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

The VENTURE trial was the first phase 3, open-label, multicenter study to evaluate setmelanotide — an MC4R receptor agonist — in very young children (2 to 5 years) with rare MC4R pathway-associated obesity: POMC deficiency, LEPR deficiency, or Bardet-Biedl syndrome (BBS). 12 children were included for daily subcutaneous treatment over 52 weeks, with extension up to 18 months.

The primary endpoints were reduction in BMI Z-score (appropriate pediatric parameter) and percentage BMI change:

• 10 of 12 (83%) children achieved BMI Z-score reduction >=0.2 (primary endpoint)
• Mean BMI reduction of ~18% at 52 weeks
• In pediatric MC4R-OB patients (n=8 with 18-month follow-up), BMI reduction was -23.3%
• 91% of caregivers reported significant reduction in hunger (hyperphagia), the most debilitating symptom of these conditions
• Normal growth and development were maintained

The most common adverse events were skin hyperpigmentation (an expected and reversible effect from peripheral melanocortin activation) and mild injection-site reactions. There were no serious adverse events related to treatment, nor negative effects on linear growth, pubertal function, or cognitive development.

VENTURE expanded the use of setmelanotide to the youngest age group, where early treatment may offer greater benefit by preventing the metabolic and psychosocial consequences of extreme obesity from early childhood. The data supported FDA approval for use in children >=2 years with monogenic obesity, making setmelanotide one of the few obesity pharmacotherapies approved in such young pediatric populations.