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Setmelanotide is setmelanotide is indicated to treat obesity caused by genetic POMC, PCSK1, or LEPR deficiencies or Bardet-Biedl syndrome.
Setmelanotide is setmelanotide is indicated to treat obesity caused by genetic POMC, PCSK1, or LEPR deficiencies or Bardet-Biedl syndrome.
Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein. Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons. Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R. Orexigenic and anorexigenic neurons contain prohormone convertase 1/3 (PC1/3), which is encoded by the gene proprotein subtilisin/kexin type 1. PC1/3 preforms activation cleavage of a number of peptide hormone precursors, including α-melanocyte simulating hormone. Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R. It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC of 0.27 nM. By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved. MC4R is a 332 amino acid G-protein coupled receptor (G-PCR). Although the lack of cardiovascular adverse effects with setmelanotide treatment are not well understood, it is believed that earlier MC4R antagonists activated multiple G-protein signalling pathways. Earlier drugs that targeted G-PCRs either bound with high affinity to the highly conserved orthosteric binding site, or with high specificity to less conserved allosteric sites. Setmelanotide is an atypical bitopic ligand that interacts with both the orthosteric and putative allosteric binding site, allowing for both high affinity and specificity.
Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency as determined by an approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance. These conditions affect the MC4R signalling pathway. Setmelanotide is also indicated for chronic weight management in patients 6 years and older with obesity due to Bardet-Biedl syndrome. The drug is not reported to be effective in patients with POMC, PCSK1, or LEPR variants classified as benign or likely benign, as well as other types of obesity not listed above.
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