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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Dysfunctional melanocortin signaling caused by MC4R mutation is linked to obesity. Setmelanotide is an MC4R agonist that has been tested clinically for decreasing food intake and body weight control. In patients with leptin receptor deficiency, setmelanotide treatment significantly reduced food intake and body weight (Kuhnen et al. 2016). Unlike other MC4R agonists, no increase in blood pressure or severe adverse effect related to setmelanotide was observed in the study. However, in obese MC4R mutation carriers, setmelanotide treatment produces no significant difference in body weight change compared to control (Collet et al. 2017). These findings suggest that MC4R is required for setmelanotide to produce an inhibitory effect on food intake and body weight. In POMC-deficient patients, treatment with setmelanotide restores the MC4R signaling pathway, which leads to severe weight loss (Kuhnen et al. 2016; Clement et al. 2018). According to the mechanism for the MC4R-activated signaling in controlling neuronal activity, both Kir7.1 and KATP channels may contribute to the decrease in food intake by setmelanotide.
Future Directions in Obesity and Weight Management
Published in James M. Rippe, Lifestyle Medicine, 2019
Likewise, other new agents under development show promise for incremental gains in efficacy. In a phase I study of two patients with a rare genetic POMC defect, setmelanotide produced impressive short-term reductions in weight and hunger.48 In patients with other POMC defects, the results were more modest.49
A narrative review of anti-obesity medications for obese patients with osteoarthritis
Published in Expert Opinion on Pharmacotherapy, 2022
Win Min Oo, Ali Mobasheri, David J Hunter
Setmelanotide is an agonist of melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, which regulates energy balance and body weight [128]. Mutations in the MC4R gene result in hyperphagia and severe childhood-onset obesity (0.5% to 5.8% of childhood-onset obesity) [129]. It is approved for treating childhood obesity arising from pro-opiomelanocortin (POMC) [80% (n = 10) achieved ≥10% weight loss at 1 year [130]], proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency [45% (n = 11) achieved ≥10% weight loss at one year [130]] in a personalized medicine approach. In a phase-3 trial, 34.5% (n = 31) achieved a ≥ 10% weight loss in patients with Bardet–Biedl or Alström syndrome [131]. It is administered once daily by the subcutaneous route, using a titration schedule up to a maximum of 3 mg daily [132].
Anorectic state of obesity medications in the United States. Are leaner times ahead?
Published in Expert Opinion on Pharmacotherapy, 2020
Currently, there are five FDA-approved pharmacotherapies for the long-term management of obesity. An additional five potential pharmacotherapies are in phase II/III clinical trials. These include two monotherapies and three combinational therapies. Semaglutide is a monotherapy that is a long acting GLP-1 receptor agonist and is currently FDA approved for the management of type II diabetes. Another monotherapy, setmelanotide, is a novel MC4 agonist and the current trials are restricted to genetically obese populations. Two combination therapies, dapagliflozin/metformin and GLP-1/glucagon agonists (MEDI0382) are being investigated in diabetic obese populations for the management of weight loss. Another combinational therapy, tesofensine/metoprol is under investigation in hypothalamic-injured obese and Prader Willi populations.
An update on pharmacotherapeutic strategies for obesity
Published in Expert Opinion on Pharmacotherapy, 2021
Beverly G. Tchang, Mohamad Sirri Tarazi, Mohini Aras, Alpana P. Shukla
Setmelanotide is a melanocortin-4-receptor (MC4R) agonist that causes anorexia. In phase II, nonrandomized, open-label pilot studies, it was administered as a subcutaneous injection at doses of 1.5–2.0 mg daily, resulting in 11.4–21.6% weight loss over 26–36 weeks in three individuals with leptin receptor deficiency [83] and 13.4–16.6% weight loss over 12–13 weeks in two individuals with POMC deficiency [84]. The FDA has recently approved setmelanotide for chronic weight management in patients 6 years and older with obesity due to POMC deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor deficiency due to confirmed pathogenic genetic variants [85].