Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide

Abstract

Context 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. Design This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). Setting These were multicenter trials. Patients Patients had obesity due to POMC/PCSK1 or LEPR deficiency. Intervention During the trial, patients were treated with setmelanotide. Measure 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. Conclusions 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.

Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity

“…Of note, five participants achieved 15% or greater weight loss with two participants reaching 20% or greater weight loss [18 && ]. There was only one enrolled patient with PCSK1 deficiency in the POMC/PCSK1 trial; this individual's weight was greater than the 95th percentile at the time of study recruitment [19]. This patient lost 7.1% of their body weight during the initial 12-week treatment period.…”

“…There was only one enrolled patient with PCSK1 deficiency in the POMC/PCSK1 trial; this individual's weight was greater than the 95th percentile at the time of study recruitment [ 19 ]. This patient lost 7.1% of their body weight during the initial 12-week treatment period.…”

Naringenin and β-carotene convert human white adipocytes to a beige phenotype and elevate hormone- stimulated lipolysis

“…POMC and PCSK1 were both elevated by NRBC in adipocytes. The important role of POMC is shown in studies linking severe obesity in humans to rare genetic mutations in POMC or PCSK1 ( 77 ). S100b, which has been characterized in brown adipocytes of mice, stimulates neurite outgrowth of sympathetic terminals in adipose tissue following cold exposure ( 78 ).…”

“…Neuromedin B is a peptide that acts on hypothalamic neurons to promote satiety, and a missense mutation is linked to hyperphagia and obesity in genetic studies (74, 75). Proopiomelanocortin (POMC), a peptide prohormone that is cleaved by PCSK1 into the hormone a-MSH, is involved in the suppression of food intake (76). POMC and PCSK1 were both elevated by NRBC in adipocytes.…”

New developments and therapies in pediatric endocrinology

“…POMC is then cleaved into melanocortin ligands (by PCSK-1) which bind to and activate the melanocortin-4 receptor pathway. Mutations in the key genes in this upstream pathway (POMC, PCSK1, LEPR) cause severe early-onset obesity and Setmelanotide is now available for treatment for these patients [43].…”