Wabitsch Martin, Farooqi Sadaf, Flück Christa E, Bratina Natasa, Mallya Usha G, Stewart Murray, Garrison Jill, van den Akker Erica, Kühnen Peter
Division of Pediatric Endocrinology and Diabetes, Center for Rare Endocrine Diseases, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
J Endocr Soc. 2022 Apr 15;6(6):bvac057. doi: 10.1210/jendso/bvac057. eCollection 2022 Jun 1.
Rare homozygous or biallelic variants in , , and can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity. In pivotal Phase 3 clinical trials, treatment with the MC4R agonist setmelanotide reduced hunger and weight in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.
To characterize the historical weight trajectory in these patients.
This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening.
A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year.
In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals.
阿黑皮素原（POMC）、前蛋白转化酶枯草溶菌素/kexin 1型（PCSK1）和瘦素受体（LEPR）中的罕见纯合或双等位基因变异可破坏黑皮质素-4受体（MC4R）途径的信号传导，导致食欲亢进和严重的早发性肥胖。在关键的3期临床试验中，使用MC4R激动剂setmelanotide治疗可减轻因POMC、PCSK1或LEPR缺乏导致肥胖的患者的饥饿感和体重。
描述这些患者的历史体重轨迹。
该分析纳入了来自2项关键的单臂、开放标签3期试验（NCT02896192、NCT03287960）的数据。这些是多中心试验。患者因POMC/PCSK1或LEPR缺乏而肥胖。在试验期间，患者接受setmelanotide治疗。在筛查期间获得了测量体重和身高的历史数据。
本分析纳入了17例有体重和身高历史数据的患者（POMC，n = 8；PCSK1，n = 1；LEPR，n = 8）。在使用setmelanotide治疗前，因POMC/PCSK1或LEPR缺乏导致肥胖的患者在整个儿童期体重均高于第95百分位数，体重持续增加，并且在接受干预（如饮食、手术、运动）后未出现长期体重减轻。在1年的观察期内，setmelanotide治疗使体重和体重指数轨迹减缓。
在POMC、PCSK1或LEPR缺乏的患者中，传统的减肥干预措施对严重早发性肥胖的轨迹影响有限。然而，setmelanotide治疗使体重和体重指数轨迹减缓，并使大多数个体体重减轻且有益健康。
