Setmelanotide, sold under the brand nameImcivree, is amedication used for the treatment of genetic obesity caused by arare single-gene mutation.[4][5][6]
The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others.[5] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment.[5] Depression and suicidal ideation have also occurred with setmelanotide.[5]
Setmelanotide isindicated 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, andleptin receptor (LEPR) deficiency confirmed bygenetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.[4][5][6] Setmelanotide is the first FDA-approved treatment for these genetic conditions.[5]
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.[5]
Setmelanotide has been reported to possess the followingactivity profile (cAMP,EC50):MC4 (0.27 nM) >MC3 (5.3 nM) ≈MC1 (5.8 nM) >MC5 (1600 nM) ≟MC2 (>1000 nM).[13] (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)
Setmelanotide was invented atIpsen.[14] It was initially known as BIM-22493 and then as RM-493 and IRC-022493.
It was evaluated in two one-year clinical studies.[5] 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.[5] Most participants had lost more than 10% of their initial body weight after a year of treatment.[5] Some participants also reported feeling less hungry.[5]
The U.S.Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review.[5] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.[5][7]
Setmelanotide is a peptidedrug and investigationalanti-obesity medication which acts as a selectiveagonist of theMC4 receptor;[17][12] the structure of the bound complex has recently been determined.[18] 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 byRhythm Pharmaceuticals for the treatment ofobesity anddiabetes.[17] In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment ofPrader–Willi syndrome (PWS), agenetic disorder which includes MC4 receptor deficiency and associated symptoms such asexcessive appetite and obesity.[19] As of December 2014, the drug is inphase IIclinical trials for obesity and PWS.[17][20][21][needs update] So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.[22]
The drug has some efficacy in obese people who lack the genetic variants that the drug is approved for, but its safety and efficacy in this wider population is not well understood.[15]
^abcde"Imcivree EPAR".European Medicines Agency (EMA). 19 May 2021. Retrieved22 July 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^abcLee EC, Carpino PA (2015). "Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)".Pharmaceutical Patent Analyst.4 (2):95–107.doi:10.4155/ppa.15.1.PMID25853469.
^Jackson VM, Price DA, Carpino PA (August 2014). "Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies".Expert Opinion on Investigational Drugs.23 (8):1055–1066.doi:10.1517/13543784.2014.918952.PMID25000213.S2CID23198484.
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