Evidence Grade A — Regulatory approved. 190 published studies. 25 registered clinical trials.
Medically reviewed by a licensed medical professional
Loading...
Setmelanotide (sold as Imcivree) is a precision medicine treatment for severe obesity caused by specific rare genetic mutations that break the brain's hunger control system. People with these mutations experience constant, insatiable hunger from early childhood. Setmelanotide is the first drug that directly fixes the broken signalling pathway — but only in patients whose genes have been tested and confirmed to carry an eligible mutation.
Setmelanotide is also known by these brand and alternate names:
190 published studies: 110 human, 10 animal, 11 in-vitro, 79 reviews
Setmelanotide is marketed as Imcivree (Rhythm Pharmaceuticals; approved November 2020 for POMC, PCSK1, or LEPR deficiency; June 2022 for Bardet-Biedl syndrome; December 2024 expanded to patients aged 2 years and older). Genetic testing confirming an eligible mutation is required before treatment.
In patients with POMC or PCSK1 deficiency, approximately 80% achieved at least 10% weight loss in clinical trials. In Bardet-Biedl syndrome, 32.3% achieved the same threshold. The most common side effects are injection-site reactions and skin darkening (due to the melanocortin pathway's connection to pigmentation). Setmelanotide exemplifies precision medicine — it is highly effective in the specific genetic populations it targets but is not indicated for common obesity.
In a healthy brain, a pathway runs from the hormone leptin through a series of intermediary signals (POMC, PCSK1) to the melanocortin-4 receptor (MC4R), which controls feelings of fullness. When any link in this chain is broken by a genetic mutation, the MC4R never receives the 'you are full' signal, resulting in constant, insatiable hunger and severe obesity from early childhood. Setmelanotide bypasses the broken links by directly activating the MC4R, restoring the satiety signal that was genetically absent.
In patients with POMC or PCSK1 gene deficiencies, approximately 80% achieved at least 10% weight loss, with average losses of 23% — remarkable results in a population that had no previous treatment option. In Bardet-Biedl syndrome (a broader genetic condition), 32% achieved the same threshold. The expanding list of approved genetic conditions shows the manufacturer's strategy to widen the eligible population. Setmelanotide exemplifies precision medicine: it is highly effective in the specific genetic populations it targets but is not indicated or expected to work for common obesity. Side effects include injection-site reactions, skin darkening (because the melanocortin pathway also controls pigmentation), and monitoring for depression and suicidal thoughts is required. The eligible patient population is very small — approximately 2,500–3,000 diagnosed patients in the US across all approved indications.
PeptideTrace tracks 25 registered clinical trials for Setmelanotide sourced from ClinicalTrials.gov.
An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)
A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
A Study of Setmelanotide in Patients With Prader-Willi Syndrome
Open-Label Extension Study of Setmelanotide
FDA ORIG 1
EMA Marketing Authorisation
FDA SUPPL 1
Health Canada Market Authorisation
FDA SUPPL 5
FDA SUPPL 7
FDA SUPPL 8
Setmelanotide is a cyclic 8-amino-acid peptide that acts as a selective melanocortin-4 receptor (MC4R) agonist. It is a precision medicine therapy designed to treat obesity caused by specific genetic defects in the leptin-melanocortin satiety signaling pathway.
Setmelanotide directly activates MC4R, restoring the downstream satiety signaling that is lost when upstream components (POMC, PCSK1, LEPR) are genetically deficient. In patients with these rare monogenic obesity disorders, the leptin-melanocortin pathway is disrupted at various upstream points, but MC4R itself remains functional. Setmelanotide bypasses the defect by directly activating the intact downstream receptor. Unlike bremelanotide, setmelanotide does not cause tachycardia or hypertension (a critical differentiator for a chronic obesity medication).
Setmelanotide is marketed as Imcivree (Rhythm Pharmaceuticals). Approved November 25, 2020 for obesity due to POMC, PCSK1, or LEPR deficiency; June 2022 for Bardet-Biedl syndrome; December 20, 2024 expanded to patients aged ≥2 years. Requires genetic testing confirming eligible mutations. POMC/PCSK1 trial (N=10): 80% achieved ≥10% weight loss; mean −23.1%. LEPR trial (N=11): 45.5% achieved ≥10% loss; mean −9.7%. BBS trial (N=32): 32.3% achieved ≥10% loss. Hyperpigmentation occurred in 51–61% (MC1R cross-activation).
Danuglipron's original twice-daily formulation achieved 8–13% weight loss in Phase IIb but with treatment discontinuation rates exceeding 50%, with nausea affecting up to 73% of patients. Pfizer discontinued the twice-daily formulation and is developing a once-daily modified-release version. Danuglipron is not a peptide. Its development trajectory illustrates that even effective weight loss compounds can fail commercially if tolerability is inadequate. The reformulation effort aims to reduce peak drug concentrations that likely drive the gastrointestinal side effects.
CT-388 is in Phase II/III development (not yet approved). Phase II results (469 patients, 48 weeks) showed 22.5% placebo-adjusted weight loss at the highest dose, with low discontinuation rates due to adverse events (5.9%). Phase III trials are underway. The combination of high efficacy and low discontinuation rates in Phase II is notable — many obesity drugs achieve high weight loss but suffer from tolerability-driven dropouts. Roche's $2.7 billion acquisition of the developer signals significant confidence in the programme.
Amycretin is in early-phase development (not yet approved). The oral formulation achieved 13.1% weight loss at just 12 weeks — substantially faster than existing oral options. The subcutaneous formulation achieved 24.3% at 36 weeks. Both results are from Phase I/II trials with relatively small patient numbers. Amycretin's significance lies in its oral formulation achieving weight loss approaching injectable drugs. If the early results are confirmed in larger trials, an effective oral dual-agonist could significantly expand the obesity treatment population. Phase III trials are anticipated.
Timelines
Regulatory Status
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
