Setmelanotide
aka Imcivree · RM-493 · MC4R agonist
Setmelanotide is a synthetic cyclic peptide that acts as a selective agonist of the melanocortin 4 receptor (MC4R). It was FDA-approved in 2020 under the brand name Imcivree for the treatment of chronic weight management in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing. By restoring MC4R pathway signalling that is disrupted in these rare genetic obesity conditions, setmelanotide reduces hyperphagia and promotes clinically significant weight loss. It represents a precision medicine approach to obesity, targeting the specific molecular defect rather than broadly suppressing appetite. Clinical trials demonstrated sustained weight reduction in the indicated populations with an acceptable safety profile.
Sequence
Mechanism of action
Setmelanotide binds to and activates the melanocortin 4 receptor (MC4R) in the hypothalamus, restoring impaired MC4R signalling that regulates hunger and energy expenditure. In patients with POMC, PCSK1, or LEPR deficiency, normal production of alpha-MSH or its upstream signalling is disrupted, leading to severe hyperphagia and early-onset obesity. Setmelanotide bypasses these upstream defects by directly stimulating MC4R, thereby reducing hunger drive and increasing satiety signalling. This targeted mechanism normalises energy balance in genetically susceptible individuals.
What the evidence actually shows
Setmelanotide has been evaluated in multiple Phase 3 clinical trials demonstrating significant reductions in hunger and body weight in patients with POMC, PCSK1, and LEPR deficiency. The pivotal trials showed that approximately 80% of POMC-deficient patients and 45% of LEPR-deficient patients achieved at least 10% weight loss. FDA approval was granted in 2020 based on robust clinical evidence. Long-term extension studies continue to support sustained efficacy and acceptable safety profiles.
Regulatory status
Pharmacokinetics
Dosing — what backs each figure
Setmelanotide is FDA-approved as IMCIVREE with a fully specified once-daily subcutaneous regimen: a 2-week starting dose that varies by age and indication (0.5 mg, 1 mg or 2 mg) followed by a 3 mg daily maintenance dose, with weight-based dosing in the youngest patients and reductions in severe renal impairment. It is indicated only for acquired hypothalamic obesity, Bardet-Biedl syndrome and genetically confirmed POMC/PCSK1/LEPR deficiency, and the label explicitly excludes general obesity.
Acquired hypothalamic obesity, age 4 and older: 0.5 mg subcutaneously once daily for 2 weeks, then titrate to a 3 mg once-daily maintenance dose (ages 4-6 dosed by body weight)
adults and pediatric patients aged 4 years and older with acquired hypothalamic obesity · subcutaneous
Bardet-Biedl syndrome or POMC/PCSK1/LEPR deficiency: age 12+, 2 mg once daily for 2 weeks then 3 mg maintenance; ages 6-12, 1 mg once daily for 2 weeks then 3 mg maintenance; ages 2-6, 0.5 mg once daily for 2 weeks then a weight-determined maintenance dose. Reduced dosing in severe renal impairment; not recommended in end-stage renal disease
adults and pediatric patients aged 2 years and older with Bardet-Biedl syndrome, or genetically confirmed POMC, PCSK1 or LEPR deficiency · subcutaneous
Handling and storage
No light-protection requirement is stated in the IMCIVREE prescribing information, and no freeze-thaw tolerance is claimed.
Source ↗Safety
References (2)
- Clement K, van den Akker E, Argente J, et al. (2020) 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. ↗The Lancet Diabetes & EndocrinologyPMID 33137293DOI
Two single-arm open-label Phase 3 trials in POMC and LEPR deficiency; the pivotal evidence supporting the original FDA approval of setmelanotide.
- Haqq AM, Chung WK, Dollfus H, Haws RM, et al. (2022) Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. ↗The Lancet Diabetes & EndocrinologyPMID 36356613DOI
Randomised placebo-controlled Phase 3 trial (NCT03746522, 38 patients); 32.3% of patients aged 12 or older with Bardet-Biedl syndrome achieved at least 10% bodyweight reduction after 52 weeks on up to 3.0 mg subcutaneous setmelanotide daily. Results were inconclusive in Alstrom syndrome. Skin hyperpigmentation (61%) and injection-site erythema (48%) were the commonest adverse events.
Data provenance
Chemistry and citations on this page were checked against primary sources on 2026-08-14. Values that could not be verified were left blank rather than filled with a plausible guess.
Could not verify
regulatory.wada, storage.lightSensitive