Weight & metabolic
Setmelanotide
Imcivree
Setmelanotide is a melanocortin-4 receptor agonist approved in the US to reduce excess body weight and maintain weight reduction long term in specific rare conditions affecting the MC4R pathway: acquired hypothalamic obesity in patients aged 4 and over, and Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency in patients aged 2 and over. Deficiency must be confirmed by genetic testing showing variants interpreted as pathogenic, likely pathogenic, or of uncertain significance; variants classified as benign or likely benign are excluded. It is explicitly not indicated for general polygenic obesity or obesity from other genetic syndromes. The label carries warnings for serious hypersensitivity including anaphylaxis, depression and suicidal ideation, disturbance in sexual arousal, and skin hyperpigmentation with new or darkening moles.
- Status
- Setmelanotide is approved by the U.S. FDA and has official prescribing information.
- Evidence
- Approved labeling. Official prescribing information exists, based on clinical trials in people.
- Half-life
- Effective elimination half-life approximately 11 hours (human population pharmacokinetics, label section 12.3).
- How it's taken
- Subcutaneous injection.
- Mechanism
- Melanocortin receptor
- Pathways
- Melanocortin
How Setmelanotide works
Setmelanotide is a cyclic peptide agonist of the melanocortin-4 receptor, a node in the hypothalamic pathway regulating hunger, satiety and energy expenditure, with roughly 20-fold weaker activity at the melanocortin-3 and melanocortin-1 receptors. Based on nonclinical evidence, setmelanotide may re-establish MC4 receptor pathway activity in people whose signaling is impaired upstream by genetic variants or hypothalamic injury, reducing food intake and promoting weight loss through decreased caloric intake and increased energy expenditure. Agonism at the MC1 receptor on melanocytes drives melanin accumulation and is the direct cause of the skin hyperpigmentation seen in most treated patients.
What research has looked at
- Primary endpoint, acquired hypothalamic obesity (Trial 1, randomized double-blind placebo-controlled, 142 patients analyzed): mean percent change in BMI at 52 weeks was -15.84 percent on setmelanotide versus +2.55 percent on placebo, a placebo-adjusted difference of -18.40 percent (95 percent CI -21.94 to -14.85, p<0.0001). A supportive responder analysis not controlled for type I error found 61.0 percent achieved at least a 10 percent BMI reduction versus 4.7 percent on placebo.
- Bardet-Biedl syndrome, placebo-controlled portion (Trial 2, 14 weeks, 44 patients): mean BMI change -4.6 percent on setmelanotide versus -0.1 percent on placebo, placebo-adjusted -4.5 percent (95 percent CI -6.5 to -2.5).
- Bardet-Biedl syndrome, uncontrolled open-label active-treatment period (31 patients, no placebo comparator): mean BMI change -7.9 percent at 52 weeks, with 61.3 percent achieving at least a 5 percent and 38.7 percent at least a 10 percent BMI reduction. Five early discontinuers were counted as non-responders.
- POMC or PCSK1 deficiency (Trial 3, open-label single-arm, 10 patients): 80 percent (8 of 10) achieved at least 10 percent weight loss at 1 year, the trial's primary endpoint. LEPR deficiency (Trial 4, open-label single-arm, 11 patients): 46 percent (5 of 11) achieved at least 10 percent weight loss at 1 year. In a blinded withdrawal period, responders regained an average of 5.5 kg and 5.0 kg respectively over 4 weeks off drug.
- Hunger improved modestly versus placebo in hypothalamic obesity patients aged 12 and over: change in weekly average most-hunger score -2.27 versus -1.44 on an 11-point scale, a placebo-adjusted difference of -0.82 points (95 percent CI -1.62 to -0.02, p=0.04).
Evidence level: Approved labeling. Official prescribing information exists, based on clinical trials in people. These are areas studied or reported, not promised effects.
Reported side effects and risks
- Contraindicated after a prior serious hypersensitivity reaction, including anaphylaxis, to setmelanotide or any of its excipients.
- Serious hypersensitivity reactions including anaphylaxis have been reported in treated patients, generally within minutes to hours after injecting. Seek medical attention promptly and discontinue if a hypersensitivity reaction occurs.
- Depression and suicidal ideation have occurred; patients with a history of depression or suicidal ideation may be at increased risk of recurrent episodes. The label directs monitoring for new or worsening depression, suicidal thoughts or behavior, or unusual mood changes, and consideration of discontinuation.
- Disturbance in sexual arousal: spontaneous and increased-frequency penile erections in males (7 percent versus 4 percent on placebo in the hypothalamic obesity trial) and sexual adverse reactions in females; an erection lasting longer than 4 hours requires emergency medical attention.
- Generalized or focal skin hyperpigmentation occurred in the majority of treated patients (58 percent versus 10 percent on placebo in the hypothalamic obesity trial), along with darkening of pre-existing moles and development of new melanocytic nevi (15 percent versus 6 percent). Full-body skin examination is directed before and periodically during treatment. The pigmentation change is reversible on discontinuation.
- In patients with acquired hypothalamic obesity and secondary adrenal insufficiency, serious adverse reactions related to acute adrenal insufficiency occurred in 5 percent of treated patients versus none on placebo; monitor for clinical signs.
- In patients with acquired hypothalamic obesity and concomitant central diabetes insipidus, hyponatremia occurred in 6 percent (versus 2 percent placebo) and hypernatremia in 5 percent (versus 4 percent placebo); monitor serum sodium with changes in fluid intake and hydration.
- Pregnancy: discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Weight loss during pregnancy offers no benefit and may result in fetal harm, including small for gestational age. Not recommended while breastfeeding.
- Renal: not recommended in end stage renal disease, and not recommended in acquired hypothalamic obesity with severe renal impairment. Reduced maintenance dosing applies in the other indications with severe renal impairment.
- Most common reactions (at least 20 percent in at least one indication) were skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Gastrointestinal reactions are most prominent during initiation and titration.
- Evidence quality varies sharply by indication: hypothalamic obesity rests on a randomized placebo-controlled trial, Bardet-Biedl on a short controlled period plus a longer uncontrolled period, and POMC/PCSK1 and LEPR on open-label single-arm trials of about ten patients each. The small open-label results should not be read as precise effect sizes.
Sources
- PubMed research on Setmelanotide · NIH · National Library of Medicine
- DrugBank record for Setmelanotide · DrugBank
- Active clinical trials for Setmelanotide · U.S. National Library of Medicine
Track Setmelanotide in Peptide Vault
Log every dose, set reminders on your own schedule, rotate injection sites and keep your vials organized. Peptide Vault records what you enter. It doesn't recommend compounds or doses. iPhone, on-device.
Related compounds
Setmelanotide FAQ
What is Setmelanotide?
Setmelanotide is a melanocortin-4 receptor agonist approved in the US to reduce excess body weight and maintain weight reduction long term in specific rare conditions affecting the MC4R pathway: acquired hypothalamic obesity in patients aged 4 and over, and Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency in patients aged 2 and over. Deficiency must be confirmed by genetic testing showing variants interpreted as pathogenic, likely pathogenic, or of uncertain significance; variants classified as benign or likely benign are excluded. It is explicitly not indicated for general polygenic obesity or obesity from other genetic syndromes. The label carries warnings for serious hypersensitivity including anaphylaxis, depression and suicidal ideation, disturbance in sexual arousal, and skin hyperpigmentation with new or darkening moles.
How does Setmelanotide work?
Setmelanotide is a cyclic peptide agonist of the melanocortin-4 receptor, a node in the hypothalamic pathway regulating hunger, satiety and energy expenditure, with roughly 20-fold weaker activity at the melanocortin-3 and melanocortin-1 receptors. Based on nonclinical evidence, setmelanotide may re-establish MC4 receptor pathway activity in people whose signaling is impaired upstream by genetic variants or hypothalamic injury, reducing food intake and promoting weight loss through decreased caloric intake and increased energy expenditure. Agonism at the MC1 receptor on melanocytes drives melanin accumulation and is the direct cause of the skin hyperpigmentation seen in most treated patients.
Is Setmelanotide FDA approved?
Yes. Setmelanotide is approved by the U.S. FDA and has official prescribing information. Evidence level: approved labeling. Official prescribing information exists, based on clinical trials in people.
What is the half-life of Setmelanotide?
Reported half-life: Effective elimination half-life approximately 11 hours (human population pharmacokinetics, label section 12.3).
How is Setmelanotide taken?
Subcutaneous injection.
What side effects have been reported with Setmelanotide?
Reported in the sources: Contraindicated after a prior serious hypersensitivity reaction, including anaphylaxis, to setmelanotide or any of its excipients; Serious hypersensitivity reactions including anaphylaxis have been reported in treated patients, generally within minutes to hours after injecting. Seek medical attention promptly and discontinue if a hypersensitivity reaction occurs; Depression and suicidal ideation have occurred; patients with a history of depression or suicidal ideation may be at increased risk of recurrent episodes. The label directs monitoring for new or worsening depression, suicidal thoughts or behavior, or unusual mood changes, and consideration of discontinuation; Disturbance in sexual arousal: spontaneous and increased-frequency penile erections in males (7 percent versus 4 percent on placebo in the hypothalamic obesity trial) and sexual adverse reactions in females; an erection lasting longer than 4 hours requires emergency medical attention; Generalized or focal skin hyperpigmentation occurred in the majority of treated patients (58 percent versus 10 percent on placebo in the hypothalamic obesity trial), along with darkening of pre-existing moles and development of new melanocytic nevi (15 percent versus 6 percent). Full-body skin examination is directed before and periodically during treatment. The pigmentation change is reversible on discontinuation; In patients with acquired hypothalamic obesity and secondary adrenal insufficiency, serious adverse reactions related to acute adrenal insufficiency occurred in 5 percent of treated patients versus none on placebo; monitor for clinical signs; In patients with acquired hypothalamic obesity and concomitant central diabetes insipidus, hyponatremia occurred in 6 percent (versus 2 percent placebo) and hypernatremia in 5 percent (versus 4 percent placebo); monitor serum sodium with changes in fluid intake and hydration; Pregnancy: discontinue when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. Weight loss during pregnancy offers no benefit and may result in fetal harm, including small for gestational age. Not recommended while breastfeeding; Renal: not recommended in end stage renal disease, and not recommended in acquired hypothalamic obesity with severe renal impairment. Reduced maintenance dosing applies in the other indications with severe renal impairment; Most common reactions (at least 20 percent in at least one indication) were skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection. Gastrointestinal reactions are most prominent during initiation and titration; Evidence quality varies sharply by indication: hypothalamic obesity rests on a randomized placebo-controlled trial, Bardet-Biedl on a short controlled period plus a longer uncontrolled period, and POMC/PCSK1 and LEPR on open-label single-arm trials of about ten patients each. The small open-label results should not be read as precise effect sizes.
Educational summary compiled from the sources listed above. Not medical advice. Peptide Vault does not sell, source or recommend any compound. Talk to a qualified clinician before starting or changing anything.