Dawid Frączkowski

Setmelanotide – from genes to targeted therapy in some rare forms of obesity
2021-08-28

Obesity is a serious public health concern. It significantly affects an individual’s quality of life and is associated with an increased risk of developing other conditions, including diabetes, hypertension, and cardiovascular complications. The increasing health, social, and economic impacts of this chronic disease means there is an urgent need for effective pharmacological treatment to achieve relevant weight loss. Defects in the hypothalamic leptin/melanocortin pathway contribute to a variety of rare forms of obesity. Insufficient efficacy of lifestyle intervention or bariatric surgery in individuals with mutations in genes encoding melanocortin 4 receptor (MC4R) pathway components demonstrates the dominance of this pathway in body weight homeostasis. Loss of function mutations in the MC4R pathway including mutations in the pro-opiomelanocortin (POMC), prohormone convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), or the MC4R genes have been shown to be causative of early-onset severe obesity. MC4R is the key regulator in the appetite-controlling pathway within the hypothalamus. Its activation stimulates energy expenditure and inhibits food intake, resulting in a negative energy balance and potentially reducing obesity. The most common cause of monogenic obesity are mutations in the gene encoding the MC4R protein. Managing patients with monogenic non-syndromic obesity is clinically challenging since they display complex phenotypes and the obesity is often refractory to classical treatments. Until recent years, there has been a lack of targeted and effective pharmacological therapies except for leptin (LEP) therapy that was available for leptin deficiency. Fortunately, the picture has changed and promising molecules acting on the leptin/melanocortin pathway such as setmelanotide are now emerging as targeted therapeutic opportunities. Setmelanotide is a synthetic, cyclic, 8-amino acid, peptide, potent and selective second‑generation MC4R agonist, an analog of the naturally occurring alpha‑melanocyte‑stimulating hormone (-MSH). It restores the activity of the MC4 receptor pathway to reduce hunger and promote weight loss. Setmelanotide appears to be the most promising for patients with POMC or LEPR deficiency. Unfortunately, obesity is highly prevalent worldwide, and the percentage of affected individuals is rising year by year, making this is a disease that needs to be treated more often.

Keywords: setmelanotide, obesity, hyperphagia, leptin, MC4R.

© Farm Pol, 2021, 77(6): 349–359

Setmelanotide – from genes to targeted therapy in some rare forms of obesity

Obesity is a serious public health concern. It significantly affects an individual’s quality of life and is associated with an increased risk of developing other conditions, including diabetes, hypertension, and cardiovascular complications. The increasing health, social, and economic impacts of this chronic disease means there is an urgent need for effective pharmacological treatment to achieve relevant weight loss. Defects in the hypothalamic leptin/melanocortin pathway contribute to a variety of rare forms of obesity. Insufficient efficacy of lifestyle intervention or bariatric surgery in individuals with mutations in genes encoding melanocortin 4 receptor (MC4R) pathway components demonstrates the dominance of this pathway in body weight homeostasis. Loss of function mutations in the MC4R pathway including mutations in the pro-opiomelanocortin (POMC), prohormone convertase subtilisin/kexin type 1 (PCSK1), leptin receptor (LEPR), or the MC4R genes have been shown to be causative of early-onset severe obesity. MC4R is the key regulator in the appetite-controlling pathway within the hypothalamus. Its activation stimulates energy expenditure and inhibits food intake, resulting in a negative energy balance and potentially reducing obesity. The most common cause of monogenic obesity are mutations in the gene encoding the MC4R protein. Managing patients with monogenic non-syndromic obesity is clinically challenging since they display complex phenotypes and the obesity is often refractory to classical treatments. Until recent years, there has been a lack of targeted and effective pharmacological therapies except for leptin (LEP) therapy that was available for leptin deficiency. Fortunately, the picture has changed and promising molecules acting on the leptin/melanocortin pathway such as setmelanotide are now emerging as targeted therapeutic opportunities. Setmelanotide is a synthetic, cyclic, 8-amino acid, peptide, potent and selective second‑generation MC4R agonist, an analog of the naturally occurring alpha‑melanocyte‑stimulating hormone (-MSH). It restores the activity of the MC4 receptor pathway to reduce hunger and promote weight loss. Setmelanotide appears to be the most promising for patients with POMC or LEPR deficiency. Unfortunately, obesity is highly prevalent worldwide, and the percentage of affected individuals is rising year by year, making this is a disease that needs to be treated more often.

Keywords: setmelanotide, obesity, hyperphagia, leptin, MC4R.

© Farm Pol, 2021, 77(6): 349–359