Imcivree
Evidence Grade A — Regulatory approved. 180 published studies. 25 registered clinical trials.
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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.
180 published studies: 107 human, 10 animal, 9 in-vitro, 77 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.
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
Liraglutide is marketed as Victoza for type 2 diabetes (approved 2010) and Saxenda for weight management (approved 2014). The LEADER trial, involving over 9,300 patients followed for nearly four years, established that liraglutide reduced the risk of major cardiovascular events by 13% — a landmark finding that helped establish GLP-1 treatments as a class with heart benefits. Saxenda is also approved for adolescents aged 12 and older. While historically significant, liraglutide has been substantially surpassed by newer agents. In a direct comparison, semaglutide achieved 15.8% weight loss compared to liraglutide's 6.4%. Liraglutide remains relevant as a lower-intensity option and as a benchmark against which newer treatments are measured. It has over a decade of real-world safety data, making it one of the best-understood medications in this class.
HGH Fragment 176-191 has no marketing authorisation. A Phase IIa trial in obesity (approximately 300 patients) failed to demonstrate statistically significant weight loss at any dose tested. The clinical development programme was discontinued. The disconnect between animal data (which showed significant fat reduction in obese mice) and the failed human trial is the defining feature of this compound's development history. Products available through unregulated channels lack pharmaceutical quality assurance. The failed Phase II trial represents the highest level of clinical evidence available.
5-Amino-1MQ has no marketing authorisation. No human clinical trials have been conducted. The key preclinical study treated diet-induced obese mice for 11 days and reported body weight and fat mass changes. No human pharmacokinetic, safety, or efficacy data exist. 5-Amino-1MQ is not a peptide. Products available through unregulated channels lack pharmaceutical quality assurance. The absence of any human data means effects, safety, interactions, and appropriate dosing in humans are entirely unknown.
