{
    "comments": "Setmelanotide is an agonist of melanocortin receptors, with approximately 20-fold selectivity for the melanocortin 4 receptor subtype <Reference id=31400/>. Chemically it is an eight-amino-acid cyclic peptide, that is able to cross the blood-brain barrier when administered peripherally. Setmelanotide offers anti-obesity potential.<br>The INN record documents the sequence as N<sup>2</sup>-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide.",
    "bioactivityComments": "EC<sub>50</sub> values for cAMP production <i>in vitro</i> <i>vs</i>. human melanocortin receptors are MC4R (0.27mM), MC3R (5.3nM), MC1R (5.8nM), and rat MC4R (0.28nM) <Reference id=31400/>.",
    "clinicalUse": "Phase 1 results from <a href=\"https://clinicaltrials.gov/show/NCT01867437\">NCT01867437</a> indicated that short-term administration of setmelanotide (RM-493) increased resting energy expenditure and shifted substrate oxidation to fat <Reference id=31401/>. A Phase 2 trial in an extremely restircted patient population with the ultra-rare disease, proopiomelanocortin deficiency (<a href=\"https://clinicaltrials.gov/show/NCT02507492\">NCT02507492</a>), reported a reduction in hyperphagia and substantial and sustained weight loss <Reference id=31402/>. The drug was progressed to evaluations in Phase 2 and 3 trials in patients with other genetic forms of obesity (<i>e.g</i>. leptin receptor deficiency, Prader-Willi syndrome, Bardet Biedl syndrome and Alstr&ouml;m syndrome). One side-effect of setmelanotide treatment is darkening of the skin and hair, likely as a result of off-target activation of melanocortin receptors (MC<sub>1</sub>R) in peripheral melanoctyes.<br><br>The FDA approved setmelanotide in 2020 to control pro-opiomelanocortin deficiency-associated hyperphagia and thereby treat the obesity that occurs in this rare, genetic, early-onset condition. In the EU, setmelanotide was initially granted orphan designation for several rare genetic-driven obesity conditions, including pro-opiomelanocortin deficiency, Prader-Willi syndrome, Bardet Biedl syndrome, Alstr&ouml;m syndrome and leptin receptor deficiency. In all of these conditions setmelanotide is proposed to restore appetite control and so reduce food intake and weight gain. Regular EMA approval followed in July 2021.<br><br>In spring 2026, the FDA approved setmelanotide as a treatment for acquired hypothalamic obesity (HO), which is a condition that can arise from tumour- or stroke-mediated hypothalamic injury with MC<sub>4</sub>R pathway disruption leading to hyperphagia and weight gain.",
    "mechanismOfAction": "Melanocortin-4 receptor (MC4R) has a central role in the brain's regulation of appetite and energy control. That mutations in the gene encoding melanocortin receptor agonists, or the MC4R gene have been reported to cause obesity <Reference id=14127/>, confirms MC4R activation as a pharmacological intervention with potential benefit in obesity treatment <Reference id=31403/>. Although not a deficiency of MC4R, proopiomelanocortin deficiency patients lack the hormones derived from proopiomelanocortin (adrenocorticotropic hormone (ACTH) and the melanocyte-stimulating hormones). So, in these patients setmelanotide is being used as hormone replacement therapy, to reinstate MC4R activity in the brain and regain control of appetite and energy expenditure.",
    "absorptionAndDistribution": "",
    "metabolism": "",
    "elimination": "",
    "populationPharmacokinetics": "",
    "organFunctionImpairment": "",
    "immuno": "",
    "gtmp": ""
}