--- title: "Setmelanotide | PepTracker Pro" url: https://peptrackerpro.com/peptides/setmelanotide description: "A once-daily subcutaneous cyclic octapeptide melanocortin-4 receptor (MC4R) agonist, FDA-approved for several rare genetic and acquired forms of obesity that act through the leptin-melanocortin pathway." lang: en --- Skip to main content **Educational information only.** This site does not provide medical advice. Read full disclaimer (https://peptrackerpro.com/disclaimer) **Research-only content.** This page is for educational purposes and does not constitute medical advice. Read full disclaimer → (https://peptrackerpro.com/research-disclaimer) # Setmelanotide High Evidence A once-daily subcutaneous cyclic octapeptide melanocortin-4 receptor (MC4R) agonist, FDA-approved for several rare genetic and acquired forms of obesity that act through the leptin-melanocortin pathway. Aliases Imcivree +3 more Evidence High Evidence Last Updated 2026-07-21 Reading Time 4 min ## What It Is Setmelanotide (brand name Imcivree, developed by Rhythm Pharmaceuticals) is a synthetic cyclic eight-amino-acid peptide that selectively activates the melanocortin-4 receptor (MC4R) in the hypothalamus. MC4R is a central control point of the leptin-melanocortin pathway, the circuit that regulates hunger, satiety and energy expenditure; its natural agonist is alpha-melanocyte-stimulating hormone (alpha-MSH), which is cleaved from pro-opiomelanocortin (POMC). When the pathway upstream of MC4R is broken — for example by loss-of-function variants in POMC, PCSK1 or the leptin receptor (LEPR), or by the higher-order ciliopathy defects of Bardet-Biedl syndrome — patients experience severe, early-onset obesity driven by relentless hyperphagia. Setmelanotide is designed to bypass those upstream defects by directly and potently agonizing MC4R, restoring melanocortin signaling and reducing hunger. Unlike the GLP-1 and GIP incretin peptides that dominate common obesity, setmelanotide treats rare, genetically defined disease and is dosed as a once-daily subcutaneous injection. It was first approved by the U.S. FDA in November 2020 for chronic weight management in patients aged 6 and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing, then in June 2022 for Bardet-Biedl syndrome. In March 2026 the FDA expanded its label to acquired hypothalamic obesity — a rare, severe weight gain that follows injury to the hypothalamus (often after craniopharyngioma or other hypothalamic-pituitary tumors and their treatment) — in adults and children aged 4 and older, based on the phase 3 TRANSCEND trial, which showed a placebo-adjusted BMI reduction of -18.4% at 52 weeks (-15.8% with setmelanotide vs +2.6% with placebo). It is the first and only approved therapy for acquired hypothalamic obesity. Setmelanotide carries warnings for disturbances in sexual arousal, depression and suicidal ideation, and skin hyperpigmentation/darkening of pre-existing nevi, and it is a prescription drug used under specialist supervision — not a self-experimentation research peptide. Also known as: Imcivree, RM-493, BIM-22493, IRC-022493 ## Regulatory Status FDA-approved (2020; expanded 2022 and 2026) for MC4R-pathway and acquired hypothalamic obesity Setmelanotide (Imcivree, Rhythm Pharmaceuticals) was first FDA-approved in November 2020 for chronic weight management in patients aged 6+ with obesity due to genetically confirmed POMC, PCSK1, or LEPR deficiency; expanded in June 2022 to Bardet-Biedl syndrome; and expanded again in March 2026 to acquired hypothalamic obesity in adults and pediatric patients aged 4+. It is a prescription once-daily subcutaneous injection used under specialist supervision, not a compounding-pharmacy research peptide. Effective: June 2026 View FDA Source (https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1) ## Why Researchers Study It Setmelanotide is the leading clinical proof that directly agonizing a single hypothalamic receptor (MC4R) can reverse severe, genetically driven hyperphagia and obesity that does not respond to lifestyle change or general weight-loss drugs. It is studied as a precision-medicine model — matching a targeted peptide to patients whose obesity has a defined molecular cause in the leptin-melanocortin pathway — and increasingly for how far that logic extends, from rare single-gene deficiencies and Bardet-Biedl syndrome to acquired hypothalamic injury and other MC4R-pathway disorders such as Prader-Willi syndrome. ## Proposed Mechanisms - Selectively activates the melanocortin-4 receptor (MC4R), a central regulator of appetite and energy balance, as a synthetic cyclic octapeptide agonist - Mimics the action of the endogenous POMC-derived agonist alpha-melanocyte-stimulating hormone (alpha-MSH) at MC4R - Bypasses upstream defects in the leptin-melanocortin pathway (e.g., POMC, PCSK1, or leptin-receptor loss of function) by acting directly on MC4R neurons - Reduces hyperphagia (pathological hunger) and food intake by restoring downstream melanocortin signaling - Lowers body weight and BMI and improves satiety in MC4R-pathway and acquired hypothalamic obesity - Formulated for once-daily subcutaneous self-injection ## Evidence Snapshot High Evidence Low Medium High | Study Type | Model | Outcome | Link | | --- | --- | --- | --- | | RCT (human, phase 3 — TRANSCEND) | Acquired hypothalamic obesity — adults and children aged 4+, once-daily subcutaneous, 52 weeks | Positive: placebo-adjusted BMI reduction -18.4% at week 52 (-15.8% setmelanotide vs +2.6% placebo); basis for March 2026 FDA approval | Source: https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1 | | Clinical trials (human, phase 3 — POMC/LEPR) | Severe obesity due to POMC or LEPR deficiency — single-arm, open-label, multicentre | Positive: clinically meaningful weight loss and reduced hunger; basis for first FDA approval (2020). Lancet Diabetes Endocrinol 2020 | Source: https://pubmed.ncbi.nlm.nih.gov/33137293/ | | RCT (human, phase 3 — Bardet-Biedl/Alstrom) | Bardet-Biedl syndrome and Alstrom syndrome with obesity | Positive in Bardet-Biedl syndrome: significant reductions in weight and hunger; basis for 2022 FDA approval. Lancet Diabetes Endocrinol 2022 | Source: https://pubmed.ncbi.nlm.nih.gov/36356613/ | | Regulatory review / approvals | POMC/PCSK1/LEPR deficiency (2020), Bardet-Biedl (2022), acquired hypothalamic obesity (2026) | Approved by U.S. FDA across three indications; first and only approved therapy for acquired hypothalamic obesity (March 2026) | Source: https://www.ajmc.com/view/fda-approves-setmelanotide-for-adult-and-pediatric-patients-with-acquired-hypothalamic-obesity | ## Commonly Discussed Benefits Weight Management: https://peptrackerpro.com/benefits/weight-management Appetite Regulation: https://peptrackerpro.com/benefits/appetite-regulation Researching Setmelanotide? Track it, set reminders, and keep notes in the free app. Track in App (https://app.peptrackerpro.com/?add=setmelanotide) ## Safety & Cautions - A prescription drug indicated only for specific, genetically or clinically defined rare obesity (POMC/PCSK1/LEPR deficiency, Bardet-Biedl syndrome, acquired hypothalamic obesity) — not a general weight-loss peptide - Carries warnings for disturbances in sexual arousal (including spontaneous penile erections) and for depression and suicidal ideation; patients should be monitored - Causes skin hyperpigmentation and darkening of pre-existing moles/nevi because MC4R-related melanocortin receptors also affect pigmentation; periodic skin exams are advised - Common adverse effects include injection-site reactions, nausea, headache, and diarrhea - Not established as safe in pregnancy; benefit must be weighed individually and used under specialist endocrinology/obesity-medicine supervision - Requires genetic testing or a defined clinical diagnosis to confirm an appropriate indication before use ## Comparisons See how Setmelanotide compares to related peptides: Setmelanotide vs Avexitide: https://peptrackerpro.com/compare/setmelanotide-vs-avexitide Setmelanotide vs Difelikefalin: https://peptrackerpro.com/compare/setmelanotide-vs-difelikefalin Setmelanotide vs MT-1 (Melanotan I): https://peptrackerpro.com/compare/setmelanotide-vs-mt-1 Setmelanotide vs MT-2 (Melanotan II): https://peptrackerpro.com/compare/setmelanotide-vs-mt-2 Setmelanotide vs Palopegteriparatide: https://peptrackerpro.com/compare/setmelanotide-vs-palopegteriparatide Setmelanotide vs PT-141: https://peptrackerpro.com/compare/setmelanotide-vs-pt-141 Setmelanotide vs Semaglutide: https://peptrackerpro.com/compare/setmelanotide-vs-semaglutide Setmelanotide vs Vosoritide: https://peptrackerpro.com/compare/setmelanotide-vs-vosoritide ## Calculator Tools Use our research tools to explore dosing and reconstitution data: Reconstitution Calculator: https://peptrackerpro.com/calculators ## Citations 1. [1] Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE (setmelanotide) for Patients with Acquired Hypothalamic Obesity (2026) PubMed (https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-approval-imcivreer-1) 2. [2] FDA Approves Setmelanotide for Adult and Pediatric Patients With Acquired Hypothalamic Obesity — AJMC (2026) PubMed (https://www.ajmc.com/view/fda-approves-setmelanotide-for-adult-and-pediatric-patients-with-acquired-hypothalamic-obesity) 3. [3] Clement K et al. — Efficacy and safety of setmelanotide, an MC4R agonist, in severe obesity due to LEPR or POMC deficiency: phase 3 trials. Lancet Diabetes Endocrinol 2020 PubMed (https://pubmed.ncbi.nlm.nih.gov/33137293/) 4. [4] Haqq AM et al. — Efficacy and safety of setmelanotide in Bardet-Biedl syndrome and Alstrom syndrome: phase 3 trial. Lancet Diabetes Endocrinol 2022 PubMed (https://pubmed.ncbi.nlm.nih.gov/36356613/) 5. [5] Setmelanotide — overview (mechanism, MC4R agonism). ScienceDirect Topics PubMed (https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/setmelanotide) 6. [6] Rhythm Pharmaceuticals — New MC4R agonist data in acquired hypothalamic obesity, Bardet-Biedl and Prader-Willi at ENDO 2026 PubMed (https://www.globenewswire.com/news-release/2026/06/15/3312120/0/en/rhythm-pharmaceuticals-announces-multiple-new-data-presentations-from-mc4r-agonists-in-acquired-hypothalamic-obesity-ho-bardet-biedl-syndrome-bbs-and-prader-willi-syndrome-pws-at-e.html) ### Keep researching in the app - Log Setmelanotide to your private tracker - Set a dosing reminder - Compare it side-by-side with your stack Open PepTracker Pro Free: https://app.peptrackerpro.com/?add=setmelanotide Browse more peptides: https://peptrackerpro.com/peptides ## Related Peptides ### Avexitide Medium Evidence A first-in-class once-daily injectable GLP-1 receptor ANTAGONIST (exendin 9-39) from Amylyx for hyperinsulinemic hypoglycemia. 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Its defining property is what it cannot do: the molecule is hydrophilic and bulky enough that it does not meaningfully cross the blood-brain barrier, so it reaches kappa receptors on peripheral sensory nerve endings, keratinocytes and immune cells while leaving the central kappa receptors that produce dysphoria and hallucinations largely untouched. It has no activity at the mu opioid receptor, so it carries neither euphoria nor respiratory depression. In the Phase 3 KALM-1 and KALM-2 trials in hemodialysis patients with moderate-to-severe chronic-kidney-disease-associated pruritus, roughly 40-51% of difelikefalin-treated patients achieved a clinically meaningful (>=3-point) reduction on the 10-point Worst Itching Intensity NRS at 12 weeks versus roughly 20-28% on placebo. The FDA approved intravenous difelikefalin in August 2021; the EU approved it as Kapruvia in April 2022. 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An inert methoxy-PEG carrier is attached to PTH(1-34) through a TransCon linker that auto-cleaves at physiologic pH and temperature, releasing unmodified native-sequence PTH slowly enough to hold hormone levels inside the physiologic range for a full 24 hours. It is the first therapy approved as a true hormone replacement for chronic hypoparathyroidism rather than as an add-on to calcium and active vitamin D: in the Phase 3 PaTHway trial 78.7% of treated adults met a composite endpoint of normal serum calcium plus independence from conventional therapy at week 26, versus 4.8% on placebo. The FDA approved Yorvipath on August 9, 2024. 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First FDA-approved in November 2021 for children 5 and older with open growth plates, its label was expanded in 2023 to cover children under 5 (all ages with open growth plates). In 2026 BioMarin reported new long-term and early-treatment data and advanced a once-weekly successor CNP peptide, BMN 333. Bone Growth: https://peptrackerpro.com/benefits/bone-growth View Details: https://peptrackerpro.com/peptides/vosoritide \+ Compare: https://peptrackerpro.com/compare?select=vosoritide Track in App: https://app.peptrackerpro.com/?add=vosoritide ## Structured data ```json [ { "@context": "https://schema.org", "@type": "Organization", "name": "PepTracker Pro", "url": "https://peptrackerpro.com", "logo": "https://peptrackerpro.com/favicon.png", "description": "Evidence-based educational resource dedicated to improving peptide research literacy.", "contactPoint": { "@type": "ContactPoint", "email": "hello@peptrackerpro.com", "contactType": "customer support" }, "sameAs": [] }, { "@context": "https://schema.org", "@type": "MedicalWebPage", "name": "Setmelanotide", "description": "A once-daily subcutaneous cyclic octapeptide melanocortin-4 receptor (MC4R) agonist, FDA-approved for several rare genetic and acquired forms of obesity that act through the leptin-melanocortin pathway.", "url": "https://peptrackerpro.com/peptides/setmelanotide", "lastReviewed": "2026-07-21", "reviewedBy": { "@type": "Organization", "name": "PepTracker Pro Research Team", "url": "https://peptrackerpro.com" }, "isPartOf": { "@type": "WebSite", "name": "PepTracker Pro", "url": "https://peptrackerpro.com" } }, { "@context": "https://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": 1, "name": "Home", "item": "https://peptrackerpro.com" }, { "@type": "ListItem", "position": 2, "name": "Peptides", "item": "https://peptrackerpro.com/peptides" }, { "@type": "ListItem", "position": 3, "name": "Setmelanotide", "item": "https://peptrackerpro.com/peptides/setmelanotide" } ] }, { "@context": "https://schema.org", "@type": "FAQPage", "mainEntity": [ { "@type": "Question", "name": "People researching MC4R agonists and the leptin-melanocortin pathway in obesity?", "acceptedAnswer": { "@type": "Answer", "text": "Setmelanotide is a research peptide studied in preclinical models. A once-daily subcutaneous cyclic octapeptide melanocortin-4 receptor (MC4R) agonist, FDA-approved for several rare genetic and acquired forms of obesity that act through the leptin-melanocortin pathway." } }, { "@type": "Question", "name": "Patients, families, and clinicians dealing with rare genetic obesity, Bardet-Biedl syndrome, or hypothalamic obesity after brain tumor treatment?", "acceptedAnswer": { "@type": "Answer", "text": "Setmelanotide is a research peptide studied in preclinical models. A once-daily subcutaneous cyclic octapeptide melanocortin-4 receptor (MC4R) agonist, FDA-approved for several rare genetic and acquired forms of obesity that act through the leptin-melanocortin pathway." } }, { "@type": "Question", "name": "Those interested in precision-medicine obesity peptides that work outside the GLP-1/GIP incretin class?", "acceptedAnswer": { "@type": "Answer", "text": "Setmelanotide is a research peptide studied in preclinical models. 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