Melanocortin-4 receptor (MC4R) agonist
Setmelanotide
Approvedaka RM-493, Imcivree
Setmelanotide is a prescription peptide used under medical supervision for chronic weight management in specific rare genetic forms of obesity that disrupt the brain's melanocortin-4 receptor pathway. Approval rests on single-arm, open-label Phase 3 trials in small numbers of genetically defined patients, in which most participants with POMC or PCSK1 deficiency and roughly half of those with LEPR deficiency lost at least 10 percent of body weight over about a year. It is indicated only for genetically or clinically confirmed conditions and is not a general weight-loss medicine.
Mechanism
In plain terms, setmelanotide replaces a missing fullness signal in people whose brain appetite-control pathway is broken by a genetic defect. Technically, it is a synthetic agonist of the melanocortin-4 receptor (MC4R), which normally sits downstream of POMC, PCSK1 and the leptin receptor, and by activating MC4R directly it restores signaling that reduces hunger and increases energy expenditure.
Regulatory Status by Region
- United States (FDA)Approved. Initial U.S. approval November 2020 for chronic weight management in patients with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. The label was later extended to Bardet-Biedl syndrome (2022), to children as young as 2 years (2024), and to acquired hypothalamic obesity in patients 4 years and older (2026).
- Australia (TGA)Not registered on the Australian Register of Therapeutic Goods (ARTG). Any access in Australia would be through unapproved-goods pathways such as the Special Access Scheme.
- European Union (EMA)Authorized. Marketing authorisation valid throughout the EU since 16 July 2021 for weight management in patients 6 years and older with obesity due to POMC, PCSK1 or LEPR deficiency, and Bardet-Biedl syndrome.
- WADANot listed on the WADA Prohibited List and not in the 2026 Monitoring Program (which names only markers of semaglutide and tirzepatide among metabolic agents). An MC4R agonist is not prohibited in or out of competition.
Key Studies
- Pivotal Phase 3 POMC and LEPR deficiency trials (Clement et al.) (opens in a new tab) (Lancet Diabetes Endocrinol 2020;8(12):960-970; DOI 10.1016/S2213-8587(20)30364-8; PMID 33137293; NCT02896192, NCT03287960)
- IMCIVREE (setmelanotide) FDA prescribing information (DailyMed) (opens in a new tab) (Initial U.S. Approval 2020; MC4R agonist; indications for acquired hypothalamic obesity, Bardet-Biedl syndrome, and POMC/PCSK1/LEPR deficiency)
- Phase 3 setmelanotide (RM-493) in early-onset POMC deficiency obesity (ClinicalTrials.gov record) (opens in a new tab) (Rhythm Pharmaceuticals; open-label 1-year Phase 3 with double-blind placebo-controlled withdrawal; NCT02896192)
Related Clinical Trials
- Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)Phase 2 · Not Yet Recruiting
- A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)Phase 3 · Recruiting
- A Study of Setmelanotide in Patients With Prader-Willi SyndromePhase 2 · Active Not Recruiting
- Open-Label Extension Study of SetmelanotidePhase 3 · Enrolling By Invitation
- Gastric Sleeve-Induced Weight Loss on Shortness of Breath in ObesityPhase 4 · Withdrawn
- A Trial of Setmelanotide in Acquired Hypothalamic ObesityPhase 3 · Active Not Recruiting
- Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic ObesityPhase 4 · Recruiting
- Setmelanotide in Pediatric Participants With Rare Genetic Diseases of ObesityPhase 3 · Completed
Latest research
- Current Approaches and Therapeutic Strategies for Hypothalamic Syndrome in Patients with Childhood-onset Craniopharyngioma. (opens in a new tab)
Journal of clinical research in pediatric endocrinology · Jul 1, 2026
Common Questions
- What is Setmelanotide?
- Setmelanotide (Imcivree, Rhythm Pharmaceuticals) is an injectable melanocortin-4 receptor (MC4R) agonist approved for chronic weight management in specific rare genetic forms of obesity. The FDA first approved it in 2020 for obesity due to POMC, PCSK1 or LEPR deficiency, later extending it to Bardet-Biedl syndrome and acquired hypothalamic obesity, and the EMA has authorized it across the EU since July 2021.
- Is Setmelanotide approved for medical use?
- Setmelanotide is approved for one or more medical uses in at least one major jurisdiction. United States (FDA): Approved. Initial U.S. approval November 2020 for chronic weight management in patients with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing. The label was later extended to Bardet-Biedl syndrome (2022), to children as young as 2 years (2024), and to acquired hypothalamic obesity in patients 4 years and older (2026). European Union (EMA): Authorized. Marketing authorisation valid throughout the EU since 16 July 2021 for weight management in patients 6 years and older with obesity due to POMC, PCSK1 or LEPR deficiency, and Bardet-Biedl syndrome. Australia (TGA): Not registered on the Australian Register of Therapeutic Goods (ARTG). Any access in Australia would be through unapproved-goods pathways such as the Special Access Scheme.
- How does Setmelanotide work?
- In plain terms, setmelanotide replaces a missing fullness signal in people whose brain appetite-control pathway is broken by a genetic defect. Technically, it is a synthetic agonist of the melanocortin-4 receptor (MC4R), which normally sits downstream of POMC, PCSK1 and the leptin receptor, and by activating MC4R directly it restores signaling that reduces hunger and increases energy expenditure.
- Is Setmelanotide legal in Australia?
- Setmelanotide in Australia (TGA): Not registered on the Australian Register of Therapeutic Goods (ARTG). Any access in Australia would be through unapproved-goods pathways such as the Special Access Scheme.
- Is Setmelanotide banned in sport?
- Setmelanotide under the World Anti-Doping Agency (WADA) code: Not listed on the WADA Prohibited List and not in the 2026 Monitoring Program (which names only markers of semaglutide and tirzepatide among metabolic agents). An MC4R agonist is not prohibited in or out of competition.