Setmelanotide
Metabolic
ABOUT
Setmelanotide is an MC4R agonist approved as Imcivree for obesity caused by specific defects in the melanocortin pathway. Its label is narrow by design and it is explicitly not indicated for general obesity.
EVIDENCE OVERVIEW
Supported by controlled human trials
WHAT THIS MEANS
Established. Review the research and limitations before relying on this record.
IDENTITY
HALF-LIFE
HOW IT IS THOUGHT TO WORK
A synthetic cyclic octapeptide MC4R agonist, binding the human MC4 receptor with a Ki of 2.1 nM and activating it with an EC50 of 0.27 nM. It restores signalling downstream of a defective melanocortin pathway. Unlike some earlier MC4R agonists it did not increase blood pressure or heart rate in obese monkeys, which is why it survived development where others did not.
PHARMACOKINETICS
Half-life approximately 10 to 12 hours in humans, given once daily by subcutaneous injection - substantially longer than the endogenous alpha-MSH ligand it substitutes for.
REVIEW
PUBLISHED PAIR RECORDS
with PT-141
Shared melanocortin-receptor activityPT-141 and Setmelanotide are both melanocortin-receptor agonists, so they converge on the same receptor family rather than on separate mechanisms - but they are not interchangeable within it: bremelanotide is comparatively selective, acting principally at MC4 and MC1, and is approved for a single defined indication; setmelanotide is a selective MC4-receptor agonist approved for defined melanocortin-pathway obesity, whose labelling records that no dedicated drug-interaction studies have been conducted. Overlapping activity at MC1 drives pigmentary effects and at MC4 drives appetite, sexual and cardiovascular effects, so which receptors a pair shares determines which effects stack. No study has characterised any two of these given together. Peppy reports curated pharmacology, not a safety verdict. A prescriber or pharmacist should review any intended combination.
Reviewed 21 Aug 2026with Melanotan II
Shared melanocortin-receptor activityMelanotan II and Setmelanotide are both melanocortin-receptor agonists, so they converge on the same receptor family rather than on separate mechanisms - but they are not interchangeable within it: melanotan II is non-selective across melanocortin receptors, has never been submitted for regulatory review, and carries a published case literature of priapism, rhabdomyolysis with acute kidney injury, renal infarction and melanocytic change; setmelanotide is a selective MC4-receptor agonist approved for defined melanocortin-pathway obesity, whose labelling records that no dedicated drug-interaction studies have been conducted. Overlapping activity at MC1 drives pigmentary effects and at MC4 drives appetite, sexual and cardiovascular effects, so which receptors a pair shares determines which effects stack. No study has characterised any two of these given together. Peppy reports curated pharmacology, not a safety verdict. A prescriber or pharmacist should review any intended combination.
Reviewed 21 Aug 2026with Melanotan-1 (MT-1)
Shared melanocortin-receptor activityAfamelanotide and Setmelanotide are both melanocortin-receptor agonists, so they converge on the same receptor family rather than on separate mechanisms - but they are not interchangeable within it: afamelanotide is an MC1-receptor agonist supplied as a bioresorbable implant, approved for erythropoietic protoporphyria, whose labelling records that no drug-interaction studies were conducted and that twice-yearly skin examination is recommended because it darkens existing naevi; setmelanotide is a selective MC4-receptor agonist approved for defined melanocortin-pathway obesity, whose labelling records that no dedicated drug-interaction studies have been conducted. Overlapping activity at MC1 drives pigmentary effects and at MC4 drives appetite, sexual and cardiovascular effects, so which receptors a pair shares determines which effects stack. No study has characterised any two of these given together. Peppy reports curated pharmacology, not a safety verdict. A prescriber or pharmacist should review any intended combination.
Reviewed 21 Aug 2026HUMAN EVIDENCE
FDA-approved in 2020 for obesity due to POMC, PCSK1 or LEPR deficiency, then for Bardet-Biedl syndrome, then extended to children aged 2 and older, and in March 2026 to acquired hypothalamic obesity in patients aged 4 and older. The pivotal POMC and LEPR trials enrolled 21 patients in total against a success criterion of at least 10% mean weight reduction at one year. The 2026 hypothalamic obesity approval was supported by the TRANSCEND trial with a 15.8% BMI reduction.
REPORTED EFFECTS
Common labelled adverse reactions are injection-site reactions (erythema, pruritus, oedema, pain, induration, bruising, hypersensitivity, haematoma), skin hyperpigmentation - expected from melanocortin-receptor activity - nausea, headache, and disturbances in sexual arousal. The only contraindication is prior serious hypersensitivity. The label states it is not indicated for other types of obesity including general polygenic obesity.
RESEARCH LIMITATIONS
This is a source-backed summary, not a recommendation. Read the mechanism, pharmacokinetic, human-evidence and reported-effect fields separately: a mechanism is not an outcome. Availability, legal status and product quality differ by jurisdiction; consult a qualified clinician.
CURATED SOURCES · 3