{"id":"setmelanotide","name":"Setmelanotide","aliases":["Imcivree","RM-493","BIM-22493","MC4R agonist"],"url":"https://lyoresearch.com/compounds/setmelanotide","class":{"id":"melanocortins","name":"Melanocortin agonists","url":"https://lyoresearch.com/classes/melanocortins"},"summary":"Setmelanotide is a cyclic analogue of α-MSH that activates the MC4 receptor, the brain's main satiety switch. In people whose obesity is caused by rare mutations upstream of that receptor — POMC, PCSK1 or LEPR deficiency, or Bardet-Biedl syndrome — it restores the signal: 80% of POMC-deficient and 45% of LEPR-deficient patients lost at least a tenth of their body weight in a year, with hunger scores falling by a quarter to a half. Those trials had ten and eleven participants. In obesity that follows damage to the hypothalamus, a 120-person randomised trial found BMI fell 16.5% against a 3.3% rise on placebo; Canada approved that use in September 2026. It has no role in common obesity.","overall_grade":"B","overall_grade_meaning":"probable, not settled","human_trials":"Single-arm phase 3 trials (n=10, n=11) with placebo-withdrawal; BBS trial (n=38); acquired hypothalamic obesity phase 3 RCT (n=120)","regulatory_status":"Approved (Rx) — rare genetic obesity; hypothalamic obesity in Canada","molecule":{"formula":"C49H68N18O9S2","molecular_weight":"1117.3","cas":"920014-72-8","pubchem_cid":11993702,"note":null},"pharmacokinetics":{"basis":"label","route":"Subcutaneous injection, once daily","half_life":"About 11 hours","licensed_regimen":"Adults and children ≥12 years: 2 mg daily for 2 weeks, then 3 mg daily; 6 to <12 years: 1 mg daily for 2 weeks, then 3 mg daily","product":"Imcivree","source":{"title":"Imcivree prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=70c3ccf7-4df0-4c75-ba07-fede9970c8d9"}},"outcomes":[{"outcome":"Weight loss in POMC / LEPR deficiency obesity","grade":"B","grade_meaning":"probable, not settled","effect_size":"large","adverse":false,"human_studies":"2 single-arm phase 3 trials (n=10, n=11) with 8-wk placebo withdrawal","evidence":"Eight of ten POMC-deficient and five of eleven LEPR-deficient participants lost at least 10% of body weight at about a year, with weight regained during the blinded placebo-withdrawal weeks. Large effects; tiny trials.","references":[{"citation":"Clément 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.","where":"Lancet Diabetes Endocrinol, 2020","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}],"verbatim":{"text":"Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year.","citation":"Clément 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.","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}},{"outcome":"Hunger in POMC / LEPR deficiency","grade":"B","grade_meaning":"probable, not settled","effect_size":"large","adverse":false,"human_studies":"Same trials","evidence":"The 'most hunger' score fell by 27% and 44% — the mechanism working as designed in people whose hunger signal is broken.","references":[{"citation":"Clément 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.","where":"Lancet Diabetes Endocrinol, 2020","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}],"verbatim":{"text":"The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial.","citation":"Clément 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.","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}},{"outcome":"Weight loss in Bardet-Biedl syndrome","grade":"B","grade_meaning":"probable, not settled","effect_size":"moderate","adverse":false,"human_studies":"1 phase 3 with 14-wk placebo-controlled period (n=38)","evidence":"The basis of the 2022 approval extension; the only setmelanotide trial with a randomised placebo period.","references":[{"citation":"Haqq AM, et al. Efficacy and safety of setmelanotide in Bardet-Biedl syndrome: a phase 3 randomised, placebo-controlled trial.","where":"Lancet Diabetes Endocrinol, 2022","url":"https://pubmed.ncbi.nlm.nih.gov/?term=Haqq+setmelanotide+Bardet-Biedl+phase+3+2022"}]},{"outcome":"Weight loss in acquired hypothalamic obesity","grade":"B","grade_meaning":"probable, not settled","effect_size":"large","adverse":false,"human_studies":"1 phase 3 RCT (TRANSCEND, n=120, 52 wk)","evidence":"TRANSCEND, published in the New England Journal of Medicine in July 2026: 120 people aged 4 to 66 whose obesity followed a hypothalamic tumour, lesion or injury were randomised 2:1 to setmelanotide or placebo. BMI fell 16.5% on setmelanotide and rose 3.3% on placebo at 52 weeks, and hunger scores fell further on the drug. Serious adverse events were reported in 28% against 8%. One randomised trial, so B. Health Canada approved this use on 22 September 2026.","references":[{"citation":"Miller JL, et al. Setmelanotide for the treatment of acquired hypothalamic obesity (TRANSCEND).","where":"N Engl J Med, 2026;395(2):138–150","url":"https://pubmed.ncbi.nlm.nih.gov/42418774/"},{"citation":"Rhythm Pharmaceuticals. Health Canada approval of Imcivree (setmelanotide) for weight management in adult and paediatric patients 4 years of age and older with acquired hypothalamic obesity.","where":"Press release, 22 Sep 2026","url":"https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-health-canada-approval-0"}],"verbatim":{"text":"The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009).","citation":"Miller JL, et al. Setmelanotide for the treatment of acquired hypothalamic obesity (TRANSCEND).","url":"https://pubmed.ncbi.nlm.nih.gov/42418774/"}},{"outcome":"Common (polygenic) obesity","grade":"D","grade_meaning":"no human evidence","effect_size":"not measurable","adverse":false,"human_studies":"No approved use; early trials only","evidence":"Not developed for obesity without a monogenic cause. Early-phase work in general obesity showed effects too small to pursue; no controlled trial supports the use and no regulator has approved it.","references":[{"citation":"Imcivree (setmelanotide) — European public assessment report.","where":"EMA, 2021 onward","url":"https://www.ema.europa.eu/en/medicines/human/EPAR/imcivree"}]},{"outcome":"Adverse effects","grade":"B","grade_meaning":"probable, not settled","effect_size":"moderate","adverse":true,"human_studies":"Same trials","evidence":"Injection-site reactions and skin darkening in every participant, nausea and vomiting in a third to a half; hyperpigmentation is the MC1-receptor effect the drug cannot avoid.","references":[{"citation":"Clément 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.","where":"Lancet Diabetes Endocrinol, 2020","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}],"verbatim":{"text":"The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants.","citation":"Clément 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.","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/"}}],"regions":[{"region":"European Union","status":"Approved, prescription-only","note":"Centrally authorised (Imcivree) 2021 for POMC, PCSK1 or LEPR deficiency obesity; 2022 for Bardet-Biedl syndrome. Genetic confirmation required."},{"region":"United States","status":"Approved, prescription-only","note":"FDA-approved November 2020 for POMC, PCSK1 or LEPR deficiency; June 2022 for Bardet-Biedl syndrome."},{"region":"United Kingdom","status":"Licensed, prescription-only","note":"Licensed for the same genetic indications."},{"region":"Australia","status":"Prescription-only","note":"LYO did not verify an ARTG entry at review; no approval for common obesity anywhere."},{"region":"Canada","status":"Approved, prescription-only","note":"According to the manufacturer, Health Canada approved Imcivree in 2023 for obesity due to Bardet-Biedl syndrome or POMC, PCSK1 or LEPR deficiency (age 6 and over), and on 22 September 2026 for acquired hypothalamic obesity (age 4 and over)."},{"region":"Sport (WADA)","status":"Not prohibited","note":"Not on the Prohibited List."}],"faq":[{"q":"Can setmelanotide be used for ordinary obesity?","a":"No. It restores a signal that is broken by specific mutations. In people without those mutations the signal is not broken, early studies found little effect, and no regulator has approved it for that use."},{"q":"Why is an approved drug graded B?","a":"Because the pivotal trials had ten and eleven participants and no parallel placebo group — the design regulators accept for ultra-rare diseases. The effect is large and the grade reflects certainty, not size."},{"q":"How is it different from Melanotan II or PT-141?","a":"All three are α-MSH analogues, but setmelanotide is selective for MC4R, the appetite receptor, and is approved for a genetic disease. PT-141 targets sexual desire; Melanotan II is a non-selective grey-market product. The skin darkening is shared."}],"references":[{"cite":"Clément 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.","where":"Lancet Diabetes Endocrinol, 2020","url":"https://pubmed.ncbi.nlm.nih.gov/33137293/","note":"POMC n=10, LEPR n=11."},{"cite":"Imcivree (setmelanotide) — European public assessment report.","where":"EMA, 2021 onward","url":"https://www.ema.europa.eu/en/medicines/human/EPAR/imcivree","note":"Licensed indications; genetic confirmation required."},{"cite":"Haqq AM, et al. Efficacy and safety of setmelanotide in Bardet-Biedl syndrome: a phase 3 randomised, placebo-controlled trial.","where":"Lancet Diabetes Endocrinol, 2022","url":"https://pubmed.ncbi.nlm.nih.gov/?term=Haqq+setmelanotide+Bardet-Biedl+phase+3+2022","note":"n=38; 14-week placebo-controlled period."},{"cite":"Miller JL, et al. Setmelanotide for the treatment of acquired hypothalamic obesity (TRANSCEND).","where":"N Engl J Med, 2026;395(2):138–150","url":"https://pubmed.ncbi.nlm.nih.gov/42418774/","note":"120 randomised 2:1, 52 weeks; BMI −16.5% vs +3.3%. NCT05774756."},{"cite":"Rhythm Pharmaceuticals. Health Canada approval of Imcivree (setmelanotide) for weight management in adult and paediatric patients 4 years of age and older with acquired hypothalamic obesity.","where":"Press release, 22 Sep 2026","url":"https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-health-canada-approval-0","note":"Also states the 2023 Canadian approval for Bardet-Biedl syndrome and POMC, PCSK1 or LEPR deficiency. Company source."}],"last_reviewed":"2026-10-07","literature_searched_to":"2026-10-07","changelog":[{"date":"2026-10-07","note":"New row for acquired hypothalamic obesity from the published TRANSCEND trial (N Engl J Med, July 2026; n=120), graded B. Canada row updated: approved, including the acquired hypothalamic obesity indication of 22 Sep 2026. Other grades unchanged."},{"date":"2026-09-10","note":"Initial publication. Grade B for the genetic indications on tiny single-arm trials; D for common obesity."}],"license":"CC BY 4.0 — cite as “LYO Research” with a link.","methodology":"https://lyoresearch.com/methodology"}