Setmelanotide
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Selective MC4R agonist cyclic octapeptide; FDA-approved for chronic weight management in genetic obesity due to POMC, PCSK1, or LEPR deficiency — the first precision medicine for monogenic obesity.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Imcivree, RM-493, BMS-470539 derivative, setmelanotide acetate |
| Category | Metabolic / Melanocortin |
| Sequence | Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2 (cyclic via disulfide bond Cys2-Cys8) |
| Molecular Weight | ~1117 Da |
| Molecular Formula | C49H68N18O9S2 |
| PubChem CID | 90489182 |
| Administration | SubQ (abdomen) |
| Typical Dose Range | 2 mg/day (pediatric 6-12 yrs); 3 mg/day (adolescents and adults) |
| Half-Life | ~11 hours |
| Storage | Refrigerated (2-8C); protect from light |
| FDA Status | Approved (2020) — Imcivree for chronic weight management in patients >=6 years with obesity due to POMC, PCSK1, or LEPR deficiency confirmed by genetic testing |
| WADA Status | Not prohibited (FDA-approved medication for rare genetic condition) |
Mechanism of Action
Setmelanotide is a cyclic octapeptide (8 amino acids) engineered for selective agonism at the melanocortin-4 receptor (MC4R), the central hypothalamic receptor controlling energy balance, appetite, and satiety. It restores melanocortin signaling in patients with genetic defects upstream of MC4R — specifically in the POMC, PCSK1, or LEPR genes.
In the normal leptin-melanocortin pathway: leptin binds its receptor (LEPR) on arcuate nucleus neurons, stimulating POMC expression. POMC is cleaved by PCSK1 (prohormone convertase 1) into alpha-MSH, which then activates MC4R on paraventricular nucleus neurons to promote satiety and increase energy expenditure. Genetic loss of POMC, PCSK1, or LEPR disrupts this cascade, leaving MC4R unstimulated and producing insatiable hunger (hyperphagia) and severe early-onset obesity.
Setmelanotide bypasses all upstream defects by directly activating MC4R, restoring the satiety signal. Unlike bremelanotide (PT-141) and the melanotan peptides (Melanotan 1, Melanotan II), which are non-selective melanocortin agonists acting on MC1R (pigmentation), MC3R, MC4R, and MC5R, setmelanotide was optimized for MC4R selectivity to maximize metabolic effects while minimizing off-target activity. However, some MC1R cross-reactivity persists, explaining the common adverse effect of skin hyperpigmentation (PMID: 33638809).
MC4R signaling in the hypothalamus operates through Gs/cAMP pathways to modulate downstream effectors including BDNF, SIM1, and the melanocortin-responsive circuits controlling food intake, energy expenditure, and glucose homeostasis. Setmelanotide's long half-life (~11 hours) provides sustained receptor activation from a single daily injection.
Critical distinction: Setmelanotide is effective ONLY in patients with confirmed genetic deficiency in the MC4R pathway. It has NOT shown efficacy in common (polygenic) obesity, where MC4R signaling is intact but overridden by other factors (PMID: 35528826).
Key Research Areas
- Pivotal Phase 3 trials in POMC and LEPR deficiency — 80% of POMC/PCSK1-deficient patients and 45% of LEPR-deficient patients achieved >=10% weight loss; mean weight reduction 25.6% and 12.5% respectively (PMID: 33137293)
- MC4R pathway biology and precision medicine — Establishes the melanocortin-4 receptor as a validated drug target for genetically defined obesity, with implications for understanding the broader melanocortin peptide family (PT-141, KPV, Melanotan 1, Melanotan II) (PMID: 33638809)
- Natural history of MC4R pathway defects — Characterization of POMC, PCSK1, and LEPR deficiency phenotypes and the impact of targeted MC4R agonism on disease trajectory (PMID: 35528826)
- Hunger reduction — Patient-reported hunger scores improved significantly, often preceding measurable weight loss, highlighting the satiety-restoring mechanism
- Expanded indications — VENTURE trial evaluating children 2-5 years; ongoing studies in Bardet-Biedl syndrome and Alstrom syndrome (other genetic obesity syndromes with MC4R pathway involvement)
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Systematic reviews | 0 | — |
| Human RCTs | 1 | Phase 3 pivotal trials (POMC + LEPR cohorts) |
| Human observational | 0 | — |
| Animal in vivo | 0 | — |
| In vitro | 0 | — |
| Narrative reviews | 2 | Drug approval review + natural history review |
Clinical Applications
- Weight Management — Chronic weight management in genetically confirmed POMC, PCSK1, or LEPR deficiency obesity (FDA-approved)
- Bardet-Biedl syndrome — Under investigation (expanded genetic indications)
- Hypothalamic obesity — Under investigation
Protocols Using This Peptide
- No current vault protocols use setmelanotide (FDA-approved precision medication for rare genetic conditions, not a general research peptide)
Ageless Peps Products
- Not sold by Ageless Peps. Setmelanotide is an FDA-approved prescription medication (Imcivree) requiring genetic confirmation of POMC, PCSK1, or LEPR deficiency. Available only through specialty pharmacies with genetic testing prerequisite.
Dosing Reference
FDA-Approved Dosing
| Indication | Dose | Route | Frequency | Duration | Source |
|---|---|---|---|---|---|
| Genetic obesity (adults, adolescents >=12 yrs) | 3 mg | SubQ | Once daily | Ongoing | FDA label |
| Genetic obesity (pediatric 6-11 yrs) | 2 mg | SubQ | Once daily | Ongoing | FDA label |
| Genetic obesity (pediatric 2-5 yrs) | 1 mg titrated to 2 mg | SubQ | Once daily | Ongoing | VENTURE trial |
Cycling
Setmelanotide is administered continuously; it does not address the underlying genetic defect but provides ongoing MC4R activation to substitute for the missing endogenous signal. Discontinuation results in resumption of hyperphagia and weight regain, consistent with a pathway-replacement rather than disease-modifying mechanism.
Contraindications & Safety
- Contraindications: No efficacy in patients without confirmed genetic deficiency in POMC, PCSK1, or LEPR; not indicated for common obesity
- Boxed warning: None
- Common side effects: Injection site reactions (45%), skin hyperpigmentation (40%, due to residual MC1R activity), nausea, diarrhea, abdominal pain
- Hyperpigmentation: Expected pharmacological effect from MC1R cross-activation; generally cosmetically significant but not medically harmful; may darken existing nevi (monitoring recommended)
- Sexual adverse effects: Spontaneous penile erections reported in some male patients (MC4R-mediated, same pathway as bremelanotide/PT-141); depression/suicidal ideation monitoring recommended per label
- Drug interactions: No clinically significant drug interactions documented
- Pregnancy/nursing: Not recommended (insufficient data); effective contraception advised
- Special populations: Requires genetic testing before prescribing; renal/hepatic impairment data limited
Synergistic Combinations
- Setmelanotide is used as monotherapy for its genetic indications
- Cross-reference to melanocortin pharmacology: Understanding setmelanotide's selective MC4R agonism helps contextualize other melanocortin-active peptides in the vault:
- PT-141 (bremelanotide) — MC4R/MC1R agonist optimized for sexual function
- Melanotan 1 (afamelanotide) — MC1R agonist for erythropoietic protoporphyria
- Melanotan II — Non-selective melanocortin agonist (MC1R-MC5R)
- KPV — C-terminal alpha-MSH fragment with anti-inflammatory (NF-kB) activity
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 33137293 | Setmelanotide Phase 3 Trials: POMC and LEPR Deficiency Obesity | 2020 | RCT |
| 33638809 | Setmelanotide: First Approval | 2021 | Narrative Review |
| 35528826 | Natural History of POMC/PCSK1/LEPR Deficiency and Setmelanotide Impact | 2022 | Narrative Review |
References
- PMID: 33137293 — Clement et al., Lancet Diabetes Endocrinol 2020 (Phase 3 trials)
- PMID: 33638809 — Markham, Drugs 2021 (first approval review)
- PMID: 35528826 — Argente et al., J Endocr Soc 2022 (natural history)
Related
- Peptide Index
- Condition Index
- Research Index
- PT-141 — Related melanocortin receptor agonist (sexual function)
- Melanotan 1 — MC1R agonist
- Melanotan II — Non-selective melanocortin agonist
- KPV — Alpha-MSH fragment
#peptide #metabolic #fda-approved #not-sold #subq