Setmelanotide
Also known as: Imcivree, RM-493
Molecular Identifiers
Overview
Selective melanocortin 4 receptor (MC4R) agonist, developed for the treatment of genetically-driven obesity. Acts by restoring leptin-melanocortin pathway signaling, essential for appetite regulation and energy expenditure.
Approved by the FDA as Imcivree (2020) for the treatment of rare genetic obesity caused by POMC, PCSK1, or leptin receptor (LEPR) deficiency, in patients 6 years of age and older.
Clinical interest in setmelanotide is aimed at a specific niche: severe monogenic obesity in which genetic defects in the leptin-POMC-MC4R pathway abolish normal satiety signaling, leading to early hyperphagia and obesity refractory to diet and bariatric surgery. Setmelanotide restores that signaling by acting directly on hypothalamic MC4R, reducing appetite and increasing energy expenditure.
It was FDA-approved as Imcivree in 2020 for chronic treatment of obesity caused by confirmed POMC, PCSK1, or leptin receptor (LEPR) deficiency in patients aged 6 and older, with the indication later expanded to Bardet-Biedl syndrome. It is prescribed by endocrinologists in specialized centers, daily subcutaneously with gradual escalation (1 → 2 → 3 mg). Skin hyperpigmentation is a predictable effect from cross-activation of MC1R.
It is not indicated for common obesity — without the specific genetic defect, expected benefit is marginal and adverse effects are not justified. Prior genetic diagnosis is a mandatory part of the prescribing criteria.
Within the melanocortin family, setmelanotide is the MC4R-selective agonist for chronic use targeting a metabolic endpoint, with solid regulatory approval (Imcivree). It shares its receptor target with PT-141 (bremelanotide, MC4R for sexual function in an on-demand regimen), but indication and kinetics are opposite; it differs from Melanotan I (MC1R, pigmentation), Melanotan II (pan-agonist MC1R-MC5R), and endogenous α-MSH (very short half-life) by combining MC4R selectivity, a useful half-life, and an approved therapeutic use.
RCAHFRWC Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ Cyclic peptide with non-natural amino acids
Half-life
~11 hours
Administration Route
Subcutaneous
Category
Metabolic & Fat Loss
Mechanism of Action
- Selective MC4R receptor agonism in the hypothalamus
- Restoration of the leptin-POMC-MC4R pathway signaling
- Appetite reduction and increased satiety
- Increased basal energy expenditure
- Lipid metabolism modulation via central signaling
Dosage Protocol
Data compiled from the literature. This does not constitute medical advice.
| Parameter | Value |
|---|---|
| Dose | 1-3 mg per day (subcutaneous) |
| Frequency | Once daily |
| Timing | Morning, consistent time |
| Duration | Continuous use (chronic treatment for genetic obesity) |
Reported Side Effects
Adverse effects described in the literature. Severity and frequency vary between individuals.
- Injection site reactions
- Hyperpigmentation
- Nausea
- Diarrhea
- Abdominal pain
Product Properties
| Purity | >98% |
| Appearance | White lyophilized powder |
| Solubility | Soluble in water and bacteriostatic water |
| Source | Solid-phase peptide synthesis (SPPS) |
| Storage | Lyophilized: -20°C for up to 2 years, 2-8°C for up to 6 months. Reconstituted: 2-8°C for up to 4 weeks. Protect from light and moisture. Avoid repeated freeze-thaw cycles. |
Presentations & Preparation
Vials of Setmelanotide found in the research market:
Reconstitution
- Diluent: Bacteriostatic water
- Volume: 1 ml per vial
- Inject the diluent slowly against the vial wall
- Gently swirl until completely dissolved — never shake
- Gradual dose escalation recommended (1 mg → 2 mg → 3 mg)
Storage
- Lyophilized: Refrigerated 2-8°C
- Reconstituted: Refrigerated 2-8°C (up to 30 days)
- Protect from direct light
- Do not freeze after reconstitution
Scientific Studies
Published studies on Setmelanotide.
Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial
Argente J, Verge CF, Okorie U, Fennoy I, Kelsey MM, Cokkinias C, Scimia C, Lee HM, Farooqi IS
Efficacy and safety of setmelanotide in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Haqq AM, Chung WK, Dolber T, Haws RM, Mitchell JA, Nissen SE, Rees AH, Sethi M, Stewart M, Yuan G, Clément K
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
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, et al.
Related Peptides
5-Amino-1MQ
50 mg per capsule · 1-2 times daily
Adipotide
0.03 mg/kg body weight (Phase 1 trial starting dose) · Once daily
AICAR
0.1 mg/kg/min by intravenous infusion (CABG trial dose) · Single continuous infusion
AOD 9604
300-600 mcg per injection · Once daily
Cagrilintide
1.2-4.5 mg per week (subcutaneous) · Once weekly
Dulaglutide
0.75-4.5 mg per week (subcutaneous) · Once weekly