medwireNews: The melanocortin-4 receptor (MC4R) agonist setmelanotide effectively reduces BMI in children with early-onset severe childhood obesity caused by single gene variants that impact hunger, satiety, and energy expenditure via the MC4R signaling pathway, research shows.
Setmelanotide has previously been shown to reduce hunger and weight in children aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS), all of which are classed as MC4R pathway diseases.
However, there are currently no approved therapies for children younger than 6 years of age with these conditions.
To address this, Jesús Argente (Universidad Autónoma de Madrid, Spain) and colleagues carried out the phase 3 VENTURE trial. The study included 12 patients aged 2–5 years (mean age 3.6 years, 58% boys) with POMC or LEPR deficiency (n=7) or BBS (n=5) who were enrolled from six sites in the USA, UK, Spain, and Australia between 2022 and 2023.
They were each given subcutaneous setmelanotide once daily for 52 weeks, starting at 0.5 mg and then increasing in 0.5-mg increments every 2 weeks up to the maximum weight-based dose.
At baseline, the children had a mean BMI of 29.9 kg/m2, which corresponded to a WHO Growth Standards z score of 8.0.
The researchers report in The Lancet Diabetes & Endocrinology that, at week 52, BMI had fallen by 18%, on average, and 83% of participants had a 0.2-point or greater reduction in BMI z score, with a mean reduction of 3.4 points overall.
“A reduction in BMI Z score of 0.2 points or more has been defined as clinically important weight loss associated with cardiometabolic improvements,” Argente et al remark.
The patients with POMC or LEPR deficiency had a mean BMI reduction of 26% at week 52, while the reduction was 10%, on average, among those with BBS. Six (86%) of the seven patients with POMC or LEPR deficiency and four (80%) of the five patients with BBS reached a 0.2-point or greater reduction in BMI z score. The corresponding mean BMI z score reductions were 5.2 points and 1.3 points.
Caregivers of 10 (91%) of 11 evaluable patients reported that patients were less hungry at week 52 than at baseline, with 64% saying the children were “much less hungry.”
Caregivers also reported reduced burden on themselves due to patient hunger at week 52, with mean interview scores improving to below the threshold for risk for depression.
All patients experienced at least one treatment-emergent adverse event (AE) but there were no serious AEs or AEs leading to study discontinuation or death.
The most common mild or moderate AEs were skin hyperpigmentation (75%), vomiting (58%), nasopharyngitis (42%), upper respiratory tract infection (33%), and injection site bruising and pruritus each occurring in 33% of patients.
Argente and co-authors conclude that the VENTURE trial “supports the use of setmelanotide for the treatment of hunger and early-onset, severe obesity in paediatric patients with rare MC4R pathway-associated obesity.”
They add: “The substantial BMI and hunger reductions observed in patients, wherein the natural history is of continued weight gain and development of comorbidities, highlight the benefit of early intervention to improve obesity outcomes and the overall health trajectory of these patients.”
Commenting on the findings, Christian Roth, from University of Washington in Seattle, USA, said that the study “adds to the current literature supporting setmelanotide as an aetiological precision medicine approach for the treatment of rare genetic forms of severe early-onset obesity.”
He adds that although the results “support the overall efficacy and safety of setmelanotide in this very young age group,” further work is needed “for quantitative assessments of safety and to measure the response rates in patients with different genotypes.”
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