Setmelanotide: research

A daily injection approved for specific genetic obesity and acquired hypothalamic obesity.

Also called: Imcivree, RM-493, BIM-22493, setmelanotide acetate, CAM4072.

Melanocortin agonists · Melanocortin-4 receptor agonist · Evidence: Approved drug.

At least 28 interventional study records, including ongoing studies; rare-obesity trials support approval. Case reports and secondary analyses overlap.

Studies

Energy use: 72-hour infusion. crossover-rct, n=12, Adults with obesity, without the approved rare conditions. A short infusion raised resting energy use; it did not establish a general weight-loss regimen. (source)
MC4R variants: early dose finding. rct, n=57, Adults with obesity, including eight MC4R variant carriers. Some MC4R variants responded, but this does not support all MC4R variants or general obesity. (source)
First POMC patients. open-label, n=2, Adults with complete POMC deficiency. Two adults with POMC deficiency had large reductions in hunger and weight. (source)
First LEPR patients. open-label, n=3, Severe obesity due to LEPR deficiency. Three LEPR-deficient patients responded during roughly one year of follow-up. (source)
POMC/PCSK1: pivotal trial. open-label, n=10, POMC or PCSK1 deficiency, age ≥6 years. Weight loss varied by genetic defect; selected responders regained weight during placebo withdrawal. (source)
LEPR: pivotal trial. open-label, n=11, LEPR deficiency, age ≥6 years. Weight loss varied by genetic defect; selected responders regained weight during placebo withdrawal. (source)
BBS: first year of treatment. open-label, n=10, Bardet-Biedl syndrome, age ≥12 years. Selected BBS responders maintained weight loss during continued treatment. (source)
BBS and Alström: pivotal trial. rct, n=38, BBS n=32 and Alström n=6; age ≥6 years. BBS showed benefit; the small Alström group did not establish benefit. (source)
Acquired hypothalamic obesity: phase 2. open-label, n=18, Age 6–40 years with acquired hypothalamic injury. Early hypothalamic-obesity results were large but uncontrolled. (source)
VENTURE: ages 2–5. open-label, n=12, POMC/LEPR deficiency n=7 or BBS n=5; age 2–5 years. The trial supported genetic-obesity approvals down to age 2. (source)
TRANSCEND: published cohort. rct, n=120, Acquired hypothalamic obesity, ages 4–66. The randomized trial found substantial BMI and hunger reductions in acquired hypothalamic obesity. (source)
TRANSCEND: full FDA cohort. rct, n=142, Acquired hypothalamic obesity, age ≥4 years. The full regulatory analysis supports the new indication and identifies endocrine safety risks. (source)
Smith-Magenis: no weight benefit. open-label, n=12, Smith-Magenis syndrome, ages 11–39. This study did not show significant weight loss in Smith-Magenis syndrome. (source)
EMANATE: broader genetic obesity. rct, n=296, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Daily versus weekly formulation. pk-study, n=19, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Extension after EMANATE. open-label, n=28, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Prader-Willi: early randomized trial. rct, n=40, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
General obesity: daily and split dosing. rct, n=99, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
DAYBREAK: multiple gene groups. rct, n=164, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Kidney impairment: drug levels. pk-study, n=32, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
QT safety: up to 7 mg daily. pk-study, n=77, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Long-term extension. open-label, n=205, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Lipodystrophy: no metabolic benefit. case-report, n=1, See registry eligibility; enrollment includes all registered cohorts.. One complex lipodystrophy case did not show the hoped-for metabolic benefit. (source)
General obesity: 90-day infusion. rct, n=74, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Pseudohypoparathyroidism: single patient. open-label, n=1, See registry eligibility; enrollment is planned.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Prader-Willi: new open-label study. open-label, n=18, See registry eligibility; enrollment includes all registered cohorts.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Real-world phase 4 study. open-label, n=200, See registry eligibility; enrollment is planned.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
Congenital hypothalamic obesity. rct, n=39, See registry eligibility; enrollment is planned.. Registry results and unpublished studies broaden the evidence beyond the approved indications. (source)
First human ascending doses. pk-study, Healthy adults with obesity. Early exposure studies used an obsolete saline formulation. (source)
Formulation comparison. pk-study, n=22, Healthy adults with obesity. Formulation changes helped support once-daily injection development. (source)
Early daily and weekly formulations. pk-study, n=50, Healthy adults with obesity. Weekly formulations were studied, but the approved product remains once daily. (source)
Adults in routine care. cohort, n=17, BBS n=11, LEPR n=4, POMC n=2. Weight was 20% below highest pretreatment weight within year 1; hunger −62%, craving −41%. (source)
BBS: liver and kidney cohort. cohort, n=26, Genetically confirmed BBS; ages 6.2–51.8. BMI z-score −0.5, 95% CI −0.6 to −0.3; 85% had liver-fat resolution or stabilization at grade S1. (source)
Four children in routine care. case-series, n=4, LEPR or POMC deficiency; ages 3–9. Lower doses were reported effective in POMC than LEPR patients; no common effect size. (source)
POMC: 0.5 mg daily case. case-report, n=1, Five-year-old boy with POMC deficiency. Weight loss 30 kg, 36% below baseline. (source)
SH2B1: adult case. case-report, n=1, 22-year-old with an SH2B1 variant. Weight −5.4% at 3 months, +4% during nonadherence; −19.5% after daily treatment resumed by year 1. (source)
LEPR: age 2 case. case-report, n=1, Child age 2 years 4 months at initiation. BMI and hunger improved; exact effect size not supplied in abstract. (source)
PCSK1 case: overlapping semaglutide. case-report, n=1, Adult woman with PCSK1 N221D heterozygosity; age 40 at her initial 2010 assessment. Weight fell during overlapping setmelanotide and semaglutide use; the effect of either medicine alone cannot be isolated. (source)
ROHHAD: off-label case. case-report, n=1, Boy with ROHHAD syndrome. Weight 97 to 70 kg, −28%; after stopping, weight 70 to 77 kg in 3 months. (source)
Hypothalamic injury after infection. case-report, n=1, 22-month-old child after brain infection. Weight stabilized then fell; strongest clinical response reported at ≥1.25 mg daily. (source)
Post-craniopharyngioma case series. case-series, n=3, Young adults with hypothalamic obesity after surgery. Two lost weight and improved metabolic measures; one stopped after continued weight gain. (source)
Liraglutide followed by setmelanotide. case-report, n=1, 37-year-old man with BBS. Weight −3.4% after liraglutide; −10.5% from original baseline after subsequent setmelanotide. (source)
BBS after kidney transplant. case-series, n=2, Children ages 17 and 8 after kidney transplantation. Boy: 55.6 to 48.0 kg at 12 months. Girl: BMI 38.0 to 42.7 at 8 months despite 3 mg/day. (source)
Skin follow-up to 46 months. cohort, n=5, POMC n=2 and LEPR n=3. Skin darkened in all five; lips and moles also darkened. (source)
Dysplastic moles in a child. case-report, n=1, 12-year-old boy with LEPR deficiency. Two changing moles were removed at 6 months and had dysplastic features. (source)
Eruptive dysplastic moles. case-report, n=1, Published dermatology case; patient details not extracted. Report documents eruptive dysplastic melanocytic moles; no numerical outcome extracted. (source)
BBS: dermatology case. case-report, n=1, Patient with BBS receiving setmelanotide. Diffuse skin darkening prompted a dermatology report. (source)
2023 efficacy meta-analysis. meta-analysis, n=376, Mixed rare-obesity populations; original trials overlap. Pooled estimates need the original population, design and denominator to be interpreted. (source)
MC4R agonist meta-analysis. meta-analysis, Mixed rare-obesity populations; original trials overlap. Pooled estimates need the original population, design and denominator to be interpreted. (source)
Safety meta-analysis and reporting database. meta-analysis, n=185, Mixed rare-obesity populations; original trials overlap. Pooled estimates need the original population, design and denominator to be interpreted. (source)
BBS: matched registry comparison. cohort, n=87, 29 phase 3 participants matched to 58 registry controls. A matched comparison supports BBS benefit but adds no new randomized cohort. (source)
Rare-obesity basket: all ten cohorts. open-label, n=213, Ten rare genetic-obesity cohorts; includes BBS and Smith-Magenis participants reported separately.. Responses varied widely between genetic groups; these exploratory results did not establish new approvals. (source)

Setmelanotide dosage

Typical reported dose: Genetic obesity, age 12+: starts at 2 mg once daily

FDA: genetic obesity, age 12+: 2 mg once daily, then 3 mg once daily once daily, under the skin. Drug label. Studied in: BBS or genetically confirmed POMC, PCSK1 or LEPR deficiency; age ≥12. (source)
FDA: acquired hypothalamic obesity: 0.5 mg once daily, then 1 mg once daily, then 2 mg once daily, then 3 mg once daily once daily, under the skin. Drug label. Studied in: Acquired hypothalamic obesity; age ≥6 years. (source)
FDA: genetic obesity, ages 6–11: 1 mg once daily, then 2 mg once daily, then 3 mg once daily once daily, under the skin. Drug label. Studied in: BBS or POMC, PCSK1 or LEPR deficiency; age 6 to <12. (source)
FDA: young children, baseline weight 15 to <20 kg: 0.5 mg once daily once daily, under the skin. Drug label. Studied in: Baseline weight 15 to <20 kg; genetic obesity age 2–5, or acquired hypothalamic obesity age 4–5. (source)
FDA: young children, baseline weight 20 to <30 kg: 0.5 mg once daily, then 1 mg once daily once daily, under the skin. Drug label. Studied in: Baseline weight 20 to <30 kg; genetic obesity age 2–5, or acquired hypothalamic obesity age 4–5. (source)
FDA: young children, baseline weight 30 to <40 kg: 0.5 mg once daily, then 1 mg once daily, then 1.5 mg once daily once daily, under the skin. Drug label. Studied in: Baseline weight 30 to <40 kg; genetic obesity age 2–5, or acquired hypothalamic obesity age 4–5. (source)

These are doses reported in labels, trials or user reports, not a personal plan. Check the source behind each one.

Work out syringe units with the dosing calculator

Setmelanotide side effects and risks

Reported side effects

Darkening skin: POMC/LEPR/PCSK1: 78% of 27; BBS: 63% of 43; hypothalamic obesity: 58% vs 10% placebo., mild. Skin darkening often fades after stopping; changing moles still need review. (source)
Injection-site reactions: 96% of 27 in genetic deficiency trials; 51% of 43 in BBS; 67% of 12 children ages 2–5., mild. Rotate sites and check persistent painful, hot or spreading redness. (source)
Nausea: Genetic deficiency 56%; BBS 26%; hypothalamic obesity 55% vs 25% placebo., moderate. Dose escalation may need to pause or step back for intolerance. (source)
Vomiting: Genetic deficiency 30%; BBS 19%; hypothalamic obesity 38% vs 19%; ages 2–5: 58%., moderate. Persistent vomiting needs prompt review, especially with adrenal insufficiency or diabetes insipidus. (source)
Headache: Genetic deficiency 41%; hypothalamic obesity 37% vs 31% placebo., mild (source)
Diarrhea: Genetic deficiency 37%; BBS 14%; ages 2–5: 25%., moderate. Check hydration and sodium risk when symptoms persist. (source)
Constipation: Genetic deficiency 11%; hypothalamic obesity 12% vs 6% placebo., mild (source)
New or darker moles: Genetic deficiency 19%; BBS 14%; hypothalamic obesity 15% vs 6% placebo; ages 2–5: 33%., moderate. Arrange a skin review for new or changing pigmented lesions. (source)
Spontaneous erections: Genetic deficiency 23% of 13 males; BBS 25% of 20 males. Hypothalamic obesity label reports 7% vs 4% overall., moderate. An erection lasting more than 4 hours is an emergency. (source)
Depression: 26% of 27 in the open label genetic deficiency safety cohort., serious. Report new or worsening depression promptly; prescriber may stop treatment. (source)
Suicidal thoughts: The reported 11% concerns a 27 person cohort in the dossier. It is not an all patient incidence. Monitor new or worsening depression and suicidal thoughts., serious. Seek emergency help for suicidal thoughts or intent. (source)
Acute adrenal insufficiency: In acquired hypothalamic obesity with secondary adrenal insufficiency: serious events 5% active vs 0% placebo., serious. Urgent care for severe weakness, persistent vomiting, fainting or low blood pressure. (source)
Low or high sodium: In hypothalamic obesity with diabetes insipidus: low sodium 6% vs 2%; high sodium 5% vs 4%, active vs placebo., serious. Confusion, severe drowsiness or seizures need emergency care. (source)
Severe allergic reaction: Anaphylaxis is reported after marketing; its frequency cannot be estimated., serious. Stop and get emergency help for breathing trouble, swelling or fainting. (source)

Stop and get help if

Trouble breathing, swelling of lips or tongue, or fainting after injection: Stop injections and get emergency care for possible anaphylaxis.
Erection lasting longer than 4 hours: Get emergency care now to prevent permanent injury.
Suicidal thoughts, intent or severe new mood changes: Get urgent mental-health help; call emergency services for immediate danger.
Severe weakness, persistent vomiting, fainting or very low blood pressure: With adrenal insufficiency, follow the prescribed emergency steroid plan and get emergency care.
Confusion, severe drowsiness, seizures or severe headache with fluid changes: Get emergency care for possible dangerous sodium imbalance.
New or rapidly changing mole, bleeding pigmented spot or unusual dark lesion: Arrange prompt clinical skin assessment; do not assume every change is harmless tanning.
Low blood sugar that does not recover, confusion or collapse: Get urgent care for persistent low glucose; emergency help is needed for collapse or impaired awareness.

Who should avoid it

pregnant: Label says discontinue when pregnancy is recognized unless benefits outweigh fetal risks; human pregnancy data are absent.
breastfeeding: Use while breastfeeding is not recommended by the label; human milk and infant safety data are absent.
tryingToConceive: This is a precaution. Discuss stopping before trying to conceive; an evidence-based washout interval is unknown.
under18: This is an app rule; FDA approval includes ages ≥2 for genetic obesity and ≥4 for acquired hypothalamic obesity.
melanomaOrAtypicalMoles: The US label calls for skin examinations before and during treatment and monitoring of pigmented lesions. Prior serious hypersensitivity is the formal contraindication.
eatingDisorderHistory: This is a precautionary app rule, not a labeled contraindication.
other: Prior serious allergy to setmelanotide or its ingredients is the labeled contraindication. Anaphylaxis has been reported.
depressionOrSuicidalThoughts: Mood symptoms and suicidal thoughts may occur. Prior depression may raise recurrence risk; monitor during treatment.
kidneyDisease: Severe kidney impairment needs a lower genetic-obesity dose; acquired hypothalamic obesity use is not recommended. Avoid in end-stage kidney disease.
other: US label: not recommended at eGFR <15, or acquired hypothalamic obesity with eGFR 15–29. EU has a different kidney-impairment schedule.
other: Acquired hypothalamic obesity with secondary adrenal insufficiency: serious acute adrenal insufficiency occurred in 5% active versus 0% placebo.
other: Central diabetes insipidus can lead to dangerous sodium changes. Monitor sodium as fluid intake or hydration changes.
diabetes: Reduced food intake may lower insulin needs. One insulin-treated patient had repeated glucose <50 mg/dL.
liverDisease: EU label says do not administer with liver impairment. US label says effects on drug levels are unknown.
testedAthlete: Setmelanotide is not named on the 2026 list. Confirm the product with the athlete’s anti-doping body; no drug-specific ruling was found.

Interactions

Insulin and sulfonylureas: Less food and weight loss may lower dose needs. Hypoglycemia occurred with insulin in one published case; no formal interaction trial exists.
Desmopressin for central diabetes insipidus: In hypothalamic obesity, fluid intake changes may alter sodium control. Monitor sodium and adjust diabetes-insipidus medicines when needed.
Glucocorticoid replacement: Vomiting can prevent steroid absorption in adrenal insufficiency. Review sick-day dosing and emergency steroid plans with the endocrine team.
Other melanocortin agonists: Same-pathway combination data are absent. Added nausea, pigmentation or prolonged erections are plausible; do not assume selective MC4R action prevents them.
GLP-1 and other appetite-lowering medicines: TRANSCEND allowed stable background GLP-1 use; no dedicated combination trial was found. Added nausea and reduced intake may affect hydration and glucose control.
Oral medicines and anticoagulants: No clinical interaction studies were done. A GLP-1-like delayed-stomach-emptying interaction or specific anticoagulant effect has not been established.

Product quality risks

No independent setmelanotide-specific survey of online vial purity, sterility or dose accuracy was located.
General FDA compounding evidence shows risks of contamination and too much or too little active ingredient; no setmelanotide-specific rate is known.
An online powder or pen is not established as equivalent to the approved 10 mg/mL vial.
A purity percentage alone cannot show identity, milligrams per vial, sterility or bacterial-toxin levels.

How Setmelanotide works

It activates MC4 receptors in the brain, which help signal fullness and control energy use. This can bypass some broken hunger signals caused by rare genetic defects or hypothalamic injury. It also activates skin pigment pathways, so skin and moles can darken.

MC4 receptor: Reduces hunger and food intake; may increase energy use.
MC1 receptor: Off-target activity increases skin pigment and can darken moles.

Half-life: Effective elimination half-life about 11 hours.

Gaps: Human-study count is a lower bound: 25 NCT interventional records plus three early studies in EMA, including planned or ongoing records. It is not a count of independent positive trials. The same patients appear in early trials, extension studies, skin reports and later cohorts; published samples must not be added together. The 2026 hypothalamic-obesity paper reports 120 participants; the FDA analysis includes 142 treated participants. Their outcome and safety percentages differ. Genetic-deficiency trial pediatric doses varied by age, country and amendment; not every exact patient-level titration could be recovered. The schema uses weeks. Days 8–10, 11–13 and 14–16 in the QT study overlap calendar weeks and must be read from doseText. FDA Table 4 keeps young children weighing 20–<30 kg at 0.5 mg despite nearby general text naming 1 mg maintenance. The table-specific dose is retained. Seven milligrams daily was studied for 3 days in a QT study. It is not evidence for chronic dosing above the 3 mg daily maintenance maximum. Weekly investigational doses up to 30 mg used a dedicated formulation. They do not validate injecting a week’s worth of the daily vial at once. EMANATE failed all four primary endpoints. Full per-arm outcomes and adverse-event tables were not posted in the registry; sponsor topline data remain separate. Prader-Willi findings depend on trial and dose schedule. Newer uncontrolled sponsor updates do not override the early randomized results. Formal clinical drug-interaction trials, pregnancy outcomes, breastfeeding safety and a preconception washout interval are unavailable. TRANSCEND included stable background GLP-1 use; no dedicated randomized combination trial was located. Evidence for other peptide stacks remains absent. Community prevalence is unknown. Counts refer only to the individual posts examined; protocol suggestions are not verified users. No verified common weight-loss microdosing, split-dose, cycling or stacking schedule was found outside trials; only isolated reports are included. No noncommercial source established powder reconstitution, common water volumes or storage stability for unregulated products. No setmelanotide-specific counterfeit-pen investigation, online-product assay series or poison-center cohort was found. 503A nomination category, setmelanotide-specific PCAC decisions and FDA warning letters were not verified. Approved-component status is not blanket compounding permission. ARTG keyword search found no setmelanotide entry. Broader Australian scheduling coverage remains unresolved despite no named entry in the October 2026 standard. No specific WADA/Global DRO ruling was verified. Absence of a name on the list does not establish every product’s athlete eligibility. Long-term melanoma risk, rare psychiatric harms, growth and puberty effects, and lifelong outcomes need larger, longer studies. A 2023 meta-analysis has inconsistent skin-risk statistics in its abstract. Those estimates are not used for the safety screen. EU and US kidney and liver precautions differ. Regional label schedules must stay separate; lower-dose labels are not interchangeable. The basket registry gives per-cohort response counts. Some individual dose-escalation dates and pediatric country amendments remain unavailable. GLP-1 use was not randomized in TRANSCEND. Baseline exposure does not establish added benefit or safety for any specific combination.

Related to Setmelanotide

Bremelanotide: An as-needed injection for low libido before menopause; nausea is common.
Melanotan II: An unapproved tanning peptide with small human trials and reports of serious harm.
Melanotan I / Afamelanotide: The molecule in an approved EPP implant; online tanning powder is a different formulation.
Semaglutide: A GLP-1 medicine with strong weight, glucose, heart and kidney evidence; dose and formulation matter.
Liraglutide: A daily GLP-1 injection approved for weight management and type 2 diabetes.

Setmelanotide: the short version

Sources

503B Bulk Drug Substances List, FDA · FDA · 2026
Assessment report: IMCIVREE, European Medicines Agency · 2026
Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act, FDA · FDA · 2026
Clinical Review: Imcivree (Setmelanotide), Ginger Winston, FDA · 2026
Compounding and the FDA: Questions and Answers, FDA · FDA · 2026
FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize, FDA · 2026
IMCIVREE_10mg-ml_solution_PIL_UK_M120256AF_ver07b.indd, 2026
IMCIVREE- setmelanotide solution, DailyMed · DailyMed · 2026
IMCIVREE, INN-setmelanotide, European Medicines Agency · 2026
Product Monograph Including Patient Medication Information IMCIVREE, Health Canada · 2026
Pyrogen and Endotoxins Testing: Questions and Answers, FDA · 2026
The 2026 Prohibited List, World Anti-Doping Agency · WADA · 2026
Therapeutic Goods (Poisons Standard—October 2026) Instrument 2026, Australian Government · Australian Government · 2026
IMCIVREE, INN-setmelanotide, European Medicines Agency · 2021
Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, FDA · FDA · 2000

Sources checked: 2026-10-18.

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