Setmelanotide Shows Promise in Reducing Obesity in Young Children With Rare Genetic Deficiencies

• A Phase 3 trial of setmelanotide in children aged 2-5 years with Bardet-Biedl syndrome or POMC, PCSK1, or LEPR deficiency demonstrated clinically meaningful reductions in BMI Z-score.
• 83% of patients achieved a ≥0.2-point reduction in BMI Z-score after 52 weeks, with a mean percent change in BMI from baseline of -18%.
• Caregivers reported a 91% reduction in patient hunger compared to baseline, alongside a reduced personal burden.
• Setmelanotide was generally well-tolerated, with no new safety signals and common adverse events including skin hyperpigmentation and vomiting.

Rhythm Pharmaceuticals' Phase 3 VENTURE trial results, published in The Lancet Diabetes & Endocrinology, reveal that setmelanotide, a melanocortin-4 receptor (MC4R) agonist, significantly reduces body mass index (BMI) and hunger in children aged 2 to under 5 years with severe obesity caused by Bardet-Biedl syndrome (BBS) or pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The study highlights the potential of early intervention with targeted therapies in this vulnerable population.

The open-label, 52-week trial enrolled 12 patients and assessed the impact of setmelanotide on co-primary endpoints, demonstrating that 10 of 12 patients (83%) achieved a ≥0.2-point reduction in body mass index (BMI) Z-score. The mean percent change in BMI from baseline was -18%. Furthermore, 91% of caregivers reported reduced hunger in their children compared to baseline, with caregivers also noting a decrease in their personal burden.

Clinician Insights

Professor Jesús Argente, M.D., Ph.D., from Hospital Infantil Universitario Niño Jesús and Universidad Autónoma de Madrid, emphasized the significance of these findings: "Severe, early-onset obesity has been shown to have a negative short-term and long-term impact on a child’s health. In this study, setmelanotide demonstrated clinically meaningful reductions in hunger and body weight in patients younger than 5 years of age with severe obesity. We believe these data support the use of this targeted therapy in a patient population that could benefit from intervention as early as possible."

Safety and Tolerability

Setmelanotide was generally well-tolerated, with no serious adverse events (AEs) leading to study discontinuation or death. The most common treatment-emergent AEs were skin hyperpigmentation (75%), vomiting (58%), nasopharyngitis (42%), upper respiratory tract infection (33%), and injection site bruising (33%).

Regulatory Landscape

In July 2024, setmelanotide (IMCIVREE) received authorization in the European Union as the first precision medicine for hunger control and obesity treatment in adults and children as young as 2 years with BBS or POMC, PCSK1, or LEPR deficiency. Rhythm Pharmaceuticals has also submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand IMCIVREE's label to include pediatric patients aged 2 to under 6 years in approved indications in the United States. The FDA has granted Priority Review to the sNDA, with a Prescription Drug User Fee Act (PDUFA) goal date of December 26, 2024.