PeptideCompareMONOGRAPH No. 119
EVIDENCE BASEStrong
💪 Muscle, IGF & Body Composition
Setmelanotide — EU research guide.
Setmelanotide (Imcivree) is a melanocortin-4 receptor (MC4R) agonist approved for rare genetic obesity syndromes and, since March 2026, for acquired hypothalamic obesity.
Last reviewed:
What is Setmelanotide?
Setmelanotide directly activates MC4R, the same appetite-control receptor targeted indirectly by melanotan I/II, restoring satiety signalling in people whose obesity stems from a broken upstream part of the leptin-melanocortin pathway (POMC, PCSK1, LEPR deficiency, or Bardet-Biedl syndrome).
What does the research show?
Rhythm Pharmaceuticals' Phase 3 TRANSCEND trial supported a March 2026 FDA label expansion to acquired hypothalamic obesity, showing an 18.4% placebo-adjusted BMI reduction over 52 weeks; the EU granted marketing authorisation for the same indication shortly after. It is not indicated for common (polygenic) obesity.
EU legal status
EMA-approved prescription medicine (Imcivree) for its specific genetic and acquired-obesity indications only. It is not a generic research peptide for general weight loss.
⚠ Approved only for specific genetic obesity syndromes and acquired hypothalamic obesity — not for general weight management. Common side effects include skin hyperpigmentation, injection site reactions, nausea and headache.
✓ For the classic melanocortin-pathway research peptides, PeptideCompare tracks Melanotan I and Melanotan II from EU research vendors with COA documentation.
EVIDENCE SUMMARY
STRONG
Acquired hypothalamic obesity (TRANSCEND) — In a 52-week, placebo-controlled phase 3 trial in 120 people aged 4 to 66 with acquired hypothalamic obesity, setmelanotide produced significantly greater reductions in BMI and hunger than placebo. In the manufacturer's topline report, mean BMI change was -16.5% versus +3.3% with placebo, a difference of 19.8 percentage points.
MODERATE
POMC or LEPR deficiency (two small phase 3 trials) — Two single-arm, open-label phase 3 trials of about one year enrolled 10 people with POMC deficiency and 11 with LEPR deficiency. Weight loss of at least 10% was reached by 8 of 10 (POMC) and 5 of 11 (LEPR); no serious treatment-related adverse events were reported, while injection-site reactions and skin hyperpigmentation were very common.
STRONG
Safety profile in the EU product information — The EU product information lists hyperpigmentation disorders (66%), injection site reactions (45%), nausea (36%) and headache (19%) as the most frequent adverse reactions. These figures belong to the licensed medicine and do not describe vendor research vials.
Molecular information
Pharmacokinetics
Source: IMCIVREE EU summary of product characteristics (EMA), section 5.2, and US prescribing information (FDA): effective elimination half-life after subcutaneous administration, approximately 11 hours
This is the half-life of the licensed product in humans. It says nothing about the stability of vendor research vials, which are not the licensed medicine.
Potency retained over time
Each line is one storage condition: it starts at 100% and falls as potency is lost. Above the dashed 80% line the material is considered reliable — hover for exact values.
Freezer −20 °C
36+ mo
Stable · >95% potency
Fridge 4 °C
3-4 mo
In use · after recon
Room 20 °C
10-13 days
Limited · moderate loss
Warm 37 °C+
2-3 days
Critical · rapid degradation
⚠ Modelled per compound from molecular structure — chain length, cyclisation, oxidation- and deamidation-prone residues and light sensitivity. Indicative only, not lab-measured per batch.
Melanocortin-pathway compounds across EU suppliers
COA-verified EU vendors · Updated monthly
References
- Peer-reviewed report of the phase 3 TRANSCEND trial: 120 participants aged 4 to 66, randomised against placebo for 52 weeks. It reports significantly greater BMI and hunger reductions with setmelanotide; common adverse effects were skin darkening, nausea, vomiting and headache. It covers acquired hypothalamic obesity only, not common obesity. Miller JL, van Santen HM, Phillips SA, et al.; TRANSCEND Trial Group. Setmelanotide for the Treatment of Acquired Hypothalamic Obesity. N Engl J Med. 2026;395(2):138-150. DOIPubMed 42418774
- Report of two small single-arm, open-label phase 3 trials (10 people with POMC deficiency, 11 with LEPR deficiency, about one year). With no placebo group it shows what happened, not what would have happened otherwise; it covers the genetic-deficiency setting. Clement K, van den Akker E, Argente J, et al. 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. Lancet Diabetes Endocrinol. 2020;8:960-970. DOIPubMed 33137293
- The EU summary of product characteristics: indications (acquired hypothalamic obesity, Bardet-Biedl syndrome, POMC, PCSK1 or LEPR deficiency), an effective half-life of about 11 hours, refrigerated storage protected from light, and the most frequent adverse reactions. This is the licensed medicine, not vendor research vials. European Medicines Agency. IMCIVREE (setmelanotide): EPAR product information (summary of product characteristics). Source
- The EMA's Imcivree page: authorised in the EU since 16 July 2021, currently listing acquired hypothalamic obesity among its indications, with orphan designations. It documents regulatory status only and is not a clinical study. European Medicines Agency. Imcivree: authorisation details and indications (EPAR page). Source
- Manufacturer topline release on TRANSCEND: 120 patients, 52 weeks, BMI change -16.5% versus +3.3% (19.8-point difference). A company statement, not peer-reviewed; the peer-reviewed report is the NEJM paper above. The company's US approval release quotes a different figure (-18.4%, 142 patients) for the population used in the FDA label. Rhythm Pharmaceuticals. Pivotal Phase 3 TRANSCEND trial meets primary endpoint with -19.8% placebo-adjusted BMI reduction in patients (N=120) with acquired hypothalamic obesity. Company press release. Source
- The US label as revised in 03/2025, before the acquired hypothalamic obesity indication was added: it lists the genetic indications, an elimination half-life of about 11 hours, refrigerated storage and no boxed warning. It describes the licensed product, not vendor research vials. Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) injection: US prescribing information. US Food and Drug Administration; revised 03/2025. Source