Setmelanotide

Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure.

• IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged [ see Dosage and Administration (2.1) ]: 4 years and older with acquired hypothalamic obesity (HO) 2 years and older with syndromic or monogenic obesity due to: o Bardet-Biedl syndrome (BBS) o Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged (1): 4 years and older with acquired hypothalamic obsesity (HO).ICD-10: E66.9

• IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions have included anaphylaxis [see Warnings and Precautions (5.3)].contraindicated

Select patients for treatment who have a clinical diagnosis of acquired HO or BBS or who have genetically determined or suspected deficiency of POMC, PCSK1, or LEPR. ( 2.1 ) Recommended starting dosage injected subcutaneously for: Adults and pediatric patients aged 4 years and older with acquired HO is 0.5 mg (0.05 mL) once daily for 2 weeks. ( 2.2 ) Adults and pediatric patients aged 12 years and older with BBS or POMC, PCSK1, or LEPR deficiency is 2 mg (0.2 mL) once daily for 2 weeks. ( 2.3 ) Pediatric patients aged 6 to less than 12 years with BBS or POMC, PCSK1, or LEPR deficiency is 1 mg (0.1 mL) once daily for 2 weeks. ( 2.3 ) Pediatric patients aged 2 to less than 6 years with BBS or POMC, PCSK1, or LEPR deficiency is 0.5 mg (0.05 mL) once daily for 2 weeks. ( 2.4 ) Recommended maintenance dosage for adults and pediatric patients aged 6 years and older for all indications is 3 mg (0.3 mL) injected subcutaneously once daily. ( 2.2 , 2.3 ) Recommended maintenance dose for pediatric patients with acquired HO aged 4 years to less than 6 years and for pediatric patients with BBS or POMC, PCSK1, or LEPR deficiency aged 2 to less than 6 years is determined by body weight. ( 2.2 , 2.3 ) For recommended dosage in patients with renal impairment, see Full Prescribing Information. ( 2.4 ) For titration and administration recommendations, see Full Prescribing Information. ( 2.2 , 2.3 , 2.4 , 2.5 ) 2.1 Patient Selection Acquired HO Select patients for treatment with IMCIVREE who have acquired HO [see Clinical Studies (14.1) ].

Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention. ( 5.1 ) Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. ( 5.2 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE. ( 5.3 ). Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi: Generalized increased skin pigmentation, darkening of pre-existing nevi, and development of new nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmentary lesions. ( 5.4 ) Acute Adrenal Insufficiency in Patients with Acquired HO : Monitor patients for signs of acute adrenal insufficiency. ( 5.5 ) Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus : Monitor patients for signs and symptoms of hyponatremia and hypernatremia. (5.6) 5.1 Disturbance in Sexual Arousal Sexual adverse reactions may occur in patients treated with IMCIVREE.

The following clinically significant adverse reactions are described elsewhere in the labeling: Disturbance in Sexual Arousal [see Warnings and Precautions (5.1)] Depression and Suicidal Ideation [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New Melanocytic Nevi [see Warnings and Precautions (5.4)] Acute Adrenal Insufficiency in Patients with Acquired HO [ see Warnings and Precautions (5.5) ] Sodium Imbalance in Patients with Acquired HO and Central Diabetes Insipidus [ see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥20% in at least 1 indication) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at 1-833-789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Lactation: not recommended when breastfeeding ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. IMCIVREE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. There are no available data with IMCIVREE in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm (see Clinical Considerations). In animal reproduction studies, setmelanotide subcutaneously administered to pregnant rats from before mating to the end of organogenesis was not teratogenic at doses 11 times the maximum recommended human dose (MRHD) of 3 mg. Setmelanotide subcutaneously administered to pregnant rabbits during the period of organogenesis was not teratogenic at clinical doses. Setmelanotide administered subcutaneously to pregnant rats during organogenesis through lactation did not result in adverse developmental effects at doses 7 times the MRHD ( see Data ). The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S.

Metabolism

The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3-mg dose administered subcutaneously once daily was 31 ng/mL, 373 h*ng/mL, and 5 ng/mL, respectively simulated using individual PK model parameters from 109 adult patients with normal renal function. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide.

In the event of an overdose of IMCIVREE, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations and initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.

• Nov 25, 2020NDANDA213793Rhythm

1. 1Nausea7227%
2. 2Off Label Use6826%
3. 3Skin Hyperpigmentation6023%
4. 4Vomiting4116%
5. 5Headache3915%
6. 6Diarrhoea3614%
7. 7Fatigue3513%
8. 8Skin Discolouration3513%
9. 9Decreased Appetite249.1%
10. 10Weight Increased249.1%
11. 11Injection Site Pain228.4%
12. 12Injection Site Erythema218.0%
13. 13Injection Site Pruritus218.0%
14. 14Melanocytic Naevus218.0%
15. 15Drug Ineffective207.6%

The 10 most recently updated of 26 ClinicalTrials.gov registrations naming Setmelanotide as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• A Trial of Setmelanotide in Acquired Hypothalamic Obesity
  Active not recruiting · Phase 3 · Interventional · 143 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT05774756updated 2026-05-29
• Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)
  Not yet recruiting · Phase 2 · Interventional · 1 enrolled · Massachusetts General Hospital
  NCT07496463updated 2026-04-01
• A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
  Recruiting · Phase 3 · Interventional · 39 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT06760546updated 2026-02-12
• A Study of Setmelanotide in Patients With Prader-Willi Syndrome
  Active not recruiting · Phase 2 · Interventional · 18 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT06772597updated 2026-02-12
• EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway
  Active not recruiting · Phase 3 · Interventional · 296 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT05093634updated 2026-02-10
• Open-Label Extension Study of Setmelanotide
  Enrolling by invitation · Phase 3 · Interventional · 30 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT06596135updated 2025-09-04
• DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway
  Completed · Phase 2 · Interventional · 164 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT04963231updated 2025-07-02
• Long Term Extension Trial of Setmelanotide
  Completed · Phase 2 · Phase 3 · Interventional · 205 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT03651765updated 2025-05-31
• Gastric Sleeve-Induced Weight Loss on Shortness of Breath in Obesity
  Withdrawn · Phase 4 · Interventional · 0 enrolled · University of California, Los Angeles
  NCT05812183updated 2025-02-14
• Open-Label Study of Setmelanotide in Hypothalamic Obesity
  Completed · Phase 2 · Interventional · 18 enrolled · Rhythm Pharmaceuticals, Inc.
  NCT04725240updated 2025-02-07

Frequently asked questions

How does Setmelanotide work?

Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure.

What is Setmelanotide used for?

According to FDA labeling, Setmelanotide carries indications including: IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged [ see Dosage and Administration (2.1) ]: 4 years and older with acquired hypothalamic obesity (HO) 2 years and older with syndromic or monogenic obesity due to: o Bardet-Biedl syndrome (BBS) o Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS). IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged (1): 4 years and older with acquired hypothalamic obsesity (HO).. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Setmelanotide?

Setmelanotide is classified as Centrally acting antiobesity products, Melanocortin 4 Receptor Agonist, Melanocortin 4 Receptor Agonists.

What are the brand names for Setmelanotide?

Setmelanotide is marketed under brand names including Imcivree.

What are the contraindications for Setmelanotide?

Setmelanotide labeling lists contraindications including: IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions have included anaphylaxis [see Warnings and Precautions (5.3)].. Always consult the full prescribing information and a clinician.