials across these indications demonstrated clinically meaningful and statistically significant reductions in body weight and hyperphagia scores. The drug is not indicated for common polygenic obesity or for obesity without a documented MC4R pathway defect. Off-label use in individuals without these specific deficiencies lacks controlled human evidence of efficacy or safety.

Key Takeaways

  • Grade A: Approved and proven
  • FDA approved: FDA-approved (2020, with label expansions through 2026) for rare MC4R pathway obesity syndromes and acquired hypothalamic obesity; not approved for common obesity.
  • Compounding: Setmelanotide is available only as FDA-approved Imcivree; compounding is not appropriate because an approved product exists. Use is restricted to patients with confirmed MC4R pathway genetic defects meeting labeled indications.
Setmelanotide chemical structure
Structure via PubChem CID 11993702

Mechanism

Setmelanotide is a melanocortin-4 receptor (MC4R) agonist that restores downstream satiety and energy expenditure signaling in patients with MC4R pathway deficiency.

Evidence

Setmelanotide (Imcivree) is FDA-approved for chronic weight management in patients with obesity arising from specific rare genetic conditions affecting the melanocortin-4 receptor (MC4R) pathway, including POMC deficiency, PCSK1 deficiency, LEPR deficiency, Bardet-Biedl syndrome, and, as of March 2026, acquired hypothalamic obesity in adults and pediatric patients aged 4 years and older. Phase 3 trials across these indications demonstrated clinically meaningful and statistically significant reductions in body weight and hyperphagia scores. The drug is not indicated for common polygenic obesity or for obesity without a documented MC4R pathway defect. Off-label use in individuals without these specific deficiencies lacks controlled human evidence of efficacy or safety.

Safety and risks

The FDA label includes a Warnings and Precautions section requiring monitoring for depression and suicidal ideation: depression occurred in 26% of patients aged 6 years and older in clinical studies, and suicidal ideation was reported in 11% of that age group; patients must be monitored for new or worsening depression and suicidal thoughts, and the drug should be discontinued if clinically significant symptoms emerge. Spontaneous penile erections occurred in approximately 24% of male patients aged 6 and older and in 8% of male patients aged 2-5; patients should be informed of this effect before starting therapy. Skin hyperpigmentation occurs frequently (reported in more than 20% of patients) due to MC1R activation; new or changing pigmented lesions should be evaluated. Injection site reactions are among the most common adverse effects. Nausea, headache, diarrhea, abdominal pain, and vomiting were also reported in more than 20% of patients. Sexual adverse reactions including increased libido occurred in approximately 7% of female patients.

Interactions

No major drug interactions have been characterized in the label; serotonergic agents should be used with caution given overlapping melanocortin pathway activity and the psychiatric adverse event profile.

Federal compounding status

FDA-approved drug as of 2026-06-02.

An FDA-approved drug that should be obtained as the licensed product. It is not a 503A bulk-substance candidate; compounding from bulk is limited under federal rules and generally permitted only during a declared shortage.

Federal status only, from public FDA records. State pharmacy-board rules vary and are not covered here. This is regulatory reporting, not legal advice. All compounds.

Compounding legality

Setmelanotide is available only as FDA-approved Imcivree; compounding is not appropriate because an approved product exists. Use is restricted to patients with confirmed MC4R pathway genetic defects meeting labeled indications.

Sources

  1. 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. (2020) rct
  2. Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial. (2025) rct
  3. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. (2017) other
  4. Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome. (2024) other
  5. Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways. (2025) other
  6. Could setmelanotide be the game-changer for acquired hypothalamic obesity? (2023) rct
  7. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. (2022) rct
  8. Setmelanotide: A Novel Targeted Treatment for Monogenic Obesity. (2022) review
  9. A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation. (2022) other
  10. Setmelanotide: First Approval. (2021) review
  11. Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity. (2023) review
  12. MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels. (2024) other
  13. Structural analysis of setmelanotide binding to MC4R variants in comparison to wild-type receptor. (2022) other
  14. Setmelanotide. (2026) other
  15. Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach. (2019) other
  16. The MC4R agonist, setmelanotide, is associated with an improvement in hypercapnic chemosensitivity and weight loss in male mice. (2025) other
  17. In silico characterization of MC4R variants reveals insights into Setmelanotide pharmacogenomics and personalized medicine for obesity. (2026) other
  18. An evaluation of setmelanotide injection for chronic weight management in adult and pediatric patients with obesity due to Bardet-Biedl syndrome. (2023) other
  19. Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide. (2022) other
  20. Efficacy and Safety of Setmelanotide, a Melanocortin-4 Receptor Agonist, for Obese Patients: A Systematic Review and Meta-Analysis. (2023) review
  21. Setmelanotide: what does it mean for clinical care of patients with obesity? (2020) other
  22. Development of Dysplastic Nevi in a Child with LEPR Deficiency Treated with Setmelanotide. (2025) other
  23. Real-life experience on efficacy and safety of setmelanotide treatment in prepubertal children. (2025) other
  24. Setmelanotide optimization through fragment-growing, molecular docking in-silico method targeting MC4 receptor. (2023) other
  25. Impact of the Melanocortin-4 Receptor Agonist Setmelanotide on MASLD and Kidney Function in Bardet-Biedl Syndrome. (2026) observational

Setmelanotide is FDA approved. PeptideGrids presents evidence and regulatory status for informational purposes only. We do not sell, supply, source, or help anyone obtain this compound, and we provide no dosing or administration guidance. This is not medical advice; consult a licensed clinician. Full disclaimer.

Last reviewed June 1, 2026 by PeptideGrids editorial team (independently audited).