The FDA has broadened the approval of setmelanotide (Imcivree, Rhythm Pharmaceuticals) to include children aged 2 to 5 years who have rare genetic forms of obesity. This decision marks a significant advancement in treating early-onset obesity linked to specific genetic deficiencies.
The expanded indication is based on data from the VENTURE phase 3 trial, which was published in The Lancet Diabetes & Endocrinology. The trial involved 12 children aged 2 to 5 years with pro-opiomelanocortin (POMC) deficiency, leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome. All participants received once-daily open-label setmelanotide for one year.
Clinical Trial Results
The VENTURE trial demonstrated that 83% of children experienced a 0.2-point or greater reduction in BMI z score after one year. Overall, setmelanotide reduced BMI by 18% from baseline to one year. Children with POMC or LEPR deficiency saw a mean 26% decrease in BMI, while those with Bardet-Biedl syndrome had a mean 10% decline. Caregivers also reported a decrease in hunger for 91% of the participants.
According to Ilene Fennoy, MD, MPH, a pediatric endocrinologist, obesity specialist, and professor of pediatrics at Columbia University Medical Center, "It’s important to understand that rare melanocortin-4 receptor pathway diseases differ from general obesity as the insatiable hunger these patients experience is pathologic and a result of impairment to a pathway in the brain."
Safety Profile
All adverse events reported during the trial were mild or moderate. The most common treatment-emergent adverse events included skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, injection site bruising, injection site pruritus, pyrexia, fall, and melanocytic naevus.
Implications for Treatment
Setmelanotide is a melanocortin-4 receptor (MC4R) agonist and the first precision medicine to target impairment of the hypothalamic MC4R pathway, a root cause of hyperphagia and obesity due to BBS and POMC, PCSK1 and LEPR deficiencies. Prior to this expansion, the FDA had approved setmelanotide for chronic weight management in individuals aged 6 years and older with Bardet-Biedl syndrome (in 2022) and those with POMC deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, or LEPR deficiency (in 2020).
Tim Ogden, president of the Bardet-Biedl Syndrome Foundation, noted the significance of this expanded indication for children with Bardet-Biedl syndrome and their families: "Many children with Bardet-Biedl syndrome feel hungry or think about food regardless of how much or how recently they've eaten, leaving families to deal with children sneaking or stealing food, which makes daily life extremely stressful... Imcivree can be an important tool for their obesity."
