Setmelanotide (Imcivree)
Setmelanotide acetate (RM-493; trade name IMCIVREE)
Setmelanotide (IMCIVREE) is an FDA-approved cyclic peptide MC4R agonist used specifically for chronic weight management in adults and pediatric patients with severe obesity caused by specific genetic defects in the leptin-melanocortin pathway, including POMC, PCSK1, and LEPR deficiencies and Bardet-Biedl syndrome. It is not indicated for general (polygenic) obesity.
Last updated: 2026-03-13
Safety Summary
Side effects are generally mild to moderate and often transient, with nausea/vomiting tending to resolve within the first month of treatment. Skin hyperpigmentation is the most characteristic effect (mediated by residual MC1R agonism) and is reversible upon discontinuation, occurring in up to 83% of patients. The psychiatric warnings (depression 26%, suicidal ideation 11% in POMC/PCSK1/LEPR population) are labeled as Warnings and Precautions, requiring active monitoring especially in patients with psychiatric history. Spontaneous penile erection (~25% of males, similar to PT-141/bremelanotide) is a known pharmacologic effect requiring patient counseling. Post-marketing pharmacovigilance (FAERS, 93 cases 2020-2024) showed mostly mild adverse events with no reported deaths. Anti-drug antibodies have been detected including antibodies to endogenous alpha-MSH, but clinical significance is unclear. No evidence of abuse potential or dependence. No significant drug-drug interactions identified (no CYP metabolism).
Known Side Effects
Very common (63% BBS >=6y; 78% POMC/PCSK1/LEPR >=6y; 83% pediatric 2-<6y)
Very common (51% BBS >=6y; 96% POMC/PCSK1/LEPR >=6y; 67% pediatric 2-<6y)
Common (26% BBS >=6y; 56% POMC/PCSK1/LEPR >=6y)
Common (19% BBS >=6y; 30% POMC/PCSK1/LEPR >=6y; 58% pediatric 2-<6y)
Common (14% BBS >=6y; 37% POMC/PCSK1/LEPR >=6y; 25% pediatric 2-<6y)
Common (33% POMC/PCSK1/LEPR >=6y)
Common (7% BBS >=6y; 41% POMC/PCSK1/LEPR >=6y)
Common (25% BBS male >=6y; 23% POMC/PCSK1/LEPR male >=6y; 8% pediatric 2-<6y)
Common (26% POMC/PCSK1/LEPR >=6y)
Uncommon (11% POMC/PCSK1/LEPR >=6y)
Common (14% BBS >=6y; 19% POMC/PCSK1/LEPR >=6y; 33% pediatric 2-<6y)
Common (5% BBS >=6y; 30% fatigue / 19% asthenia POMC/PCSK1/LEPR >=6y)
Rare (postmarketing reports)
Who Should NOT Use This
Serious hypersensitivity reactions including anaphylaxis have been reported. Contraindicated per FDA label.
IMCIVREE contains 10 mg/mL benzyl alcohol preservative which can cause fatal 'gasping syndrome' in neonates. Not approved for this population.5).
Approximately 39% of setmelanotide is excreted unchanged in urine. Increased drug exposure in renal impairment. Not recommended in ESRD.5)
Per FDA label, discontinue in pregnancy unless benefits outweigh risks. No adequate human data.
Insufficient data on presence in breast milk. Avoid breastfeeding during treatment.
Depression (26%) and suicidal ideation (11%) occurred in clinical trials. Patients with psychiatric history may be at increased risk. Monitor closely; consider discontinuation if symptoms occur.2).
IMCIVREE is not expected to be effective in general obesity or obesity associated with other genetic syndromes not involving the MC4R pathway. Per Limitations of Use in FDA label.
Talk to Your Doctor
Before considering Setmelanotide (Imcivree), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-14]
Evidence Assessment
FDA-approved medication (IMCIVREE, November 2020, NDA 213793, New Molecular Entity, Priority Review, Orphan Drug). Initial approval for POMC/PCSK1/LEPR deficiency obesity in patients >=6 years. Supplemental approval for BBS (June 2022). Expanded to patients >=2 years (December 2024). Also EMA-approved (July 2021) and Health Canada-approved (May 2023). Multiple completed Phase 3 trials with published results in Lancet Diabetes & Endocrinology. Specifically indicated for genetic/syndromic obesity; not approved for general/lifestyle obesity
1Efficacy 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 trialsNCT03287960 / NCT02896192PMID 33137293
Clement K, van den Akker E, Argente J, et al. - Lancet Diabetes & Endocrinology (2020) - Phase 3, single-arm, open-label, multicentre - 21 (POMC n=10, LEPR n=11)
POMC deficiency: 80% achieved >=10% weight loss at ~1 year, mean weight change -25.6%, hunger score reduction -27% (p=0.0005). LEPR deficiency: 45% achieved >=10% weight loss, hunger reduction -44% (p<0.0001). Supported initial FDA approval.
Limitations: Very small sample sizes due to disease rarity. Single-arm design without placebo control. Industry-sponsored (Rhythm Pharmaceuticals). Limited diversity.
2Efficacy 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 periodNCT03746522PMID 36356613
Haqq AM, Chung WK, Dolber T, et al. - Lancet Diabetes & Endocrinology (2022) - Phase 3, randomized, double-blind, placebo-controlled with open-label extension - 38 BBS patients (44 total including Alstrom)
BBS: 32.3% of patients >=12y achieved >=10% weight loss at 52 weeks (95% CI 16.7-51.4%, p=0.0006 vs historical). Mean weight change -6.2% (p<0.0001). Mean hunger score reduction -30.8% (p<0.0001). 60% achieved >=25% hunger reduction. Alstrom syndrome results inconclusive (small n).
Limitations: Small sample (n=38 BBS). Short placebo-controlled period (14 weeks) followed by open-label. Industry-sponsored. Limited long-term data. Heterogeneous population.
3Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trialNCT04966741
Not extracted - Lancet Diabetes & Endocrinology (2024) - Phase 3, open-label, multicentre - 12
83% achieved >=0.2 BMI z-score reduction. Mean BMI reduction -18% to -26%. Supported FDA expansion to patients >=2 years (Dec 2024). High vomiting rate (58%) in this young population.
Limitations: Very small sample (n=12). Open-label, no control group. Mixed genetic etiologies.
4Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trialNCT04725240
Not extracted - Lancet Diabetes & Endocrinology (2024) - Phase 2, open-label, multicentre - 18
44% of patients achieved >=5% BMI reduction at 16 weeks. Supported advancement to Phase 3 TRANSCEND trial.
Limitations: Small sample (n=18). Open-label, no placebo control. Short duration.
5TRANSCEND: A Trial of Setmelanotide in Acquired Hypothalamic ObesityNCT05774756
Rhythm Pharmaceuticals (sponsor) (2026) - Phase 3 - ~120 (estimated)
Topline/expanded data released March 2026 reporting clinically meaningful BMI and hunger improvements. sNDA under FDA review with PDUFA date March 20, 2026.
Limitations: Full results not yet published at time of data collection.
6Long Term Extension Trial of SetmelanotideNCT03651765
Rhythm Pharmaceuticals (sponsor) - Phase 2/3 long-term extension - Not extracted
Completed. Provided long-term safety and efficacy data. Generally well-tolerated over extended treatment periods with no new safety signals.
Limitations: Open-label extension without placebo control.
7DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the MC4R PathwayNCT04963231
Rhythm Pharmaceuticals (sponsor) - Phase 2 - Not extracted
Completed. Explored efficacy in broader MC4R-pathway gene variants beyond approved indications.
Limitations: Details not fully extracted.
8A Study of Setmelanotide in Patients With Prader-Willi SyndromeNCT06772597
Rhythm Pharmaceuticals (sponsor) - Phase 2 - Not extracted
Active, not recruiting. Exploring setmelanotide in Prader-Willi syndrome.
Limitations: Ongoing; no results available.
9A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study)NCT06759546
Rhythm Pharmaceuticals (sponsor) - Phase 3 - Not extracted
Recruiting. Investigating setmelanotide in congenital hypothalamic obesity.
Limitations: Ongoing; no results available.
10EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R PathwayNCT05093634
Rhythm Pharmaceuticals (sponsor) - Phase 3 - Not extracted
Active, not recruiting. Continuing investigation of setmelanotide in MC4R pathway disorders.
Limitations: Ongoing.
11Efficacy and Safety of Setmelanotide, a Melanocortin-4 Receptor Agonist, for Obese Patients: A Systematic Review and Meta-AnalysisPMID 37888071
Not fully extracted - Journal of Personalized Medicine (2023) - Systematic review and meta-analysis - Pooled from multiple trials (~500 total)
Pooled analysis confirmed consistent 30-80% responder rates for >=10% weight loss across approved indications. Confirmed safety profile aligned with individual trials.
Limitations: Limited by small sizes of included trials, heterogeneous populations, industry sponsorship bias.
12Adverse event profile of setmelanotide in obesity: an integrated assessment and systematic review using disproportionality analysis, case reports and meta-analysisPMID 39924461
Sridharan K, Sivaramakrishnan G - Not extracted (2025) - Pharmacovigilance review / meta-analysis - 93 FAERS cases (2020-2024) + clinical trial data
Post-marketing safety: mostly mild AEs, no deaths reported in FAERS database. Confirmed known safety signals (hyperpigmentation, GI, injection site reactions).
Limitations: FAERS voluntary reporting, uncertain denominators, possible underreporting.
13Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-alpha-MSH and setmelanotide
Yu J, et al. - Cell Research (2021) - Structural biology (cryo-EM) - N/A (in vitro)
Resolved cryo-EM structures of MC4R-Gs complexes with setmelanotide. Confirmed bitopic binding mode (orthosteric + allosteric sites). Identified calcium coordination role. Characterized TM6 outward movement (~13 Angstrom) upon activation.
Limitations: In vitro structural study; may not fully reflect in vivo binding dynamics.
14Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach
Amin MS, et al. - ACS Omega (2019) - Computational / in silico - N/A
Identified allosteric binding mechanism. Characterized the role of disulfide bridge in maintaining cyclic structure and potency. Confirmed HFRW pharmacophore importance.
Limitations: Computational modeling only; predictions require experimental validation.