The melanocortin-4 receptor (MC4R) pathway is a key component of the central hypothalamic regulation of hunger. The importance of the MC4R pathway’s control of energy balance has made it a compelling target for the potential treatment of body weight diseases.
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.
Variants in these genes, or others involved in MC4R pathway function, may impair MC4R pathway activation. This can lead to early-onset, severe obesity and hyperphagia (or insatiable hunger), the hallmarks of MC4R pathway diseases.
Rhythm continues to develop a therapy designed to restore the function of an impaired MC4R pathway.
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 MC4R pathway diseases 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 (melanocyte-stimulating hormone). By deploying setmelanotide as a targeted therapy within the context of MC4R pathway impairment, we are studying its clinical effect when used in patients with severe obesity and hyperphagia.
We are focused on developing setmelanotide for patients with severe obesity and hyperphagia that arise due to variants in the pathway upstream of the MC4R. In these cases, setmelanotide has the potential to restore impaired pathway signaling by activating the MC4R, reestablishing downstream functionality and regulating hunger and satiety, energy intake and energy expenditure, thereby reducing body weight.