Setmelanotide Promising as Early Intervention for Rare Obesity in Young Children: Findings from VENTURE Trial

Previous research has shown that aetmelanotide reduces 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 classified as MC4R pathway diseases. However, no approved therapies currently exist for children under 6 years with these conditions.

Against the above background, Prof Jesús Argente, IMDEA Food Institute, Madrid, Spain, and colleagues aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2–5 years with POMC or LEPR deficiency or Bardet-Biedl syndrome through phase 3, open-label VENTURE trial.

The Phase 3, open-label, multicenter trial was conducted at six sites across the USA, the UK, Spain, and Australia. It included children aged 2–5 years with hyperphagia and obesity caused by biallelic POMC (including PCSK1) LEPR variants or genetically confirmed BBS. Participants received open-label subcutaneous setmelanotide once daily for 52 weeks, starting at a dose of 0.5 mg, which was increased every two weeks by 0.5 mg until the maximum dose based on weight was reached.

The primary goals at week 52 were to assess the percentage of patients achieving a reduction of 0.2 points or more in their BMI Z score—a measure that compares a child’s BMI to age- and sex-specific reference values—and the average percentage change in BMI. Secondary measures included safety, hunger levels, weight-related outcomes, and the impact on caregiver burden. 

The following were the key findings of the study:

• Between March 8, 2022, and September 18, 2023, 13 patients were screened at six sites, and 12 were enrolled in the study (seven with POMC or LEPR deficiency and five with BBS).
• One patient with BBS was excluded due to a BMI below the 97th percentile.
• Of the 12 enrolled patients, 58% were male (seven), and 42% were female (five). The mean age of participants was 3.6 years. Eleven patients completed the trial.
• At week 52, 83% achieved a reduction of 0.2 points or more in BMI Z score per WHO methodology.
• The mean percent change in BMI from baseline at week 52 was −18% for the overall safety population.
• Patients with POMC or LEPR deficiency had a mean BMI reduction of −26%, while those with BBS had a reduction of −10%.
• Secondary endpoints showed mean reductions at week 52 of 3.4 in BMI Z score and 32.5% in the percentage of the BMI 95th percentile.
• 91% of caregivers reported that patients were less hungry compared to baseline.
• All adverse events were mild or moderate, the most common being skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions.
• No serious adverse events, study discontinuations, or deaths were reported.

"To our knowledge, this is the first trial evaluating setmelanotide in patients under 6 years of age. The findings highlight the potential benefits of early intervention with the drug to manage obesity in this young population," the researchers concluded.

Reference: Lancet Diabetes Endocrinol 2024; doi:10.1016/ S2213-8587(24)00273-0