Setmelanotide

Mechanism (as reported)

Research described setmelanotide as an MC4R agonist that acts on neurons in the leptin-melanocortin pathway involved in bodyweight regulation and may affect melanocortin signalling after hypothalamic injury. (PMIDs: 36356613, 38697184, 33137293, 29031731)

Key findings (each cites a source)

• A multicentre, randomized, double-blind, placebo-controlled phase 3 trial reported that after 52 weeks, a proportion of patients aged 12 years or older with Bardet-Biedl syndrome achieved at least a 10% reduction in bodyweight when treated with setmelanotide, while results for Alström syndrome were described as inconclusive. [PMID 36356613]
• In the Bardet-Biedl syndrome/Alström syndrome phase 3 trial, the most commonly reported treatment-emergent adverse events included skin hyperpigmentation and injection site erythema, and the report stated that serious adverse events occurred but none were considered related to setmelanotide. [PMID 36356613]
• A phase 2, open-label, multicentre trial in acquired hypothalamic obesity reported that the primary endpoint was met, with most enrolled patients achieving at least a 5% reduction in BMI after 16 weeks compared with a historic control rate. [PMID 38697184]
• In the acquired hypothalamic obesity phase 2 trial, frequent adverse events included nausea, vomiting, skin hyperpigmentation, and diarrhoea; the report also described longer-term extension follow-up with mean BMI change over time among participants continuing into an extension study. [PMID 38697184]
• Two single-arm, open-label, multicentre phase 3 trials reported that in severe obesity due to POMC or LEPR deficiency, a proportion of participants achieved at least 10% weight loss at approximately 1 year, and hunger scores decreased in the reported analyses. [PMID 33137293]
• In the POMC and LEPR deficiency phase 3 trials, common adverse events included injection site reaction and hyperpigmentation, and the report stated that no serious treatment-related adverse events occurred. [PMID 33137293]
• A study evaluating MC4R deficiency reported that setmelanotide acted as a more potent MC4R agonist than endogenous alpha-melanocyte stimulating hormone in cells, described disproportionate rescue signaling for a subset of severely impaired MC4R mutants, and reported weight loss in a 28-day phase 1b human trial in obese MC4R variant carriers. [PMID 29031731]
• A development/approval milestone article described setmelanotide as having received first approval in the USA for chronic weight management in patients 6 years and older with obesity due to POMC, PCSK1, or LEPR deficiency, and it described an EMA PRIME designation for treatment of obesity and hunger control associated with deficiency disorders of the MC4 receptor pathway. [PMID 33638809]
• A review on genetic obesity described that management has largely relied on lifestyle intervention and noted that new therapeutic options—including therapies targeting the leptin-melanocortin pathway—have emerged, with implementation of genetic diagnosis emphasized. [PMID 37191347]