Setmelanotide Prevents Obesity in Mouse Model of POMC Deficiency, Study Reports

Setmelanotide Prevents Obesity in Mouse Model of POMC Deficiency, Study Reports
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Continuous setmelanotide treatment prevented the development of obesity in mice with a form of POMC deficiency in the hypothalamus area of the brain, a study reports.

The therapy was also found not to affect healthy mice fed a high-fat diet. 

The study, “Chronic Treatment Of Juvenile Hypothalamic Pomc-deficient Mice With RM-493 Prevents The Development Of Obesity,” was published in the Journal of the Endocrine Society and was scheduled to be presented at ENDO 2020, which was canceled due to the COVID-19 pandemic

POMC deficiency, caused by mutations in the POMC gene, belongs to a group of genetic conditions associated with an impaired MC4R pathway, which controls hunger, appetite, and energy balance. People with a disrupted MC4R pathway develop severe, early-onset obesity and insatiable appetite (hyperphagia).

Setmelanotide (RM-493) is an investigational therapy designed to activate the MC4R pathway. Developed by Rhythm Pharmaceuticals, the treatment has been shown to promote weight loss and less hunger in adults and children with POMC deficiency in a Phase 3 clinical trial (NCT02896192).

Rhythm is currently awaiting a regulatory decision in the U.S. and the European Union on the approval of setmelanotide as a therapy for people with POMC deficiency and LEPR deficiency, another form of genetic obesity. A decision by the U.S. Food and Drug Administration is expected by Nov. 27.

In the new study, researchers at the University of Michigan Medical School, along with a scientist at Rhythm, tested continuous setmelanotide treatment in mice missing the Pomc gene in the arcuate nucleus (Arc) of the hypothalamus — a part of the brain that regulates hunger and energy balance.

Starting at weaning, these mice typically develop hyperphagia, as well as progressive obesity, infertility, and insulin resistance

The Arc-Pomc knockout mice were fed regular food (chow) while control, or wildtype, mice were fed a high-fat diet comprising 45% fat.

At weaning, the animals were randomly divided into three groups: continuous setmelanotide treatment throughout the entire study from 4 to 24 weeks of age; treatment with setmelanotide for the first four weeks, then switch to a control (vehicle) treatment; and a group that received the vehicle only. 

Setmelanotide was delivered by subcutaneous (under-the-skin) infusion using osmotic minipumps

The team then measured food intake, body weight, body composition, glucose tolerance, and insulin tolerance, as well as several measures of metabolism, including oxygen consumption, energy expenditure, walking activity, and lipid (fat) and glucose oxidation.

Mice lacking Pomc and treated with setmelanotide throughout the study weighed significantly less than animals in the other two groups. They also had higher energy expenditure and an improved glucose-insulin index.

In mice that switched to the vehicle after setmelanotide treatment, the improvements steadily reversed within one month. 

In contrast, controls fed a high-fat diet and treated continuously with setmelanotide did not differ in any measurement when compared to the switch and vehicle groups. 

Setmelanotide treatment did not affect “the development of obesity or secondary metabolic disruptions in response to high-fat diet consumption,” the scientists wrote. 

“We conclude that the obesity syndrome caused by a loss of hypothalamic Pomc expression was completely blocked by RM-493 [setmelanotide] treatment started before the onset of obesity, with no apparent desensitization to the drug’s action over 20 weeks,” they added.

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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