Setmelanotide

1. 01Skin

   Injected under the skin

   The medicine is a small protein-like molecule, so it cannot be swallowed. It is injected into the fat just under the skin and moves slowly into the blood.

   For experts

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

2. 02Bloodstream

   Travels in the blood for about half a day

   Once in the blood, it lasts long enough that one injection a day covers the whole day. Most of it rides loosely attached to proteins in the blood.

   For experts

   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]

3. 03Brain

   Switches on the hunger-control receptor in the brain

   Deep in the brain, the hypothalamus decides how hungry you feel. Setmelanotide fits into a receptor there, called MC4R, that acts like a fullness switch, and turns it on.

   For experts

   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]

4. 04Brain

   How it grips the receptor

   Scientists froze the drug stuck to its receptor and took a very close 3D picture. It shows the drug held in a pocket, with a calcium atom helping it stay in place.

   For experts

   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]

5. 05Brain

   Stands in for a missing fullness signal

   In people with certain gene changes, or with damage to the hypothalamus, the message that says 'you are full' does not get through. Setmelanotide skips the broken step and turns on the switch directly. In trials, people felt less hungry and lost weight.

   For experts

   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]

6. 06Fat tissue

   Body burns a little more energy at rest

   Besides feeling less hungry, the body may burn slightly more energy while resting. This was seen in a short study of adults with obesity.

   For experts

   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]

7. 07Elsewhere

   What early animal studies showed

   Before human trials, the drug was tested in obese monkeys. They ate less for a while, lost weight, and did not have higher blood pressure. This is animal-only evidence.

   For experts

   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]

8. 08Skin

   Skin darkening and how the body clears it

   The drug also nudges a similar receptor in skin cells, so skin often gets darker, and moles can darken or new ones appear. The skin darkening fades after stopping. The body breaks the medicine down into small pieces, and some leaves in urine.

   For experts

   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]

Around the world

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