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Setmelanotide (RM-493)

Melanocortin-4 receptor (MC4R) agonist

Also known as Imcivree, RM-493

An MC4R agonist approved only for a handful of rare genetic obesity syndromes. A clean example of a real drug with a genuinely tiny eligible population.

Guide updated Sep 2, 2026Literature checked Sep 2, 20261 curated study40 literature recordsBaseline editorial

Overview

In shortA drug for obesity caused by specific, genetically confirmed faults in one appetite pathway. It is in this catalogue as a corrective: it gets cited in general discussion about weight, where the crucial detail quietly disappears, that you need a confirmed genetic diagnosis in a pathway that works normally in almost everyone.

Setmelanotide is a selective MC4R agonist approved for obesity caused by specific, genetically confirmed defects in the leptin-melanocortin pathway: POMC, PCSK1 and LEPR deficiency, and Bardet-Biedl syndrome.

It is in this catalogue as a corrective. It is frequently cited in general discussion of melanocortin agonists and weight, where the crucial detail, that eligibility requires a confirmed genetic diagnosis in a pathway that is intact in almost everyone, quietly disappears.

Mechanism

In shortThe receptor it targets sits downstream of leptin in the brain's appetite pathway. In people with a fault further up that chain, the pathway is under-stimulated no matter how much leptin they have. This switches the receptor back on below the break. That is why it works dramatically in those faults and why there is no strong reason to expect the same in people whose pathway already works.

MC4R sits downstream of leptin signalling in the hypothalamic melanocortin pathway and is central to energy homeostasis. In people with an upstream defect, that pathway is under-stimulated regardless of leptin levels.

Setmelanotide re-activates the receptor downstream of the break. That is why it works dramatically in those specific deficiencies and why there is no strong mechanistic reason to expect the same in people whose pathway is functioning normally.

Evidence

In shortEstablished for its specific uses, absent outside them. In the main trials most participants lost at least 10% of their body weight in a year, with big reductions in hunger. The trials are small because the conditions are very rare, and open-label because randomising against placebo when the genetic cause is known was considered difficult.

Established within its indications, absent outside them. Pivotal open-label trials in POMC and LEPR deficiency reported that a large majority of participants achieved at least 10% weight reduction at a year, with substantial reductions in hunger scores.

Trials are small, because the conditions are very rare, and open-label, because randomising against placebo in a population with a known genetic cause was considered difficult. Those are real limitations even where the effect is large.

There is no adequately powered evidence in common polygenic obesity.

Safety

In shortSkin darkening is common and expected from this receptor family. Injection site reactions, nausea and darkening of existing moles are reported, and skin checks before and during treatment are recommended. Depression and suicidal thoughts have been reported and are on the label. Changes in sexual arousal also occur.

Skin hyperpigmentation is common and expected from MC1R activity. Injection site reactions, nausea, and darkening of existing naevi are reported, with skin examination recommended before and during treatment.

Depression and suicidal ideation have been reported and are part of the labelling. Disturbances in sexual arousal also occur, consistent with central melanocortin signalling.

Regulatory status

In shortApproved in the US and the EU for the named genetic obesity syndromes, with eligibility requiring genetic confirmation. Not approved for obesity in general.

Approved in the United States and the European Union for the named genetic obesity syndromes, with eligibility requiring genetic confirmation. Not approved for obesity generally.

The literature

1 study indexed. Findings and limitations get equal weight, on purpose.

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Everything above is free to read. What an account opens is the evidence underneath it: 1 study with their limitations, and the regimen each trial actually reported.

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The wider literature

15 indexed papers and 25 registered trials mentioning Setmelanotide, straight from PubMed and ClinicalTrials.gov. 25 of 25 administer it; the rest measure it. These have not been read by us. Unlike the studies above, they carry no findings and no limitations written by anyone here, because writing either would mean claiming a reading nobody has done. They are a starting point for yours.

Registered trials (25)

  1. Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)

    Massachusetts General Hospital2026NCT07496463

    interventionalphase2enrolling by invitationn=1

  2. A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)

    Rhythm Pharmaceuticals, Inc.2025NCT06760546

    interventionalphase3recruitingn=39

  3. A Study of Setmelanotide in Patients With Prader-Willi Syndrome

    Rhythm Pharmaceuticals, Inc.2025NCT06772597

    interventionalphase2active not recruitingn=18

  4. Open-Label Extension Study of Setmelanotide

    Rhythm Pharmaceuticals, Inc.2024NCT06596135

    interventionalphase3completedn=28

  5. Real-World Effects of MC4R Agonist Therapy in BBS and Severe Genetic Obesity

    Tom Hühne2023NCT07674290

    interventionalphase4recruitingn=200

  6. A Trial of Setmelanotide in Acquired Hypothalamic Obesity

    Rhythm Pharmaceuticals, Inc.2023NCT05774756

    interventionalphase3active not recruitingn=143

  7. Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity

    Rhythm Pharmaceuticals, Inc.2022NCT04966741

    interventionalphase3completedn=12

  8. Open-Label Study of Setmelanotide in Hypothalamic Obesity

    Rhythm Pharmaceuticals, Inc.2021NCT04725240

    interventionalphase2completedn=18

  9. Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway

    Rhythm Pharmaceuticals, Inc.2021NCT05194124

    interventionalphase3completedn=19

  10. EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway

    Rhythm Pharmaceuticals, Inc.2021NCT05093634

    interventionalphase3completedn=296

  11. Study of Setmelanotide Effects on QTc (Corrected QT) Interval in Healthy Participants

    Rhythm Pharmaceuticals, Inc.2021NCT05046132

    interventionalphase4completedn=77

  12. DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway

    Rhythm Pharmaceuticals, Inc.2021NCT04963231

    interventionalphase2completedn=164

  13. A Phase 1 Study to Evaluate the Pharmacokinetics of Setmelanotide in Subjects With Varying Degrees of Renal Impairment

    Rhythm Pharmaceuticals, Inc.2020NCT04348175

    interventionalphase1completedn=32

  14. Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity

    Rhythm Pharmaceuticals, Inc.2018NCT03287960

    interventionalphase3completedn=15

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

    Rhythm Pharmaceuticals, Inc.2018NCT03746522

    interventionalphase3completedn=52

  16. Long Term Extension Trial of Setmelanotide

    Rhythm Pharmaceuticals, Inc.2018NCT03651765

    interventionalphase2phase3completedn=205

  17. Setmelanotide Phase 2 Treatment Trial in Participants With Rare Genetic Disorders of Obesity

    Rhythm Pharmaceuticals, Inc.2017NCT03013543

    interventionalphase2completedn=213

  18. Setmelanotide in a Single Patient With Partial Lipodystrophy

    Rhythm Pharmaceuticals, Inc.2017NCT03262610

    interventionalphase2completedn=1

  19. Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity

    Rhythm Pharmaceuticals, Inc.2017NCT02896192

    interventionalphase3completedn=15

  20. Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome

    Rhythm Pharmaceuticals, Inc.2015NCT02311673

    interventionalphase2completedn=40

  21. RM-493 Treatment Trial in Proopiomelanocortin (POMC) Deficient Patients

    Charite University, Berlin, Germany2015NCT02507492

    interventionalphase2unknownn=10

  22. Phase 1b/2a Study to Evaluate Safety and Efficacy of Setmelanotide in Obese Patients

    Rhythm Pharmaceuticals, Inc.2014NCT02041195

    interventionalphase1phase2completedn=99

  23. Effects of RM-493 on Energy Expenditure in Obese Individuals

    Rhythm Pharmaceuticals, Inc.2013NCT01867437

    interventionalphase1completedn=15

  24. Phase 2 Study to Evaluate Safety and Efficacy of RM-493 in Obese Participants

    Rhythm Pharmaceuticals, Inc.2013NCT01749137

    interventionalphase2completedn=74

  25. Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RM-493 Administered to Healthy, Obese, Non-diabetic Volunteers

    Rhythm Pharmaceuticals, Inc.2012NCT02431442

    interventionalphase1completedn=57

Papers (15)

  1. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.

    Miller JL, et al.The New England journal of medicine2026PMID 42418774

    journal articlerandomized controlled trialmulticenter studyclinical trial, phase iii

  2. Bardet-Biedl Syndrome.

    Patri JR, et al.2026PMID 42475468

    study guide

  3. Setmelanotide.

    Hussain A, et al.2026PMID 36943959

    study guide

  4. Pharmacotherapy for Obesity: Recent Updates.

    Fredrick TW, et al.Clinical pharmacology : advances and applications2025PMID 40995421

    journal articlereview

  5. Craniopharyngioma - What's next.

    Müller HLPituitary2025PMID 41205018

    editorial

  6. Hypothalamic obesity: from basic mechanisms to clinical perspectives.

    Argente J, et al.The lancet. Diabetes & endocrinology2025PMID 39547253

    journal articlereviewresearch support, non-u.s. gov't

  7. Approach to Obesity Treatment in Primary Care: A Review.

    Yanovski SZ, et al.JAMA internal medicine2024PMID 38466272

    journal articlereviewresearch support, n.i.h., intramural

  8. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.

    Roth CL, et al.The lancet. Diabetes & endocrinology2024PMID 38697184

    journal articleclinical trial, phase iimulticenter studyresearch support, non-u.s. gov't

  9. Pharmacotherapy of obesity: an update on the available medications and drugs under investigation.

    Chakhtoura M, et al.EClinicalMedicine2023PMID 36992862

    journal articlereview

  10. Could setmelanotide be the game-changer for acquired hypothalamic obesity?

    van Santen HM, et al.Frontiers in endocrinology2023PMID 38239988

    randomized controlled trialjournal article

  11. Current Treatments for Patients with Genetic Obesity.

    Faccioli N, et al.Journal of clinical research in pediatric endocrinology2023PMID 37191347

    reviewjournal article

  12. 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.

    Haqq AM, et al.The lancet. Diabetes & endocrinology2022PMID 36356613

    randomized controlled trialmulticenter studyclinical trial, phase iiijournal articleresearch support, non-u.s. gov't

  13. Setmelanotide: First Approval.

    Markham ADrugs2021PMID 33638809

    journal articlereview

  14. 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.

    Clément K, et al.The lancet. Diabetes & endocrinology2020PMID 33137293

    clinical trial, phase iiijournal articlemulticenter studyresearch support, non-u.s. gov't

  15. Setmelanotide.

    2012PMID 39083631

    review

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For Research & Educational Discussion Only. Not Medical Advice

This guide is educational reference material compiled from published literature. It is not medical advice, not a recommendation, and not a substitute for a clinician who knows your history. Nothing here should be used to make a decision about your own health without one.

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