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Setmelanotide

What it is. What the evidence says.

A small ring-shaped peptide that switches on the MC4 receptor, a brain signal that tells the body it is full and can burn energy.

Moderate EvidenceApproved Medicine

Predominant research setting. Clinical confidence is claim-specific.

Updated Scientific review pending
Start with the basics Regulatory status ↓
Sequence diagram and chemical structure information for Setmelanotide.
Setmelanotide Chemical Structure & Sequence · Inside Peptides Scientific Library
Compound
Setmelanotide (as acetate)
Human effectiveness
Meaningful weight and hunger reduction in small rare-disease trials and one 120-person randomized trial in hypothalamic obesity; not studied as a general obesity drug
Regulatory status
FDA-Approved Medicine
START HERE · PLAIN LANGUAGE

Setmelanotide: the basics

What is it?

A small ring-shaped peptide that switches on the MC4 receptor, a brain signal that tells the body it is full and can burn energy.

Research paper 1 ↗Research paper 2 ↗Research paper 3 ↗

What do people claim it helps with?

Weight loss and less constant hunger, but only in people whose obesity comes from specific gene changes, Bardet-Biedl syndrome, or damage to the hypothalamus.

What has research actually shown?

In small trials many people with these rare conditions lost at least a tenth of their body weight and felt less hungry. In a larger trial of hypothalamic obesity, BMI fell about 16% versus a rise with placebo.

Research paper 1 ↗Research paper 2 ↗Research paper 3 ↗

Has this been demonstrated in people?

Demonstrated in people, but mostly in small rare-disease trials, several without a full placebo group, plus one 120-person randomized trial.

Research paper 1 ↗Research paper 2 ↗Research paper 3 ↗

What side effects, risks and unknowns should I understand?

Skin and mole darkening, injection-site reactions, nausea, headache, vomiting and diarrhea are common. Spontaneous erections, depression or suicidal thoughts, and serious allergic reactions can occur. Doctors check the skin before and during treatment.

Prescribing information ↗

Is it an approved medicine?

Yes. Imcivree is FDA-approved only for obesity caused by POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome, or acquired hypothalamic obesity. It is not approved for ordinary obesity.

FDA safety information 1 ↗Prescribing information 2 ↗

Approval here means U.S. FDA approval and applies to a particular product, formulation and use. This is a starting overview, not a complete side-effect list. Sources checked 10 October 2026; independent scientific review pending.

How is it used or studied?

Prescription daily injection under the skin, started by a specialist after genetic or medical confirmation of the cause.

Different routes and formulations can have different effects. A study of one product does not validate every product with the same peptide name.

A common misunderstanding

Setmelanotide is not melanotan II or bremelanotide, even though all act on melanocortin receptors. It also differs from GLP-1 medicines such as semaglutide.

What should I ask a clinician?
  • What diagnosis or goal are we trying to address, and what established options are available?
  • Was the expected benefit shown in people like me, using this exact product?
  • How could my medicines, health conditions or pregnancy plans affect the risks?
  • What monitoring is needed, and what would tell us the treatment is helping or should be stopped?
What do the research words mean?
Peptide
A short chain of amino acids, the building blocks of proteins.
Preclinical
Research in cells, tissues or animals before dependable treatment evidence in people.
Controlled trial
A study comparing a treatment with another treatment or a placebo to help separate its effects from other explanations.
Biomarker
A measurement, such as a hormone level. A change does not necessarily mean someone feels better or lives longer.
THE AVAILABLE RESEARCH

Setmelanotide Evidence & Clinical Profile

Human Clinical Evidence

Established Clinical Trials

Setmelanotide has been investigated in clinical contexts. Patient outcomes must be evaluated against study size, design, and control cohorts.

Preclinical & Pharmacological Data

Laboratory & In Vivo Assays

Cellular and animal disease models examine receptor binding affinities and signaling cascades, which require human confirmation.

Understand our evidence labels →

IDENTITY & STRUCTURE

What is Setmelanotide?

Setmelanotide (Imcivree) is Setmelanotide is an 8-amino-acid cyclic peptide that activates the melanocortin-4 (MC4) receptor, a brain switch for hunger and fullness. Sold as Imcivree by Rhythm Pharmaceuticals, it is FDA-approved only for specific causes of severe obesity: genetic POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome, and acquired hypothalamic obesity. It is not expected to work, and is not approved, for common obesity. Aliases include: Imcivree, RM-493, BIM-22493.

Chemical sequence and molecular parameters of Setmelanotide
Primary sequence schematic · Inside Peptides Molecular Database
Chemical reference
Sequence (one-letter)
Ac-R-c[C-dA-H-dF-R-W-C]-NH2
Molecular formula
C49H68N18O9S2
Molecular weight
1117.3 g/mol
CAS Number
920014-72-8
UNII Code
N7T15V1FUY
PubChem CID
11993702

Identifiers are for the free base. The approved medicine contains setmelanotide acetate (UNII 224I1W20I7).

Identifiers checked against PubChem and FDA's Global Substance Registration System on 13 October 2026. FDA substance record ↗ · PubChem record ↗ See all names and codes in the peptide name index.

HUMAN RESEARCH

Clinical Trials & Human Cohorts

Human research can examine tolerability, symptoms or patient outcomes. The design and comparator determine what each result can establish.

Two single-arm, open-label, multicentre Phase 3 trials with a short blinded withdrawal sequence; about 1 year2020

Setmelanotide in severe obesity due to LEPR or POMC deficiency: single-arm, open-label Phase 3 trials [1]

n = 2110 participants with POMC deficiency and 11 with LEPR deficiency, aged 6 and older

What was reported

8 of 10 (80%) in the POMC trial and 5 of 11 (45%) in the LEPR trial lost at least 10% of body weight at about one year; hunger scores also fell.

What limits the conclusion

Very small, mostly open-label, no parallel placebo group. These are ultra-rare conditions, so results cannot be applied to common obesity.

Read primary source ↗ (external website)
14-week double-blind placebo-controlled period followed by 52 weeks of open-label treatment2022

Setmelanotide in Bardet-Biedl syndrome and Alström syndrome: randomised, placebo-controlled Phase 3 trial with open-label period [2]

n = 38Patients aged 6 and older with obesity and Bardet-Biedl syndrome (32) or Alström syndrome (6)

What was reported

After 52 weeks of treatment, 32.3% of Bardet-Biedl patients aged 12 and older lost at least 10% of body weight.

What limits the conclusion

Placebo comparison lasted only 14 weeks; the main endpoint came from the open-label period. Skin darkening occurred in 61%. Alström syndrome is not an approved use.

Read primary source ↗ (external website)
Randomized (2:1), double-blind, placebo-controlled Phase 3 trial; 52 weeks after dose escalation2026

Setmelanotide for the Treatment of Acquired Hypothalamic Obesity [3]

n = 120Ages 4 to 66 with obesity after a hypothalamic tumor, lesion or injury

What was reported

BMI changed by -16.5% with setmelanotide vs +3.3% with placebo at 52 weeks; weekly maximal hunger scores also fell more with setmelanotide.

What limits the conclusion

Serious adverse events were more frequent with setmelanotide (28% vs 8%). Sponsor-run trial in a rare condition; long-term outcomes beyond one year are not yet established.

Read primary source ↗ (external website)
Investigator-initiated open-label case series2016

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist [4]

n = 2Two patients with genetic POMC deficiency

What was reported

Both patients had a sustained fall in hunger and large weight loss.

What limits the conclusion

Two patients only, no control group; an early proof-of-concept report.

Read primary source ↗ (external website)
MECHANISMS OF ACTION

How the compound may work

Mechanisms describe how Setmelanotide may affect biological processes. Laboratory findings and patient outcomes answer different questions.

01
Established pharmacology (U.S. label)

Restoring MC4 receptor signalling

MC4 receptors in the brain help control hunger, fullness and energy use. In POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome and hypothalamic obesity, this pathway is under-activated; setmelanotide acts downstream to switch the receptor on directly. [5]

02
Established pharmacology (U.S. label)

MC1 receptor and skin darkening

Setmelanotide is about 20-fold less active at MC1 and MC3 receptors, but MC1 activation on melanocytes still darkens skin and moles in many patients, independent of sunlight. [5]

RESEARCH AREAS

Areas Being Studied

These research topics reflect active areas of scientific exploration, distinct from unverified commercial marketing claims.

Phase 3 single-arm trials

Monogenic MC4R-pathway obesity

POMC, PCSK1 and LEPR deficiency: ultra-rare, genetically confirmed early-onset obesity. [1]

Phase 3 randomized trial

Syndromic obesity

Bardet-Biedl syndrome (approved) and Alström syndrome (studied, not approved). [2]

Phase 3 randomized trial

Acquired hypothalamic obesity

Obesity that develops after a hypothalamic tumor, lesion or injury. [3]

AT A GLANCE

Compare the study designs.

Overview of Key Setmelanotide Studies: clinical and preclinical records
Study Design / sample Outcome type Key limitation
POMC and LEPR deficiency (Phase 3) · 2020 [1] Two single-arm, open-label, multicentre Phase 3 trials with a short blinded withdrawal sequence; about 1 year
n = 21		 Clinical endpoint evaluation Very small, mostly open-label, no parallel placebo group. These are ultra-rare conditions, so results cannot be applied to common obesity.
Bardet-Biedl syndrome (Phase 3) · 2022 [2] 14-week double-blind placebo-controlled period followed by 52 weeks of open-label treatment
n = 38		 Clinical endpoint evaluation Placebo comparison lasted only 14 weeks; the main endpoint came from the open-label period. Skin darkening occurred in 61%. Alström syndrome is not an approved use.
Acquired hypothalamic obesity (Phase 3) · 2026 [3] Randomized (2:1), double-blind, placebo-controlled Phase 3 trial; 52 weeks after dose escalation
n = 120		 Clinical endpoint evaluation Serious adverse events were more frequent with setmelanotide (28% vs 8%). Sponsor-run trial in a rare condition; long-term outcomes beyond one year are not yet established.
First POMC-deficiency patients · 2016 [4] Investigator-initiated open-label case series
n = 2		 Clinical endpoint evaluation Two patients only, no control group; an early proof-of-concept report.
FDA & SAFETY

Regulatory Status & Clinical Safety

Regulatory Classification

United States, checked 11 October 2026: Imcivree (NDA 213793, Rhythm Pharmaceuticals) is approved to reduce excess body weight and maintain weight reduction long term in patients 2 years and older with Bardet-Biedl syndrome or with POMC, PCSK1 or LEPR deficiency confirmed by genetic testing, and in patients 4 years and older with acquired hypothalamic obesity (added March 2026). The label states it is not indicated for, and would not be expected to work in, other types of obesity, including people whose POMC, PCSK1 or LEPR variants are classified benign or likely benign. Not named on the WADA Prohibited List to our knowledge.

Safety Realities & Impurities

Safety depends on the molecule, formulation, route and evidence. A laboratory purity measurement alone cannot establish safety for human use.

REGISTRY CHECK

Clinical Trials Registry Records

Official registry records from ClinicalTrials.gov. Study registration does not imply government endorsement or guaranteed efficacy.

Phase 3Completed

Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity [9]

Planned enrollment
15 (actual enrollment; the publication reports the 10-person pivotal cohort)
Posted results
Available
Sponsor
Rhythm Pharmaceuticals, Inc.
Last updated
2023-09-21
NCT02896192 · Open registry ↗ (external website)
Phase 3Completed

Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity [10]

Planned enrollment
15 (actual enrollment; the publication reports the 11-person pivotal cohort)
Posted results
Available
Sponsor
Rhythm Pharmaceuticals, Inc.
Last updated
2023-05-23
NCT03287960 · Open registry ↗ (external website)
Phase 3Completed

Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity [11]

Planned enrollment
52 (actual enrollment, including a supplemental cohort)
Posted results
Available
Sponsor
Rhythm Pharmaceuticals, Inc.
Last updated
2023-12-01
NCT03746522 · Open registry ↗ (external website)
COMPETITIVE SPORT

WADA & Anti-Doping Regulations

Not Prohibited

WADA Anti-Doping Status

Setmelanotide is not prohibited under current World Anti-Doping Agency (WADA) regulations. However, athletes must ensure unregulated preparations or unverified vendor products do not violate Section S0 (Non-approved substances). Last verified: October 2026.

SELECTED MILESTONES

Research Timeline

  1. 2016

    First patients reported

    Two people with POMC deficiency show large weight loss and less hunger. [4]

  2. 2020

    FDA approval

    FDA approves Imcivree (NDA 213793) for obesity due to POMC, PCSK1 or LEPR deficiency. [6]

  3. 2022

    Bardet-Biedl syndrome

    FDA adds an indication for patients with Bardet-Biedl syndrome. [7]

  4. 2026

    Hypothalamic obesity

    FDA adds acquired hypothalamic obesity for patients 4 years and older, based on the Phase 3 trial. [8]

OPEN QUESTIONS

What Researchers Still Don't Know

Long-term safety profiles

Multi-year observational data in broader heterogeneous cohorts remains uncharacterized.

Optimal dose-response thresholds

Comparative trials optimizing minimal effective exposure versus adverse event rates.

Formulation bioavailability

Differences between oral, subcutaneous, and modified peptide delivery vehicles.

TRACEABLE SOURCES

References

Primary sources verified against PubMed / NLM and regulatory databases.

  1. Phase 3 single-arm trials

    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 ↗ (external website)

    Clément K et al. · Lancet Diabetes Endocrinol · 2020
  2. Phase 3 RCT

    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 ↗ (external website)

    Haqq AM et al. · Lancet Diabetes Endocrinol · 2022 DOI: 10.1016/S2213-8587(22)00277-7 ↗ (external website)
  3. Phase 3 RCT

    Setmelanotide for the Treatment of Acquired Hypothalamic Obesity ↗ (external website)

    Miller JL et al. · N Engl J Med · 2026 DOI: 10.1056/NEJMoa2512275 ↗ (external website)
  4. Case series

    Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist ↗ (external website)

    Kühnen P et al. · N Engl J Med · 2016 DOI: 10.1056/NEJMoa1512693 ↗ (external website)
  5. Official prescribing information

    Imcivree (setmelanotide) injection, current U.S. label ↗ (external website)

    DailyMed / National Library of Medicine · 2026

    Rhythm SPL published April 2026; checked 11 October 2026.

  6. FDA approval record

    Drugs@FDA: Imcivree, NDA 213793 ↗ (external website)

    U.S. FDA · 2026

    Original approval 25 November 2020.

  7. FDA supplement approval letter

    NDA 213793/S-001 supplement approval: Bardet-Biedl syndrome indication ↗ (external website)

    U.S. FDA CDER · 2022
  8. FDA supplement approval letter

    NDA 213793/S-009 supplement approval: acquired hypothalamic obesity indication ↗ (external website)

    U.S. FDA CDER · 2026
  9. Official registry

    Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity ↗ (external website)

    ClinicalTrials.gov · 2023

    API record checked 11 October 2026.

  10. Official registry

    Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity ↗ (external website)

    ClinicalTrials.gov · 2023

    API record checked 11 October 2026.

  11. Official registry

    Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity ↗ (external website)

    ClinicalTrials.gov · 2023

    API record checked 11 October 2026.

  12. Official registry

    A Trial of Setmelanotide in Acquired Hypothalamic Obesity ↗ (external website)

    ClinicalTrials.gov · 2026

    API record checked 11 October 2026.