Setmelanotide: what does it mean for clinical care of patients with obesity?

Abstract

In The Lancet Diabetes & Endocrinology, Karine Clément, Erica van den Akker, and colleagues present the results of setmelanotide in participants with three of the ultrarare genetic conditions associated with severe childhood obesity. 1 Clément K van den Akker E Argente J et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020; (published online Oct 30.)https://doi.org/10.1016/S2213-8587(20)30364-8 Summary Full Text Full Text PDF Scopus (29) Google Scholar Although they occur only rarely, these conditions present enormous challenges for health-care providers, parents, and patients. The 21 participants in the setmelanotide study had biallelic variations in the prohormone pro-opiomelanocortin (POMC; n=9), proprotein convertase subtilisin and kexin type 1 (PCSK1; n=1), which is an important enzyme in activating the melanocortin 4 receptor (MC4R) pathway, or the leptin receptor (LEPR; n=11), which is essential for POMC function. These conditions produce hyperphagia and severe childhood-onset obesity and might be associated with various other endocrinopathies, such as adrenocorticotropic hormone deficiency, hypothyroidism, hypogonadism, hypopigmentation, hypoglycaemia, and others. Earlier, setmelanotide showed excellent outcomes in two patients with POMC deficiency, reversing hyperphagia and producing dramatic weight loss in both patients. 2 Kühnen P Clement K Wiegand S et al. Proopiomelanocortin deficiency treated with a melanocortin-4receptor agonist. N Engl J Med. 2016; 375: 240-246 Crossref PubMed Scopus (206) Google Scholar When given to three patients with LEPR deficiency, setmelanotide produced clinically significant reduction in both bodyweight and hyperphagia. 3 Clement K Biebermann H Farooqi IS et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24: 551-555 Crossref PubMed Scopus (107) Google Scholar The drug has also been studied in seven patients with Bardet-Biedl syndrome, showing hunger reduction and mean weight loss at 1 year of –16·3% (90% CI −19·9 to−12·8). 4 Haws R Brady S Davis E et al. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020; (published online July 6.)https://doi.org/10.1111/dom.14133 Crossref PubMed Scopus (13) Google Scholar Thus, the results reported herein have been eagerly anticipated. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trialsOur results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Full-Text PDF