Setmelanotide

Summary

Setmelanotide (Imcivree) is an MC4R agonist approved for chronic weight management in adults and children ≥6 years with obesity due to POMC, PCSK1, or LEPR deficiency, or Bardet-Biedl syndrome. It is a cyclic heptapeptide that restores defective melanocortin signaling in rare monogenic or syndromic obesities.

Mechanism of Action

Selectively activates melanocortin-4 receptor (MC4R) in the hypothalamus, restoring leptin receptor signaling pathway activity to reduce hunger and increase energy expenditure, thereby promoting weight loss in patients with specific genetic deficiencies in the leptin-melanocortin pathway.

Routes of Administration

Goals & Uses

• Investigational use in other MC4R pathway deficienciesMetabolic / ObesityModerate
• Weight reduction in Bardet-Biedl syndromeMetabolic / ObesityHigh
• Hyperphagia reductionMetabolic / Appetite ControlHigh
• Weight reduction in POMC/PCSK1/LEPR deficiency obesityMetabolic / ObesityHigh

Contraindications

• Hypersensitivity to setmelanotideAllergicHigh
• Use in obesity not caused by POMC/PCSK1/LEPR deficiency or BBSOff Label UseModerate

Adverse Effects

• Depression/suicidal ideationPsychiatricUncommon
• Injection site reactionsLocalCommon
• Sexual adverse reactionsSexual/ReproductiveUncommon
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• Spontaneous penile erectionsSexual/ReproductiveCommon
• HyperpigmentationDermatologicCommon

Drug Interactions

• Serotonergic agents (e.g., SSRIs)Low
• OpioidsLow

Population Constraints

• PregnancyReproductive SafetyRelative
• Children under 6 yearsPediatricAbsolute
• Renal impairment (severe)RenalRelative

Regulatory Status

• European UnionApprovedApproved: Treatment of obesity and control of hunger associated with POMC, PCSK1, or LEPR deficiency in adults and children ≥6 years, Treatment of obesity associated with Bardet-Biedl syndrome in adults and children ≥6 yearsEMA approved under brand name Imcivree; orphan medicinal product designation.
• United StatesApprovedApproved: Chronic weight management in adults and pediatric patients ≥6 years with obesity due to POMC, PCSK1, or LEPR deficiency, Chronic weight management in adults and pediatric patients ≥6 years with obesity due to Bardet-Biedl syndromeFDA approved November 2020 (POMC/PCSK1/LEPR); expanded June 2022 (BBS). Orphan Drug designation. REMS not required but has boxed warning for depression/suicidal ideation.
• United KingdomApprovedApproved: Obesity due to POMC, PCSK1, or LEPR deficiency, Obesity due to Bardet-Biedl syndromeApproved by MHRA post-Brexit; follows similar indications to EMA approval.

FDA approved in November 2020 for POMC, PCSK1, and LEPR deficiency obesity; expanded approval in June 2022 for Bardet-Biedl syndrome. Orphan drug designation. Not indicated for common obesity.

Evidence & Sources

No sources recorded yet.