Wabitsch, MartinMartinWabitschFarooqi, SadafSadafFarooqiFlück Pandey, Christa EmmaChrista EmmaFlück Pandey0000-0002-4568-5504Bratina, NatasaNatasaBratinaMallya, Usha GUsha GMallyaStewart, MurrayMurrayStewartGarrison, JillJillGarrisonvan den Akker, EricaEricavan den AkkerKühnen, PeterPeterKühnen2024-10-092024-10-092022-06-01https://boris-portal.unibe.ch/handle/20.500.12422/70668Context Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR 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. Objective To characterize the historical weight trajectory in these patients. Methods 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. Results 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. Conclusion 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.enLEPR MC4R pathway POMC obesity setmelanotide600 - Technology::610 - Medicine & healtharticle10.48350/1698743552882610.1210/jendso/bvac057