Setmelanotide
Setmelanotide Uses, Dosage, Side Effects, Food Interaction and all others data.
Setmelanotide is the first available treatment for patients with pro-opiomelanocortin, proprotein subilisin/kexin type 1, or leptin deficiencies. It is an agonist of the melanocortin 4 receptor. Earlier attempts at agonizing MC4R (such as LY2112688) lead to successful weight loss, but also an increase in blood pressure and heart rate. Other earlier treatments for these patients included gastric bypass surgery. Patients taking setmelanotide experienced an average weight loss of 0.6 kg/week.
Imcivree was granted EMA orphan designation on 19 November 2018 and FDA approval on 25 November 2020.
Setmelanotide agonizes MC4R, downstream of multiple potential genetic deficiencies, to induce a feeling of satiety for chronic weight management. It has a moderate duration of action as it is given daily. Patients should be counselled regarding the risk of disturbances in sexual arousal, depression and suicidal ideation, and darkening of skin pigmentation. Exercise caution in neonates and low birth weight infants, as they may experience serious adverse effects due to benzyl alcohol.
| Trade Name | Setmelanotide |
| Availability | Prescription only |
| Generic | Setmelanotide |
| Setmelanotide Other Names | Setmelanotida, Setmelanotide, Setmélanotide, Setmelanotidum |
| Related Drugs | phentermine, semaglutide, Wegovy, Saxenda, liraglutide, Alli |
| Type | |
| Formula | C49H68N18O9S2 |
| Weight | Average: 1117.32 Monoisotopic: 1116.48580819 |
| Protein binding | Setmelanotide is 79.1% protein bound. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Setmelanotide is setmelanotide is indicated to treat obesity caused by genetic POMC, PCSK1, or LEPR deficiencies.
Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin deficiency, proprotein subtilisin/kexin type 1 deficiency, or leptin receptor deficiency. These conditions affect the MC4R signalling pathway.
Setmelanotide is also used to associated treatment for these conditions: Leptin Receptor Deficiency Obesity, PCSK1 Deficiency Obesity, POMC Deficiency Obesity, Chronic Weight Management
How Setmelanotide works
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 EC50 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.
Toxicity
Data regarding overdoses of setmelanotide are not readily available. In the event of an overdose, patients should be treated with symptomatic and supportive care.
Food Interaction
No interactions found.Setmelanotide Disease Interaction
Volume of Distribution
The apparent volume of distribution of setmelanotide is 48.7 L.
Elimination Route
Setmelanotide has a Tmax of 8 hours.
Half Life
The elimination had life of setmelanotide is approximately 11 hours.
Clearance
A 3mg subcutaneous dose of setmelanotide has an estimated clearance of 4.86 L/h.
Elimination Route
A 3mg subcutaneous dose of setmelanotide is 39% eliminated in the urine as the unchanged parent compound.
Innovators Monograph
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