Setmelanotide in obesity: a profile of its use

Subcutaneous setmelanotide (IMCIVREE®), a melanocortin-4 receptor agonist, meets a previously unmet need and thus represents an important advancement in the management of patients with pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency obesity. Setmelanotide is the first approved treatment in patients aged ≥ 6 years with these conditions. In two single-arm, open-label, multicentre, phase III trials, subcutaneous setmelanotide was effective in reducing body weight by at least 10% from baseline after approximately 1 year of treatment at individualised therapeutic doses in patients aged ≥ 6 years with POMC, PCSK1 or LEPR deficiency obesity. Other outcomes relating to weight loss and self-reported hunger scores were also improved with setmelanotide therapy. Setmelanotide was generally well tolerated in clinical trials. The causes of obesity are multifactorial, one of which is genetic mutations leading to deficiencies in key ligands and receptors involved in the leptin-melanocortin pathway in the brain that regulates hunger and body weight. While lifestyle interventions and bariatric surgery are available, there is a lack of pharmacological treatment options for obesity arising from genetic factors. Subcutaneous setmelanotide (IMCIVREE®) is the first treatment to be approved in the EU and the USA for patients aged ≥ 6 years with obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. It works by activating the melanocortin-4 receptor, a crucial protein receptor in the leptin-melanocortin pathway, facilitating weight loss through hunger reduction and increased energy expenditure. In phase III trials, approximately one year of treatment with subcutaneous setmelanotide was associated with at least 10% weight reduction in a significant number of patients with POMC, PCSK1 or LEPR deficiency obesity. Improvements in other outcomes related to weight loss and self-reported hunger scores were also evident. Setmelanotide was generally well tolerated. Setmelanotide represents an important advancement in the management of patients with POMC, PCSK1 or LEPR deficiency obesity.