Setmelanotide in patients aged 2–5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial

Argente J; Verge CF; Okorie U; Fennoy I; Kelsey MM; okkinias C; Scimia C; Lee HM; Farooqi IS

doi:10.1530/ey.22.11.13

11.13

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 11.13 | DOI: 10.1530/ey.22.11.13

ESPEYB25 11. Obesity and Weight Regulation Innovative Interventions (4 abstracts)

11.13. Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial

Argente J , Verge CF , Okorie U , Fennoy I , Kelsey MM , Cokkinias C , Scimia C , Lee HM & Farooqi IS

Author affiliations

Department of Paediatrics and Paediatric Endocrinology, University Hospital Niño Jesús, Research Institute La Princesa, Universidad Autónoma de Madrid, Madrid, Spain; CIBER Fisiopatología de la obesidad y nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, Madrid, [email protected]

Lancet Diabetes Endocrinol. 2025 Jan;13(1):29-37. PMID: 39549719. doi: 10.1016/S2213-8587(24)00273-0. https://pubmed.ncbi.nlm.nih.gov/39549719/

Brief Summary: This open-label, phase 3, multicenter trial evaluated setmelanotide in 12 children aged 2–5 years with rare genetic obesity (POMC or LEPR deficiency or Bardet-Biedl syndrome). After 52 weeks, 83% achieved a meaningful reduction in BMI z-score, with improvements in hunger and caregiver burden, supporting early targeted intervention.

The VENTURE trial is the first to assess setmelanotide in children under 6 years with severe early-onset obesity due to MC4R pathway deficiencies or Bardet-Biedl syndrome, addressing an urgent need for effective early treatment. In POMC or LEPR deficiency, severe early-onset obesity driven by hyperphagia progresses rapidly, with annual weight gain over 7 kg despite intensive lifestyle or surgical interventions, underscoring the limitations of traditional approaches [1].

Setmelanotide, an MC4R agonist, has shown substantial efficacy in older patients, and this study extends those benefits to very young children, with a mean BMI reduction of 18% overall and significant hunger improvement reported by 91% of caregivers. The favourable safety profile and reduction in caregiver burden are particularly relevant given the psychosocial strain often experienced by these families.

Although the open-label design and small cohort limit generalizability, these findings suggest that early pharmacologic intervention can meaningfully alter the natural course of severe genetic obesity, potentially mitigating long-term metabolic and psychosocial complications. Future studies in larger and more diverse cohorts are needed, but the present work already represents a significant advance in precision medicine for rare forms of pediatric obesity.

Reference: 1. Wabitsch M, Farooqi S, Flück CE, et al. Natural history of obesity due to POMC, PCSK1, and LEPR deficiency and the impact of setmelanotide. J Endocr Soc. 2022;6(6):bvac057. doi: 10.1210/jendso/bvac057.