Setmelanotide (Imcivree®): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary of Setmelanotide (Imcivree®)

Setmelanotide, marketed under the brand name Imcivree®, represents a first-in-class precision medicine for the chronic management of weight in individuals with specific rare genetic disorders of obesity.[1] It is a potent, selective agonist of the melanocortin 4 receptor (MC4R), a critical component of the hypothalamic signaling pathway that governs hunger, satiety, and energy expenditure.[4] The therapeutic rationale for Setmelanotide is to restore function to this pathway when it is impaired by upstream genetic defects.

The medication is specifically indicated for chronic weight management in adults and children (aged 2 years and older) with obesity due to deficiencies in pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or the leptin receptor (LEPR), as confirmed by an FDA-approved genetic test.[2] Its indication has also been expanded to include Bardet-Biedl syndrome (BBS), another rare genetic disorder where MC4R pathway function is compromised.[5] Setmelanotide is not effective for and is not indicated in the treatment of general (polygenic) obesity or in cases where genetic variants are classified as benign.[1]

Pivotal clinical trials have demonstrated significant efficacy, with 80% of patients with POMC/PCSK1 deficiency and 45.5% of patients with LEPR deficiency achieving at least a 10% reduction in body weight after one year of treatment.[3] Efficacy has also been established in BBS, with a significant proportion of patients achieving meaningful weight loss and reduction in hunger scores.[12]