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approvedWeight Loss & Diabetes

Setmelanotide

Also known as: Imcivree, RM-493, BIM-22493

Setmelanotide is a synthetic cyclic octapeptide melanocortin-4 receptor (MC4R) agonist FDA-approved in 2020 as Imcivree for chronic weight management in patients with obesity due to specific genetic deficiencies: POMC, PCSK1, or LEPR deficiency. It is the first precision medicine for genetic obesity, restoring signaling in the leptin-melanocortin pathway. Clinical trials show dramatic weight loss of 25–40% in responders with these rare genetic conditions.

4 cited references·5 researched benefits

Quick Answer

Setmelanotide (Imcivree) is a melanocortin-4 receptor (MC4R) agonist FDA-approved for obesity caused by POMC, PCSK1, or LEPR genetic deficiency. As the first precision medicine for genetic obesity, it restores signaling in the disrupted leptin-melanocortin satiety pathway. Patients with confirmed genetic mutations experience 25–40% weight loss and dramatic hunger reduction. It is administered as a daily subcutaneous injection and is not approved for general polygenic obesity.

Key Facts

Mechanism
Setmelanotide is a cyclic octapeptide that selectively agonizes the melanocortin-4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus. In the leptin-melanocortin pathway, leptin signals from fat tissue activate POMC neurons, which release alpha-MSH to stimulate MC4R and suppress appetite. Genetic deficiencies in POMC (no alpha-MSH production), PCSK1 (no POMC processing), or LEPR (no leptin signal transduction) break this pathway, causing extreme early-onset obesity and insatiable hunger. Setmelanotide bypasses these upstream defects by directly activating MC4R, restoring satiety signaling regardless of the specific genetic lesion.
Research Status
approved
Half-Life
~11 hours
Primary Use
Weight Loss & Diabetes
Table of Contents

Benefits

  • Dramatic weight loss in genetic obesity — 25–40% body weight reduction in patients with POMC, PCSK1, or LEPR deficiencystrong
  • Profound hunger reduction — patients report transformation from insatiable hunger to normal appetite, dramatically improving quality of lifestrong
  • Precision medicine approach — genotype-guided therapy targeting the specific molecular defect in leptin-melanocortin signalingstrong
  • Sustained efficacy — multi-year follow-up data shows maintained weight loss and appetite control with continued treatmentmoderate
  • Expanded indications — phase 3 trials for Bardet-Biedl syndrome and other rare genetic obesity disorders showing positive resultsmoderate

Dosage Protocols

RouteDosage RangeFrequencyNotes
Subcutaneous injection1–3 mg (adults); 0.5–3 mg (pediatric ≥6 years)Once dailyInitiate at 2 mg daily for adults (1 mg for pediatric). If 5% weight loss not achieved after 12–16 weeks, increase to 3 mg daily. Genetic testing required before prescribing to confirm POMC, PCSK1, or LEPR deficiency.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Injection-site reactions — erythema, pain, or induration at injection site in 30–45% of patientscommon
  • Skin hyperpigmentation — darkening of skin due to MC1R cross-activation (50–80% of patients), generally mild and reversiblecommon
  • Spontaneous penile erection — reported in male patients due to melanocortin pathway activation; typically diminishes over timecommon
  • Depression and suicidal ideation — boxed warning; patients should be monitored for mood changesserious
  • Sexual adverse reactions — reports of sexual dysfunction in both male and female patientsrare

Frequently Asked Questions

Who is eligible for setmelanotide treatment?
Setmelanotide is exclusively approved for patients with obesity caused by biallelic loss-of-function variants in the POMC, PCSK1, or LEPR genes, confirmed by genetic testing. These are extremely rare conditions — estimated at fewer than 1,000 patients in the US combined. It is not approved for common polygenic obesity. Rhythm Pharmaceuticals offers a free genetic testing program (Uncovering Rare Obesity) to identify eligible patients. The drug has also been approved for Bardet-Biedl syndrome obesity.
Why does setmelanotide cause skin darkening?
Setmelanotide targets MC4R but has partial cross-reactivity with MC1R, the melanocortin receptor on melanocytes that controls skin pigmentation. MC1R activation stimulates melanin production, causing skin darkening (hyperpigmentation). This is the same pathway activated by alpha-MSH and melanotan-II. The effect is generally mild, dose-dependent, and reversible upon discontinuation. In clinical trials, 50–80% of patients experienced some degree of hyperpigmentation.
How does setmelanotide differ from melanotan-II or PT-141?
All three are melanocortin receptor peptides, but they differ in selectivity and indication. Setmelanotide is MC4R-selective and FDA-approved for genetic obesity. Melanotan-II is a non-selective melanocortin agonist (MC1R-MC5R) used for tanning, never FDA-approved. PT-141 (bremelanotide) primarily targets MC4R/MC3R and is FDA-approved for hypoactive sexual desire disorder. Setmelanotide was specifically designed for MC4R selectivity to maximize appetite effects while minimizing off-target melanocortin activity.
What happens if setmelanotide is given to someone without a genetic obesity mutation?
In patients with common polygenic obesity (no specific leptin-melanocortin pathway defect), setmelanotide phase 2 studies showed minimal weight loss (~2–3%). The melanocortin pathway is already functional in these patients, so additional MC4R stimulation provides limited benefit and may cause more side effects. This is why genetic testing is mandatory before prescribing — the drug works specifically because it replaces a missing signal, not because it amplifies an existing one.
How much does setmelanotide cost?
Setmelanotide (Imcivree) has a US list price of approximately $45,000–$55,000 per month, reflecting its orphan drug status and the extremely small patient population (~1,000 eligible patients in the US). Rhythm Pharmaceuticals offers patient assistance programs, and most commercial insurance plans cover it with prior authorization given the clear genetic diagnosis requirement. The high price is typical for rare disease therapies where development costs are amortized over very few patients.

References

  1. 1
    Setmelanotide for the treatment of POMC deficiency obesity: a phase 3, randomised, controlled trial(2020)PubMed ↗
  2. 2
    MC4R agonism promotes durable weight loss in patients with LEPR deficiency(2018)PubMed ↗
  3. 3
    Setmelanotide for Bardet-Biedl syndrome and other ciliopathy-related obesity: a phase 3 trial(2022)PubMed ↗
  4. 4
    The melanocortin system and energy homeostasis: from discovery to anti-obesity therapy(2018)PubMed ↗

Latest Research

Last updated: 2026-02-19