← All compounds · evidence tier first, by design

Evidence tier for each claimed use · ← established · unknown →
Use	E2	E3	E4
E2 Acquired hypothalamic obesity	E2
E3 Obesity in Bardet-Biedl syndrome (and Alström syndrome)		E3
E4 Obesity due to POMC, PCSK1 or LEPR deficiency			E4

Class A · Approved

Setmelanotide

Cyclic octapeptide: Ac-Arg-cyclo[Cys-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2 (disulfide between the two cysteines). Contains D-amino acids, so no plain one-letter sequence is given. Structure as described in the US prescribing information (chemical name: acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2-8)-disulfide).

Non-standard residues or modifications: no plain one-letter sequence

Codes: RM-493 · Brands: Imcivree

A synthetic cyclic peptide that activates the melanocortin-4 receptor, a brain receptor in the leptin-melanocortin pathway that regulates hunger. It is approved, under the brand Imcivree, only for specific rare forms of obesity: obesity due to POMC, PCSK1 or LEPR deficiency, Bardet-Biedl syndrome, and acquired hypothalamic obesity (approved in the US, EU, UK and Japan). The US label states it is not expected to be effective in general (polygenic) obesity.

US A approved
EU A approved
UK A approved
CA A approved
AU C gray market
JP A approved
CN ? not verified

01Regulatory status, by jurisdiction

Standing notice. Approved in United States, European Union, United Kingdom, Canada, Japan only. In Australia it is not an approved medicine: material sold there under this name is of unverified origin and is not manufactured or tested to pharmaceutical standards there.

Jurisdiction	Status	Detail and primary source
US	Approved	NDA 213793 (Imcivree), original approval 25 November 2020; acquired hypothalamic obesity indication added by supplement 9 on 19 March 2026. “IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged” IMCIVREE prescribing information (FDA, revised 03/2026) · retrieved 2026-10-10
EU	Approved	Centrally authorised (EMEA product Imcivree), orphan medicine; marketing authorisation 16 July 2021. Current indications include acquired hypothalamic obesity, Bardet-Biedl syndrome and POMC (including PCSK1) or LEPR deficiency. “Imcivree received a marketing authorisation valid throughout the EU on 16 July 2021.” Imcivree EPAR (EMA) · retrieved 2026-10-10
UK	Approved	Great Britain marketing authorisation PLGB 55587/0001; SmPC retrieved from the MHRA products database (document dated 17 August 2026). “IMCIVREE is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed Bardet Biedl syndrome (BBS) in adults and children 2 years of age and above.” IMCIVREE Summary of Product Characteristics (MHRA products database) · retrieved 2026-10-10
CA	Approved	Drug Product Database: IMCIVREE, DIN 02537745, Rhythm Pharmaceuticals; status Marketed since 12 July 2023. “Current status: Marketed” Health Canada Drug Product Database: IMCIVREE · retrieved 2026-10-10
AU	Not approved	The TGA Product and Consumer Medicine Information repository returns no documents for setmelanotide. Absence of a PI/CMI is strong but not conclusive evidence of no ARTG registration; the ARTG search itself could not be loaded on the retrieval date. “Trade Names and Active Ingredients containing setmelanotide . 0 Documents available.” TGA Product and Consumer Medicine Information search · retrieved 2026-10-10
JP	Approved	PMDA list of newly approved drugs, August 2026: Imcivree (Rhythm Pharma KK), setmelanotide acetate, approved 24 August 2026 as a new active ingredient for acquired hypothalamic obesity, orphan drug. Other indications are not approved in Japan per this list. “後天性視床下部性肥満を効能・効果とする新有効成分含有医薬品” PMDA 承認品目一覧（新医薬品：2026年8月) (list linked from pmda.go.jp/review-services/drug-reviews/review-information/p-drugs/0040.html) · retrieved 2026-10-10
CN	Not yet verified from a primary source. No status is shown rather than an unsourced one.

Sport (WADA): Not prohibited. Not named on the Prohibited List. As an approved medicine it also falls outside class S0, which covers only substances without current regulatory approval: “Any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use” WADA source

02What the human evidence shows

Acquired hypothalamic obesity

1published human RCTs

2published human trials

27registered studies

14with posted results

An open-label phase 2 trial in 18 patients reported that 16 reached at least 5% BMI reduction at 16 weeks. A double-blind, placebo-controlled phase 3 trial (TRANSCEND, about 140 enrolled) has been presented as a conference abstract and its results are posted on ClinicalTrials.gov; a full peer-reviewed publication was not found on the retrieval date. By the retrieval date the indication was approved in the US (March 2026), Japan (August 2026), the EU and the UK.

[1] 16 of 18 patients reached at least 5% BMI reduction after 16 weeks in an open-label trial
[2] Conference abstract reporting the randomised placebo-controlled phase 3 trial in acquired hypothalamic obesity

Registered-study counts: ClinicalTrials.gov intervention search “setmelanotide”, fetched 2026-10-10. Registered studies include trials of other uses; the gap between registered and reported is itself a finding.

Obesity in Bardet-Biedl syndrome (and Alström syndrome)

1published human RCTs

1published human trials

27registered studies

14with posted results

One phase 3 trial (38 randomised) had a 14-week double-blind placebo-controlled period followed by 52 weeks of open-label treatment. Its primary endpoint was single-arm: 32.3% of patients aged 12 or older with Bardet-Biedl syndrome reached at least 10% weight reduction after 52 weeks. The randomised period was short and small, so the controlled evidence is limited. Alström syndrome was included in the trial but is not an approved indication.

[3] 32.3% of patients aged 12 or older with Bardet-Biedl syndrome reached at least 10% weight reduction after 52 weeks

Obesity due to POMC, PCSK1 or LEPR deficiency

No randomised controlled trial in humans has been published for this use.

0published human RCTs

3published human trials

27registered studies

14with posted results

Evidence comes from two single-arm, open-label phase 3 trials (10 and 11 participants in the published full analysis sets) with a short blinded placebo-withdrawal sequence, and an earlier two-patient open-label report. Eight of 10 participants with POMC deficiency and 5 of 11 with LEPR deficiency reached at least 10% weight loss at about one year. There is no parallel-group randomised comparison, which is typical for ultra-rare conditions but limits the strength of inference.

[4] Weight loss of at least 10% at about one year in single-arm trials of people with POMC or LEPR deficiency obesity
[5] Reduced hunger and substantial weight loss in two patients with POMC deficiency in an open-label study

Key registered trials

NCT	Title (as registered)	Phase	Status
NCT02896192	Setmelanotide for the Treatment of Early-Onset Pro-Opiomelanocortin (POMC) Deficiency Obesity	3	Completed
NCT03287960	Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity	3	Completed
NCT03746522	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity	3	Completed
NCT05774756	A Trial of Setmelanotide in Acquired Hypothalamic Obesity	3	Active, not recruiting
NCT04725240	Open-Label Study of Setmelanotide in Hypothalamic Obesity	2	Completed

03Safety signals

S2Substantial controlled-trial safety data

There are no adequate human safety data. The absence of reported harm is not evidence of safety.

Skin hyperpigmentation, darkening of pre-existing naevi and new melanocytic naevi [6]
Listed in US prescribing information (Warnings and Precautions 5.4); skin hyperpigmentation is among the most common adverse reactions.
Disturbance in sexual arousal, including spontaneous penile erection [6]
US prescribing information, Warnings and Precautions 5.1; spontaneous penile erection listed among common adverse reactions.
Depression and suicidal ideation [6]
US prescribing information, Warnings and Precautions 5.2.
Acute adrenal insufficiency and sodium imbalance in patients with acquired hypothalamic obesity [6]
Added to US prescribing information in March 2026 (Warnings and Precautions 5.5 and 5.6).
Gastrointestinal effects (nausea, vomiting, diarrhoea, abdominal pain) and injection-site reactions [6]
Most common adverse reactions in US prescribing information section 6.1.

04What is unknown

No parallel-group randomised trial in POMC, PCSK1 or LEPR deficiency; efficacy rests on single-arm data in 21 people in the two pivotal trials
Long-term (multi-year) outcomes beyond weight and hunger, such as cardiometabolic events, are not established
Long-term consequences of persistent skin hyperpigmentation and new melanocytic naevi are not characterised
Peer-reviewed full publication of the phase 3 acquired hypothalamic obesity trial was not found on the retrieval date
Efficacy in general (polygenic) obesity is not established; the US label states it would not be expected to be effective

05Product quality

No independent purity results have been published for this compound yet. The purity programme will publish full methods and vendor-named results, passes and failures, once its protocol has had legal review.

06Citations

Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial (2024). doi:10.1016/s2213-8587(24)00087-1
P255 - ECE_1844 - Efficacy and safety of setmelanotide in acquired hypothalamic obesity: Results from a double-blind, multicentre, placebo-controlled, randomised phase 3 trial (2026). doi:10.1093/ejendo/lvag096.414
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 (2022). doi:10.1016/s2213-8587(22)00277-7
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 (2020). doi:10.1016/s2213-8587(20)30364-8
Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist (2016). doi:10.1056/nejmoa1512693
IMCIVREE (setmelanotide) injection, for subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/213793s009lbl.pdf

Every DOI is resolved against Crossref and every NCT number against ClinicalTrials.gov, title for title, before publication. Regulatory sources are cited inline above with a verbatim quote and retrieval date.

07Mechanism

Setmelanotide is an agonist of the melanocortin-4 (MC4) receptor, part of the hypothalamic leptin-melanocortin pathway that regulates hunger and energy expenditure; it is intended to act downstream of genetic or acquired defects in that pathway.

Mechanism is placed last on purpose: a plausible mechanism is not evidence that a compound works in people.

Reviewed by OSMF research team (AI-assisted, source-verified) on 2026-10-10. Found an error? It goes in the corrections log: report it.