Indications
Setmelanotide is prescribed for chronic weight management in patients aged 6 years and older who have obesity due to specific genetic deficiencies. These include pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency. An approved genetic test must confirm the presence of variants in the POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance. These conditions impact the melanocortin-4 receptor (MC4R) signalling pathway. Furthermore, Setmelanotide is indicated for patients with obesity related to Bardet-Biedl syndrome. The drug is not effective for patients whose POMC, PCSK1, or LEPR variants are classified as benign or likely benign, nor for other types of obesity not specified here.
Pharmacodynamics
Setmelanotide functions by agonizing the melanocortin-4 receptor (MC4R), which is downstream of various potential genetic deficits, thereby inducing satiety and facilitating chronic weight management. The medication exhibits a moderate duration of action, necessitating daily administration. Patients should be advised of potential side effects, including disturbances in sexual arousal, depression, suicidal ideation, and increased skin pigmentation. Special caution is recommended for neonates and low birth weight infants due to the potential for serious adverse effects from benzyl alcohol.
Absorption
Setmelanotide reaches its maximum concentration (Tmax) approximately 8 hours after administration.
Metabolism
The metabolic process of Setmelanotide is anticipated to involve its breakdown into smaller peptides and amino acids.
Mechanism of Action
Setmelanotide operates as an agonist of the melanocortin 4 receptor (MC4R) and is a peptide derived from pro-opiomelanocortin. It exhibits significantly higher potency, being roughly 20 times more effective than the endogenous α-melanocyte stimulating hormone, with an EC50 of 0.27 nM. By activating MC4R, setmelanotide circumvents upstream genetic deficiencies within the MC4R signaling pathway, leading to reduced food intake and promoting weight loss. This process involves interactions between orexigenic and anorexigenic neurons, which express prohormone convertase 1/3 (PC1/3) encoded by the proprotein subtilisin/kexin type 1 gene. PC1/3 facilitates the activation cleavage of various peptide hormone precursors, including α-melanocyte stimulating hormone, which normally inhibits MC4R activity until overridden by satiety signals like insulin or leptin. MC4R itself is a 332 amino acid G-protein coupled receptor (G-PCR). Earlier MC4R-targeting therapies elicited cardiovascular side effects, potentially due to the activation of multiple G-protein pathways. In contrast, setmelanotide functions as an atypical bitopic ligand, binding both to the conserved orthosteric site and a suggested allosteric site, thereby achieving high affinity and specificity without these adverse effects.
