The melanocortin-4 receptor (MC4R) pathway, a key component of the central melanocortin pathway, regulates hunger, caloric intake and energy expenditure, consequently affecting body weight. The importance of the MC4R pathway’s control of energy balance has made it a compelling target for the potential treatment of body weight disorders.
A functional MC4R pathway balances our energy intake and energy expenditure to help maintain a stable body weight. In the physiologic state, MC4R pathway activation begins when first-order proopiomelanocortin (POMC)-producing neurons are stimulated to release melanocyte-stimulating hormone (MSH) in response to leptin receptor (LEPR) activation (by the hormone, leptin). MSH is generated from the POMC protein by the enzyme proprotein convertase 1/3 (associated with the proprotein convertase subtilisin/kexin type 1 or PCSK1 gene), which cleaves POMC into smaller bioactive molecules. Released MSH then binds to and activates the MC4R on second order MC4R-expressing neurons to simulate a cascade of neurological signaling that ultimately leads to a suppression of hunger, a decrease in food intake and an increase in energy expenditure.
In the pathological or disease state, variants in these genes, or others involved in MC4R pathway function, can cause impaired MC4R pathway activation. This can lead to early-onset, severe obesity and hyperphagia (or insatiable hunger), the hallmarks of rare genetic disorders of obesity.
By combining our understanding of the neurobiology of the MC4R pathway, the genetics and epidemiology of obesity and our DNA sequencing infrastructure, Rhythm is uniquely positioned to identify rare genetic disorders of obesity that could be treated with our investigational drug, setmelanotide. Setmelanotide is an MC4R agonist that has been shown to activate the MC4R pathway by mimicking the effects of the natural agonist, MSH. By deploying setmelanotide as a targeted therapy within the context of MC4R pathway impairment, we are studying whether there is therapeutic value when we leverage underlying genetic causes.
We are focused on developing setmelanotide for rare genetic disorders of obesity that arise due to defects in the pathway upstream of the MC4R. In these cases, setmelanotide has the potential to restore impaired pathway function by activating the MC4R, reestablishing downstream functionality and regulating hunger, energy intake and energy expenditure, thereby reducing body weight.