Effect of setmelanotide, a melanocortin‐4 receptor agonist, on obesity in Bardet‐Biedl syndrome

Abstract

Aim: To report an analysis of 1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). Materials and methods: Individuals aged 12 years and older with BBS received oncedaily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. Results: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was −5.5% (90% CI, −9.3% to −1.6%; n = 8); change from baseline was −11.3% (90% CI, −15.5% to −7.0%; n = 8) at 6 months and −16.3% (90% CI, −19.9% to −12.8%; n = 7) at 12 months. All participants reported at least one treatmentemergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. Conclusions: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

“…First-generation melanocortin receptor agonists were effective for weight loss ( Sharma et al., 2019 ) but were associated with increased blood pressure, as predicted by studies in MC4R -deficient mice and humans ( Greenfield et al., 2009 ; Tallam et al., 2005 ). Setmelanotide, a second-generation small-molecule MC4R agonist currently in clinical trials, causes significant weight loss in complete POMC deficiency ( Kühnen et al., 2016 ) and other genetic obesity syndromes characterized by a loss of melanocortin tone ( Clément et al., 2018 , 2020 ; Collet et al., 2017 ; Haws et al., 2020 ). Interestingly, setmelanotide does not increase blood pressure.…”

The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design

“…In phase 2 and 3 clinical trials, setmelanotide treatment resulted in reduced body weight and hunger scores in individuals with obesity due to proopiomelanocortin and leptin receptor deficiency [ 14 , 15 ]. In a recent phase 2 trial of 8 individuals with BBS and 4 with Alström syndrome, setmelanotide was associated with a decrease in hunger and weight-related outcomes for up to 12 months [ 16 , 17 ].…”

2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

“…Setmelanotide acts as a selective melanocortin-4 (MC4) receptor agonist and presents a 20-fold higher potency than the endogenous agonist α-MSH [ 19 , 26 ]. In the brain, MC4 receptors are involved in regulating hunger and satiety, in addition to energy expenditure [ 27 ]. Deficiency of POMC, PCSK1, and LEPR cause the MC4 receptor pathway to be insufficiently activated.…”

“…Setmelanotide shows high efficacy with fewer side effects, especially those related to hypertension and adverse cardiovascular effects, which were observed in the first generation MC4R agonists, such as LY2112688 [ 22 , 27 , 29 ].…”