Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency

Abstract

ObjectivePro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.MethodsWe studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.ResultsIn cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.ConclusionsSetmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…Magel2 is one of several genes typically inactivated in PWS. Magel2 ‐deficient mice were found to have functionally defective POMC neurons and were responsive to pharmacological treatment with an MC4R agonist that bypasses this defect . Patients with PWS may also be responsive to therapeutic activation of the MC4R, which provides the rationale for the treatment of obesity with setmelanotide in PWS.…”

“…Setmelanotide (formerly known as RM‐493) is a potent and selective MC4R agonist in development for the treatment of rare genetic disorders of obesity. It binds with high affinity to the human MC4R, resulting in efficient activation of MC4R . Although in vitro receptor affinity and activity data show that setmelanotide also exhibits agonist activity at the MC1R, MC3R, and MC5R, much higher concentrations (at least 20‐fold) of setmelanotide are needed for activation of other melanocortin receptors than for MC4R .…”

“…It binds with high affinity to the human MC4R, resulting in efficient activation of MC4R . Although in vitro receptor affinity and activity data show that setmelanotide also exhibits agonist activity at the MC1R, MC3R, and MC5R, much higher concentrations (at least 20‐fold) of setmelanotide are needed for activation of other melanocortin receptors than for MC4R . In 2017, setmelanotide entered phase 3 clinical trials in patients with obesity bearing MC4R mutations .…”

Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin‐4 receptor

“…However, clinical trials of potent small molecule orthosteric agonists of the MC4R have failed as a result of target‐mediated pressor effects. Despite the target‐mediated pressor response resulting from most melanocortin agonists, two peptide analogues of the native MC4R ligand, α‐melanocyte‐stimulating hormone (α‐MSH), have been demonstrated to cause weight loss without a pressor response . One of these compounds, setmelanotide, has been used successfully in a clinical trial in two patients with compound heterozygous mutations in pro‐opiomelanocortin (POMC), the preprohormone precursor for α‐MSH, and in a clinical trial in patients with homozygous mutations in the gene encoding the leptin receptor .…”

“…Despite the target-mediated pressor response resulting from most melanocortin agonists, two peptide analogues of the native MC4R ligand, α-melanocyte-stimulating hormone (α-MSH), have been demonstrated to cause weight loss without a pressor response. [24][25][26][27] One of these compounds, setmelanotide, has been used successfully in a clinical trial in two patients with compound heterozygous mutations in pro-opiomelanocortin (POMC), the preprohormone precursor for α-MSH, 24 and in a clinical trial in patients with homozygous mutations in the gene encoding the leptin receptor. 28 There are no data available explaining why some MC4R agonists are capable of inducing weight loss without the target-mediated pressor response, although biased agonism must be considered in the event that multiple signalling pathways are activated downstream of MC4R.…”