Setmelanotide
Melanocortin-4 receptor (MC4R) agonist
Status
Approved
Approved by the FDA (2020) and EMA (2021) for rare genetic obesities (POMC, PCSK1 or LEPR deficiency and Bardet-Biedl syndrome), and in 2026 in both the US and EU for acquired hypothalamic obesity from age 4.
Evidence
Moderate
Approval rests on small single-arm and randomized-withdrawal trials in ultra-rare genetic obesities plus one randomized placebo-controlled phase 3 trial in acquired hypothalamic obesity.
Setmelanotide is a small cyclic peptide that activates the brain's melanocortin-4 receptor, a key hunger-control switch. It is approved as a daily injection for rare genetic obesities and, since 2026, for obesity caused by damage to the hypothalamus.
Structure
8 residuesPoint at a bead, or focus the chain and use the arrow keys, to name it. Pick a chemistry to highlight it.
D-form (mirror image), shown in lower case
Sequence as text
Ac-R-C-D-Ala-H-D-Phe-R-W-C-NH2
What it is used for
- Obesity due to POMC, PCSK1 or LEPR deficiency (approved)
- Obesity in Bardet-Biedl syndrome (approved)
- Acquired hypothalamic obesity (approved)
How it works
Setmelanotide is an eight-amino-acid cyclic analog of α-MSH that activates the melanocortin-4 (MC4) receptor, which regulates hunger, satiety and energy expenditure in the brain. When the pathway upstream of MC4R is broken (loss of POMC, PCSK1 or the leptin receptor, Bardet-Biedl syndrome, or hypothalamic injury), the brain lacks this signal and hunger is extreme; setmelanotide restores it, reducing food intake. It also weakly activates the MC1 receptor on skin pigment cells, which darkens skin.
How strong the evidence is
Moderate
In single-arm phase 3 trials (Lancet Diabetes & Endocrinology 2020), 8 of 10 people with POMC deficiency and 5 of 11 with LEPR deficiency lost at least 10% of body weight after about a year. In a Bardet-Biedl syndrome trial (2022), 32% of those 12 and older reached at least 10% weight loss at 52 weeks. The randomized TRANSCEND trial in acquired hypothalamic obesity (NEJM 2026; 120 participants) found a 16.5% BMI reduction at 52 weeks versus a 3.3% increase with placebo.
Risks and side effects
- Skin hyperpigmentation, darkening of existing moles and new moles
- Injection-site reactions, nausea and vomiting
- Depression and suicidal thoughts (label warning)
- Disturbances in sexual arousal, including spontaneous erections
- In acquired hypothalamic obesity: acute adrenal insufficiency and sodium imbalance in people with central diabetes insipidus
Label dosing
Label: once-daily subcutaneous injection starting at 0.5 to 2 mg depending on age and indication, titrated to a usual 3 mg daily maintenance dose in patients 6 and older.
Regulatory status
| Region | Year | Approved for |
|---|---|---|
| USFDA | 2020 | Obesity due to POMC, PCSK1 or LEPR deficiency (from age 2 since December 2024) |
| USFDA | 2022 | Obesity due to Bardet-Biedl syndrome |
| USFDA | 2026 | Acquired hypothalamic obesity in adults and children 4 and older |
| EUEMA | 2021 | Obesity due to POMC, PCSK1 or LEPR deficiency, later extended to Bardet-Biedl syndrome |
| EUEMA | 2026 | Acquired hypothalamic obesity in adults and children 4 and older |
Status by country
| Jurisdiction | Status | Source |
|---|---|---|
| USUnited States | Authorised medicine | Source 3 |
| EUEuropean Union | Authorised medicine | Source 9 |
| UKUnited Kingdom | Authorised medicine | Source 10 |
| AUAustralia | No authorised medicine | Source 11 |
| CACanada | Authorised medicine | Source 12 |
Trials of Setmelanotide to watch
Congenital hypothalamic obesity(opens the source in a new tab)
A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
EMANATE(opens the source in a new tab)
EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway
Timeline
2027
2026
- ApprovalFDA approves setmelanotide (Imcivree) for acquired hypothalamic obesity
- Approved, US (FDA)Acquired hypothalamic obesity in adults and children 4 and older
- Approved, EU (EMA)Acquired hypothalamic obesity in adults and children 4 and older
2025
2022
- Approved, US (FDA)Obesity due to Bardet-Biedl syndrome
2021
- Approved, EU (EMA)Obesity due to POMC, PCSK1 or LEPR deficiency, later extended to Bardet-Biedl syndrome
2020
- Approved, US (FDA)Obesity due to POMC, PCSK1 or LEPR deficiency (from age 2 since December 2024)
Sources
- 01Imcivree (setmelanotide) injection: prescribing information(opens the source in a new tab)
- 02Setmelanotide (CID 11993702)(opens the source in a new tab)
- 03Drugs@FDA: Imcivree (NDA 213793) approval history(opens the source in a new tab)
- 04Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency(opens the source in a new tab)
- 05Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE)(opens the source in a new tab)
- 06Efficacy and safety of setmelanotide in patients with Bardet-Biedl syndrome and Alström syndrome(opens the source in a new tab)
- 07Setmelanotide for the Treatment of Acquired Hypothalamic Obesity (TRANSCEND)(opens the source in a new tab)
- 08Rhythm Pharmaceuticals announces FDA approval of Imcivree for patients with acquired hypothalamic obesity(opens the source in a new tab)
- 09Imcivree: EPAR (European public assessment report)(opens the source in a new tab)
- 10IMCIVREE 10 mg/ml solution for injection: Summary of Product Characteristics(opens the source in a new tab)
- 11Australian Register of Therapeutic Goods (ARTG)(opens the source in a new tab)
- 12Drug Product Database: Imcivree (DIN 02537745)(opens the source in a new tab)
Educational information, not medical advice. Talk to a licensed clinician before starting, stopping or changing any medicine.