Inside the body with Setmelanotide

Given by subcutaneous injection. Absorption is slow: median Tmax is about 8 hours. Labelled routes exclude intravenous and intramuscular use.[src]

Apparent volume of distribution 75.2 L and plasma protein binding 79.1%. Elimination half-life is about 11 hours, consistent with once-daily administration.[src]

Setmelanotide is an MC4R agonist with about 20-fold less activity at MC3R and MC1R. MC4R signalling in the hypothalamic melanocortin pathway regulates hunger, satiety and energy expenditure. The receptor's role is established from human genetics and the label; that the drug engages MC4R neurons in people is inferred from its clinical effects rather than measured directly.[src][src]

Cryo-EM structures of the setmelanotide-MC4R-Gs complex (2.6 A, PDB 7PIU) include a calcium ion, which the authors describe as a ligand-adaptable cofactor. They describe setmelanotide as a cyclic agonist with signalling biased toward Gq/11 and highlight transmembrane helix 3 as key to ligand-specific interactions. These are structural and in vitro pharmacology findings; how the bias contributes to clinical effect is not established.[src][src]

In POMC/PCSK1 and LEPR deficiency the pathway is impaired upstream of MC4R, and in acquired hypothalamic obesity the hypothalamic circuit is damaged; an MC4R agonist acts downstream. In two POMC-deficient patients, weight fell by 51.0 kg over 42 weeks and 20.5 kg over 12 weeks with sustained reduction in hunger (NEJM 2016). In the phase 3 TRANSCEND trial, BMI fell 16.5% versus a 3.3% rise on placebo at 52 weeks, and the weekly average of the maximal daily hunger score (participants aged 12 or older) fell by 2.73 versus 1.45 points (P = 0.009).[src][src][src]

In a randomised, double-blind, placebo-controlled crossover study of 12 adults with obesity given a 72-hour continuous subcutaneous infusion of setmelanotide (RM-493), resting energy expenditure rose 6.4% (about 111 kcal/day) versus placebo (P = .03), with a lower respiratory quotient suggesting more fat oxidation. This was a short-term study in people without a genetic MC4R-pathway disease. The FDA release states the drug increases resting metabolism; the long-term contribution to weight loss is not established here.[src][src]

In diet-induced obese rhesus macaques treated for 8 weeks, the compound (BIM-22493/RM-493) produced about 13.5% weight loss with transient food-intake reduction and improved insulin sensitivity, without increases in blood pressure or heart rate, unlike an older MC4R agonist (LY2112688). This is animal-only evidence in a non-genetic obesity model and does not establish human benefit.[src]

MC1R activation on melanocytes increases melanin; the label reports generalised or focal hyperpigmentation in the majority of treated patients, reversible on discontinuation, with darkening of nevi and new nevi possible. Setmelanotide is expected to be catabolised into small peptides; about 39% is excreted unchanged in urine over the 24-hour dosing interval.[src]