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This is an approved / prescription medicine. Do not use without a prescription and medical supervision.

EMA-approvedaka Imcivree, RM-493

Setmelanotide — Complete Research Guide (2026)

Last updated 2026-06-30

TL;DR

Setmelanotide (also known as Imcivree) is a peptide catalogued under Cognitive & Nootropic (MC4R agonist). It is described as: MC4R agonist. Documented context: Genetic obesity (POMC/LEPR/PCSK1/BBS). Neutral reference entry; EU status: EU-approved prescription medicine.

What is Setmelanotide?

Setmelanotide (brand name Imcivree) is a synthetic melanocortin-4 receptor (MC4R) agonist given by daily subcutaneous injection.

It is approved by the FDA and EMA for chronic weight management in patients with obesity due to genetically confirmed POMC, PCSK1, or LEPR deficiency, and for Bardet-Biedl syndrome, with approvals extended to younger children.

Its evidence base is human and includes single-arm and placebo-controlled phase 3 trials, but it targets rare monogenic and syndromic obesity, not common obesity.

How does Setmelanotide work?

Setmelanotide activates MC4R in the hypothalamus, a key node of the leptin-melanocortin pathway that regulates hunger and energy expenditure.

In patients whose obesity stems from upstream defects (POMC, PCSK1, LEPR) that impair MC4R signaling, directly stimulating the receptor helps restore satiety signaling and reduce hyperphagia.

What does the research say about Setmelanotide?

  • In single-arm phase 3 trials, most patients with POMC or LEPR deficiency achieved clinically meaningful weight loss and reduced hunger on setmelanotide. [2]
  • In a placebo-controlled phase 3 trial in Bardet-Biedl syndrome, setmelanotide produced greater reductions in weight and hunger than placebo. [3]
  • An early proof-of-concept report showed marked weight loss and appetite normalization in patients with POMC deficiency treated with setmelanotide. [1]

Clinical research & studies

The references below are the primary sources cited throughout this guide. Each links directly to PubMed or the regulator. Where evidence is preclinical (animal or in-vitro), that is stated rather than implied.

  • [1] Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist — Kuhnen P et al., New England Journal of Medicine 2016. (Proof-of-concept clinical report)
  • [2] 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 — Clement K et al., Lancet Diabetes and Endocrinology 2020. (Phase 3 single-arm open-label trials)
  • [3] Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period — Haqq AM et al., Lancet Diabetes and Endocrinology 2022. (Phase 3 randomized placebo-controlled trial)
  • [4] MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency — Clement K et al., Nature Medicine 2018. (Clinical study)
  • [5] Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency — Collet TH et al., Molecular Metabolism 2017. (Clinical evaluation)
  • [6] Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide — Wabitsch M et al., Journal of the Endocrine Society 2022. (Natural-history / observational analysis)

Dosing context

This is not medical advice or a usage recommendation. Dosing figures are reported research context only, cited from the published literature.

In its approved use, setmelanotide is a once-daily subcutaneous injection titrated by a specialist, with continuation depending on a documented weight response after an initial treatment period.

This is regulatory context only; eligibility, dosing, and monitoring are determined by a physician managing a confirmed monogenic or syndromic obesity diagnosis.

Side effects & safety profile

The most commonly reported adverse effects across trials were injection-site reactions, skin hyperpigmentation, nausea, and increased sexual arousal or spontaneous erections, reflecting broader melanocortin-receptor activity.

Because it can darken skin and change naevi, dermatologic monitoring is advised, and it carries warnings around depression or suicidal ideation and use in pregnancy.

It is a specialist prescription medicine requiring genetic confirmation of an eligible diagnosis and clinician supervision, not a general weight-loss drug.

Stacking & combinations

There is no evidence base for combining setmelanotide with other peptides or weight-loss agents outside clinical trials, and any such combination is unstudied and off-label.

Finding Setmelanotide vendors

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Frequently asked questions

It is approved for chronic weight management in people with obesity caused by genetically confirmed POMC, PCSK1, or LEPR deficiency, and for Bardet-Biedl syndrome. It is not approved for common (polygenic) obesity.

References

  1. [1] Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist — Kuhnen P et al., New England Journal of Medicine 2016. PMID: 27468060. View sourceStudy: Proof-of-concept clinical reportSetmelanotide produced substantial weight loss and reduced hunger in patients with POMC deficiency.
  2. [2] 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 — Clement K et al., Lancet Diabetes and Endocrinology 2020. PMID: 33137293. View sourceStudy: Phase 3 single-arm open-label trialsMost patients with POMC or LEPR deficiency achieved clinically meaningful weight loss and reduced hunger.
  3. [3] Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period — Haqq AM et al., Lancet Diabetes and Endocrinology 2022. PMID: 36356613. View sourceStudy: Phase 3 randomized placebo-controlled trialSetmelanotide reduced weight and hunger versus placebo in Bardet-Biedl syndrome.
  4. [4] MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency — Clement K et al., Nature Medicine 2018. PMID: 29736023. View sourceStudy: Clinical studySetmelanotide produced durable weight loss in patients with leptin receptor deficiency.
  5. [5] Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency — Collet TH et al., Molecular Metabolism 2017. PMID: 29031731. View sourceStudy: Clinical evaluationAssessed setmelanotide responses across MC4R-pathway variants, informing which genotypes respond.
  6. [6] Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide — Wabitsch M et al., Journal of the Endocrine Society 2022. PMID: 35528826. View sourceStudy: Natural-history / observational analysisDescribes the severe early-onset obesity course in these deficiencies and setmelanotide's impact.
This article is for educational and research purposes only. Peptides discussed here are not approved for human consumption by the FDA, EMA, or equivalent regulators outside of specific clinical contexts. Always consult a licensed medical professional before any therapeutic use.