Setmelanotide, sold as Imcivree by Rhythm Pharmaceuticals, is a small synthetic peptide that switches on the melanocortin 4 (MC4) receptor in the brain. That receptor is a key part of the circuit that tells the body it has eaten enough. The FDA first approved setmelanotide in November 2020 for severe obesity caused by specific genetic defects in this pathway.
The label has been expanded several times since. In March 2026 the FDA added acquired hypothalamic obesity, the severe weight gain that can follow a tumor, surgery or other damage to the hypothalamus. The single most important fact for readers of this site: the label states setmelanotide would not be expected to work in ordinary (polygenic) obesity, and it is not approved for it.
This page summarizes what the current FDA label, the clinical trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Melanocortin 4 (MC4) receptor agonist; cyclic 8-amino-acid peptide analog of α-MSH |
| Brand / approval | Imcivree (Rhythm Pharmaceuticals), NDA 213793; FDA approval November 25, 2020; EU authorization July 16, 2021 |
| Approved uses (US) | Acquired hypothalamic obesity (age 4 and up); Bardet-Biedl syndrome and POMC, PCSK1 or LEPR deficiency (age 2 and up) |
| Route | Subcutaneous injection, once daily |
| Strength | 10 mg/mL in a 1 mL multiple-dose vial |
| Labeled maintenance dose | 3 mg once daily for ages 6 and up; weight-based in younger children |
| Half-life (label) | About 11 h; peak level about 8 h after injection |
| Signature side effect | Skin darkening (hyperpigmentation), via the MC1 receptor |
| US status | Prescription drug; not a controlled substance |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Setmelanotide (research code RM-493) is an 8-amino-acid cyclic peptide modeled on alpha-melanocyte-stimulating hormone (α-MSH), the body’s own signal at melanocortin receptors. A disulfide bridge closes the peptide into a ring, and two of its building blocks are D-amino acids (mirror-image forms of the natural ones). The label gives its molecular formula as C₄₉H₆₈N₁₈O₉S₂ and its mass as 1117.3 daltons, supplied as the acetate salt (FDA label).
How it works
In the hypothalamus, the leptin-melanocortin pathway links the fat-derived hormone leptin to the MC4 receptor. Signals pass through the leptin receptor (LEPR) and through pro-opiomelanocortin (POMC), the precursor of α-MSH, which activates MC4 receptors to reduce hunger. A break anywhere in this chain causes intense, constant hunger (hyperphagia) and severe obesity starting in early childhood:
- LEPR deficiency: the leptin receptor does not work;
- POMC or PCSK1 deficiency: the body cannot make α-MSH;
- Bardet-Biedl syndrome (BBS): a genetic disorder of cell cilia that may impair signaling in this pathway (Haqq et al., Lancet Diabetes Endocrinol 2022);
- Acquired hypothalamic obesity: the hypothalamus itself is damaged, for example by a tumor affecting it or by surgery or radiation used to treat that tumor (Roth et al., Lancet Diabetes Endocrinol 2024).
Setmelanotide bypasses the broken upstream steps by activating the MC4 receptor directly. According to the label, it has about 20-fold less activity at the MC3 and MC1 receptors. The MC1 receptor sits on pigment cells, and activating it raises melanin production independently of sunlight. This is why skin darkening is the drug’s signature side effect (FDA label).
The library has separate pages on other melanocortin agonists, including Melanotan I, Melanotan II and PT-141 (bremelanotide). Setmelanotide’s label describes it as MC4-focused, with weaker action at MC1 and MC3 receptors.
Pharmacokinetics
From the current label (FDA label):
| Parameter | Value |
|---|---|
| Time to peak (median) | 8 h after subcutaneous injection |
| Effective elimination half-life | About 11 h |
| Time to steady state | Within 2 days of daily dosing (1–3 mg) |
| Accumulation over 12 weeks | About 30% |
| Steady-state peak / trough, 3 mg daily (adults) | 31 ng/mL / 5 ng/mL |
| Apparent volume of distribution | 75.2 L |
| Plasma protein binding | 79.1% |
| Metabolism | Expected to be broken down into small peptides |
| Excreted unchanged in urine | About 39% of the dose over 24 h |
Exposure rises as kidney function falls. Total exposure (AUC) was about 13–15% higher in mild, 34–35% higher in moderate and 86–96% higher in severe renal impairment. Children aged 6 to under 12 had about 88% higher exposure than adults at the same dose. The label found a low potential for drug interactions through liver enzymes (CYP), transporters or protein binding, but no clinical interaction studies have been done.
Approved medical use
The FDA approval history, from FDA approval letters and the Drugs@FDA record:
| Date | Action |
|---|---|
| November 25, 2020 | Original approval: obesity due to POMC, PCSK1 or LEPR deficiency, age 6 and up |
| June 16, 2022 | Bardet-Biedl syndrome added, age 6 and up |
| December 20, 2024 | BBS and POMC/PCSK1/LEPR indications extended to children aged 2 to under 6 |
| March 19, 2026 | Acquired hypothalamic obesity added, age 4 and up |
The current label covers reducing excess body weight and keeping it off long term in (FDA label):
- adults and children aged 4 and up with acquired hypothalamic obesity;
- adults and children aged 2 and up with BBS;
- adults and children aged 2 and up with POMC, PCSK1 or LEPR deficiency, confirmed by a genetic test showing variants read as pathogenic, likely pathogenic or of uncertain significance.
Limitations of use. The label states setmelanotide is not indicated, and would not be expected to be effective, in obesity from POMC, PCSK1 or LEPR variants classified as benign or likely benign, or in other types of obesity, including other genetic syndromes and general (polygenic) obesity.
Labeled dosing
All doses are once daily by subcutaneous injection, at the start of the day, with or without food. The label starts low and titrates up every 2 weeks if tolerated:
| Population | Starting dose | Maintenance dose |
|---|---|---|
| Acquired HO, age 6 and up | 0.5 mg for 2 weeks, then 1 mg, 2 mg (2 weeks each) | 3 mg from week 7 |
| Acquired HO, age 4 to under 6 | 0.5 mg for 2 weeks | Based on body weight |
| BBS or POMC/PCSK1/LEPR, age 12 and up | 2 mg for 2 weeks | 3 mg |
| BBS or POMC/PCSK1/LEPR, age 6 to under 12 | 1 mg for 2 weeks, then 2 mg | 3 mg |
| BBS or POMC/PCSK1/LEPR, age 2 to under 6 | 0.5 mg for 2 weeks | Based on body weight |
The label does not recommend setmelanotide in end-stage kidney disease (eGFR under 15 mL/min/1.73 m²) or in acquired HO with severe renal impairment. For BBS and POMC/PCSK1/LEPR deficiency with severe renal impairment, it sets lower doses (for example, a 1.5 mg maintenance dose for ages 12 and up).
In the European Union, Imcivree has held a marketing authorization since July 16, 2021, and EMA lists indications covering acquired hypothalamic obesity, BBS and POMC, PCSK1 or LEPR deficiency. It has orphan designations for these rare conditions (EMA).
What the research shows
Acquired hypothalamic obesity
The pivotal phase 3 trial, TRANSCEND, was randomized, double-blind and placebo-controlled, with 52 weeks of treatment after a dose-escalation period. In the published report, 120 participants aged 4 to 66 were randomized 2:1 (Miller et al., NEJM 2026). The FDA label analyzes a larger set of 142 patients (94 setmelanotide, 48 placebo) from the same trial (FDA label):
| Outcome at 52 weeks (label analysis) | Setmelanotide (n = 94) | Placebo (n = 48) |
|---|---|---|
| Change in BMI | −15.8% | +2.6% |
| Placebo-adjusted difference | −18.4% (95% CI −21.9 to −14.9) | — |
| At least 5% BMI reduction | 75.8% | 9.7% |
| At least 10% BMI reduction | 61.0% | 4.7% |
| At least 15% BMI reduction | 50.1% | 2.2% |
| Change in maximal daily hunger score (0–10 scale, ages 12 and up) | −2.27 | −1.44 |
The NEJM report found a similar result: BMI fell by 16.5% with setmelanotide versus a 3.3% rise with placebo (p under 0.001). Serious adverse events were reported in 28% vs 8% of participants. The hunger difference was modest (placebo-adjusted −0.82 points on the label’s 11-point scale). The label also notes reductions in waist circumference and numeric improvements in blood pressure, lipids and blood sugar markers.
An earlier 16-week, open-label phase 2 trial in 18 patients aged 6–40 had reported a mean BMI reduction of 15% (Roth et al., Lancet Diabetes Endocrinol 2024).
POMC, PCSK1 and LEPR deficiency
The first human report described two patients with POMC deficiency who lost 51.0 kg over 42 weeks and 20.5 kg over 12 weeks, with lasting reductions in hunger (Kühnen et al., NEJM 2016).
Two identically designed, single-arm, open-label phase 3 trials followed. Each included an 8-week double-blind withdrawal period (4 weeks of drug, then 4 weeks of placebo) for patients who responded (Clément et al., Lancet Diabetes Endocrinol 2020; FDA label):
| Outcome at about 1 year | POMC or PCSK1 (n = 10) | LEPR (n = 11) |
|---|---|---|
| At least 10% weight loss | 80% | 46% |
| Mean weight change | −23.1% (95% CI −31.9 to −14.4) | −9.7% (95% CI −16.0 to −3.3) |
| Median change in daily hunger score (ages 12 and up) | −2.0 | −3.4 |
The withdrawal period showed how dependent the effect is on continued dosing. When responders were switched to placebo, they regained an average of 5.5 kg (POMC/PCSK1) and 5.0 kg (LEPR) within 4 weeks, and lost weight again when setmelanotide was restarted.
Bardet-Biedl syndrome
A phase 3 trial combined a 14-week randomized, double-blind, placebo-controlled period with 52 weeks of open-label treatment (Haqq et al., Lancet Diabetes Endocrinol 2022). In the published primary cohort, 32.3% of BBS patients aged 12 and up lost at least 10% of body weight after 52 weeks. Results in the small group with Alström syndrome were inconclusive, and that condition is not an approved indication.
The FDA label reports these results for patients with BBS (FDA label):
| Outcome | Result |
|---|---|
| BMI change at 14 weeks vs placebo (n = 44) | −4.6% vs −0.1%; placebo-adjusted −4.5% (95% CI −6.5 to −2.5) |
| BMI change after 52 weeks of treatment (n = 31) | −7.9% (95% CI −10.4 to −5.5) |
| At least 5% BMI reduction at 52 weeks | 61.3% |
| At least 10% BMI reduction at 52 weeks | 38.7% |
| Change in daily hunger score, ages 12 and up (n = 14) | −2.12 points |
Young children (age 2 to under 6)
The open-label VENTURE trial treated 12 children aged 2–5 with POMC or LEPR deficiency or BBS for 52 weeks. Mean BMI fell by 18% overall: 26% in the POMC/LEPR group and 10% in the BBS group (Argente et al., Lancet Diabetes Endocrinol 2025). With only 3–5 children per condition and no control group, these figures are imprecise.
General obesity and energy expenditure
Setmelanotide is not approved for common obesity, and the label states it would not be expected to work there. The main human data in people without these conditions come from a small mechanistic study. Twelve healthy adults with obesity received a continuous subcutaneous infusion of 1 mg per 24 h or placebo for 72 hours each, in a randomized crossover design (Chen et al., JCEM 2015):
- resting energy expenditure rose by 6.4% (95% CI 0.68–13.02%), about 111 kcal per day;
- the body shifted toward burning more fat (lower respiratory quotient);
- heart rate and blood pressure did not change.
A 3-day inpatient study cannot show weight loss, and the label states that safety and effectiveness have not been established in this population.
Side effects and risks
Setmelanotide has no boxed warning. Its contraindication is a prior serious hypersensitivity reaction to setmelanotide or any ingredient in the product.
Common side effects
The label lists the most common reactions (20% or more in at least one indication) as skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression and spontaneous penile erection (FDA label).
| Adverse reaction | Acquired HO, setmelanotide (n = 94) | Acquired HO, placebo (n = 48) | POMC/PCSK1/LEPR, open-label (n = 27) |
|---|---|---|---|
| Skin hyperpigmentation | 58% | 10% | 78% |
| Nausea | 55% | 25% | 56% |
| Vomiting | 38% | 19% | 30% |
| Headache | 37% | 31% | 41% |
| New or darkening moles (nevi) | 15% | 6% | 19% |
| Injection site reaction | not in table | not in table | 96% |
| Depression | not in table | not in table | 26% |
| Spontaneous penile erection | 7% | 4% | 23% (of 13 males) |
In the BBS trial’s 14-week placebo-controlled period, hyperpigmentation occurred in 67% of setmelanotide patients versus 0% on placebo.
Skin darkening and moles
Generalized or focal skin darkening occurred in most treated patients and reverses after the drug is stopped. Setmelanotide can also darken existing moles and cause new ones. The label calls for a full-body skin exam before starting and periodically during treatment.
Sexual effects
Spontaneous erections, and more frequent erections, occurred in males; sexual adverse reactions also occurred in females. The label instructs patients to seek emergency care for an erection lasting over 4 hours.
Depression and suicidal thoughts
Depression and suicidal ideation occurred in trials; suicidal ideation was reported in 11% of the 27 patients in the POMC/PCSK1/LEPR trials. People with a history of depression may be at higher risk. The label advises monitoring mood and considering stopping the drug if suicidal thoughts or persistent depression develop.
Hypersensitivity
Serious allergic reactions, including anaphylaxis, have been reported after approval, generally within minutes to hours of an injection.
Risks specific to acquired hypothalamic obesity
These warnings were added with the 2026 indication:
- Acute adrenal insufficiency: in patients with secondary adrenal insufficiency, serious events linked to adrenal crisis occurred in 5% of setmelanotide patients and none on placebo.
- Sodium imbalance: in patients who also have central diabetes insipidus (arginine vasopressin deficiency), low sodium occurred in 6% vs 2% and high sodium in 5% vs 4% on placebo. The label calls for sodium monitoring when fluid intake or hydration changes.
Pregnancy, breastfeeding and other groups
The label advises stopping setmelanotide when pregnancy is recognized unless benefits outweigh risks, because weight loss offers no benefit in pregnancy and may harm the fetus. It is not recommended while breastfeeding. Trials did not include anyone 65 or older.
Antibodies
Across five trials of at least 52 weeks, 1.6% of patients developed antibodies to setmelanotide and 6.9% had antibodies to α-MSH, generally at low levels. Their effect on safety and efficacy is unknown.
Legal status and use outside medicine
Setmelanotide is a prescription drug in the US and is not listed among the DEA’s Schedule III anabolic steroids (21 CFR 1308.13). It is not named on the WADA 2026 Prohibited List.
Interest in setmelanotide for fat loss outside its rare-disease indications is not supported by the evidence. The label’s own limitations of use exclude general obesity. The only data in people without these conditions is a 72-hour metabolic study, and the drug’s weight effect faded quickly when stopped even in the patients it was designed for.
Key takeaways
- A targeted MC4 receptor agonist. Setmelanotide replaces a missing signal in the brain’s leptin-melanocortin satiety pathway rather than acting as a general appetite suppressant.
- Approved only for rare forms of obesity. The label covers acquired hypothalamic obesity (added March 2026), Bardet-Biedl syndrome and POMC, PCSK1 or LEPR deficiency, and excludes general obesity.
- Large effects where the pathway is broken. BMI fell 18.4% more than placebo in acquired hypothalamic obesity, and 80% of POMC/PCSK1-deficient patients lost at least 10% of body weight in a year.
- The effect depends on continued use. Responders regained about 5 kg within 4 weeks on placebo.
- Skin darkening is near-universal. It affected 58–78% of patients in key trials, via MC1 receptors, alongside nausea, injection site reactions, erections and mood effects.
- Daily injection with a short half-life. The half-life is about 11 hours; the label specifies one injection a day, started low and titrated up every 2 weeks.
Sources
- Rhythm Pharmaceuticals. Imcivree (setmelanotide) injection prescribing information, revised 03/2026 (SPL version 14, April 2, 2026). DailyMed.
- Food and Drug Administration. Supplement approval letter, NDA 213793/S-009 (acquired hypothalamic obesity), March 19, 2026. FDA.
- Food and Drug Administration. Supplement approval letter, NDA 213793/S-001 (Bardet-Biedl syndrome), June 16, 2022. FDA.
- Food and Drug Administration. Corrected supplement approval letter, NDA 213793/S-007 (patients aged 2 to under 6), effective December 20, 2024. FDA.
- Food and Drug Administration. Approval letter, NDA 213793 (original approval), November 25, 2020. FDA.
- European Medicines Agency. Imcivree (setmelanotide): EPAR. EMA.
- Miller JL, van Santen HM, Phillips SA, et al. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity. N Engl J Med. 2026;395(2):138–150. PubMed.
- Roth CL, Scimia C, Shoemaker AH, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. 2024;12(6):380–389. PubMed.
- Kühnen P, Clément K, Wiegand S, et al. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016;375(3):240–246. PubMed.
- Clément K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960–970. PubMed.
- Haqq AM, Chung WK, Dollfus H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022;10(12):859–868. PubMed.
- Argente J, Verge CF, Okorie U, et al. Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial. Lancet Diabetes Endocrinol. 2025;13(1):29–37. PubMed.
- Chen KY, Muniyappa R, Abel BS, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100(4):1639–1645. PubMed.
- US Drug Enforcement Administration. Schedules of controlled substances: Schedule III, 21 CFR 1308.13. eCFR.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.