Setmelanotide in children aged 2 to 5: the VENTURE trial

Why this study matters

Some children develop severe obesity and intense hunger in their first years because of rare gene changes affecting the brain's appetite pathway. These include POMC deficiency, LEPR deficiency and Bardet-Biedl syndrome (BBS). Setmelanotide acts on the MC4R pathway that these conditions disrupt, and had been studied in people aged 6 and older. VENTURE was the first trial of the medicine in children under 6. For Canadian families affected by these rare conditions, it is the only evidence in this age group that we reviewed.

Who was in the study

Thirteen children were screened at six sites in the United States, the United Kingdom, Spain and Australia between March 8, 2022 and September 18, 2023. Twelve were enrolled: seven with POMC or LEPR deficiency and five with BBS. One child with BBS was excluded because their BMI was below the 97th percentile. Seven children (58%) were boys and five (42%) were girls. The mean age was 3.6 years (standard deviation 0.9). All had hyperphagia, meaning extreme and persistent hunger, and obesity. Eleven children completed the 52-week trial.

What the researchers did

This was a phase 3, open-label, single-arm, multicentre trial. Open-label means everyone knew the child was receiving the medicine. Single-arm means there was no placebo or comparison group, so every result is a before-and-after change within the same children.

Setmelanotide was given by injection under the skin once daily for 52 weeks. Dosing started at 0.5 mg and increased every 2 weeks in 0.5 mg steps until reaching the maximum dose for the child's weight. The summary we reviewed does not report the final maintenance doses.

There were two co-primary outcomes at week 52: the percentage of children whose BMI Z score fell by at least 0.2 points, and the mean percent change in BMI. Body mass index (BMI) compares weight with height. A Z score shows how far a child's BMI sits from what is typical for their age and sex; a drop means BMI moved closer to the typical range.

What they found

Ten of the 12 children (83%) reached a reduction of at least 0.2 points in BMI Z score at week 52, with a 95% confidence interval of 58.7% to 99.8% (R32-C88). A confidence interval is the range in which the true value most likely sits; with only 12 children it is very wide.

The mean percent change in BMI at week 52 was -18% (standard deviation 13) across all children (R32-C88). Standard deviation shows how spread out individual results were; here it means responses varied a lot.

Caregivers of 91% of the children reported that the child was less hungry than at the start.

Side effects and people who stopped

All side effects were mild or moderate. The most common were skin hyperpigmentation (darkening of the skin), vomiting, nasopharyngitis (common cold symptoms), upper respiratory tract infection, and injection site reactions. No serious side effects, no deaths, and no side effects leading to stopping the study were reported. Eleven of 12 children completed the trial; the summary we reviewed does not say why one did not.

What this study does not tell you

• With 12 children, this is a very small trial. It cannot detect uncommon harms and gives wide confidence intervals.
• There was no placebo or untreated comparison group, so some of the change could reflect growth or other factors.
• The trial was open-label, so caregivers' reports of hunger could be influenced by knowing the child was on treatment.
• The two genetic groups responded differently, and each group is even smaller than the whole.
• The trial lasted 52 weeks. It does not show longer-term effects or what happens after stopping.
• This is research in a rare population. It does not by itself mean the medicine is authorized in Canada for this age group, and it says nothing about children with common obesity.
• The trial was funded by the maker of setmelanotide.

What it means in Canada

The trial sites were in the United States, the United Kingdom, Spain and Australia. Its results apply only to young children with confirmed POMC deficiency, LEPR deficiency or Bardet-Biedl syndrome, and does not say whether the medicine is right for any child. For information on the medicine, see setmelanotide in Canada. For what provincial plans pay for, see public drug coverage by province.

Related reading

Other studies in this library that bear on the same question.

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