|Other names||RM-493; BIM-22493; IRC-022493; N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide|
|Main uses||Specific genetic causes of obesity|
|Side effects||Injection site reactions, increased skin pigmentation, headache, nausea, diarrhea, abdominal pain, depression|
|Typical dose||3 mg OD|
|Chemical and physical data|
|Molar mass||1117.32 g·mol−1|
|3D model (JSmol)|
Setmelanotide, sold under the brand name Imcivree, is a medication used to treat specific genetic causes of obesity. This includes significant pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR) deficiency, and Bardet-Biedl syndrome (BBS). It is used in those at least 6 years old. It is given by injection under the skin.
Common side effects include injection site reactions, increased skin pigmentation, headache, nausea, diarrhea, abdominal pain, and depression. Other side effects may include sexual arousal and thoughts of suicide. Use in not recommended in pregnancy or breast feeding. It is a melanocortin 4 (MC4) receptor agonist.
Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.
In three small studies 40% to 80% of people had a 10% decrease in their weight.
Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.
Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects. In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans. Importantly, unlike certain other MC4 receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in heart rate or blood pressure.
Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM). (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)
It was evaluated in two one-year clinical studies. The first study enrolled 10 participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled 11 participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older. Most participants had lost more than 10% of their initial body weight after a year of treatment. Some participants also reported feeling less hungry.
The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review. The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Setmelanotide is the first FDA-approved treatment for these genetic conditions.
Society and culture
Setmelanotide was approved for medical use in the European Union in July 2021.
Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor; the structure of the bound complex has recently been determined. Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II clinical trials for obesity and PWS.[needs update] So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.
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