Setmelanotide lowers BMI by 5% or more for most people with hypothalamic obesity
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Key takeaways:
- Setmelanotide reduced BMI by a mean 18% for children and 6% for adults with hypothalamic obesity at 16 weeks.
- Twelve participants who continued setmelanotide in an extension trial cut their BMI by 26% at 1 year.
Setmelanotide reduced BMI by at least 5% at 16 weeks among 89% of children and adults with hypothalamic obesity, according to findings from a phase 2 trial published in The Lancet Diabetes & Endocrinology.
“This was the first study to investigate the use of the melanocortin-4 receptor agonist setmelanotide (Imcivree, Rhythm Pharmaceuticals) as a targeted treatment for hypothalamic obesity,” Christian L. Roth, MD, professor of pediatrics in the division of endocrinology and diabetes at the University of Washington and Seattle Children’s Research Institute, told Healio. “We observed a consistent reduction in body weight and hunger that far exceeds anything we’ve seen from other treatments before.”
Hypothalamic obesity occurs when people have rapid weight and hyperphagia after a hypothalamus injury, which is most commonly caused by some brain tumors, according to Roth. The phase 2, open-label, proof-of-concept trial enrolled 18 children and adults aged 6 to 40 years diagnosed with craniopharyngioma or another nonmalignant brain tumor affecting the hypothalamic region who had a BMI in the 95th percentile or higher for age and sex for those younger than 18 years, or a BMI of 35 kg/m2 for adults aged 18 years and older (mean age, 15 years; 61% male; 78% white). All participants had undergone treatment for intracranial tumors 6 months to 15 years before screening and had a history of hypothalamic damage on an MRI scan within 8 months of screening. Participants received once-daily subcutaneous setmelanotide for 16 weeks. The study’s primary endpoint was the percentage of participants with a BMI reduction of at least 5% at 16 weeks. Change in BMI z score for children, percentage of body weight change for adults, and change in maximal daily hunger score from baseline to 16 weeks were assessed as secondary outcomes.
Reductions in BMI, hunger
The study group included 13 children younger than 18 years and five adults aged 18 years and older. At 16 weeks, 89% of participants had a 5% or greater reduction in BMI. Children had a mean 18% BMI decrease and adults had a 6% drop in BMI from baseline to 16 weeks.
BMI z score decreased by 1.3 points at 16 weeks for children in the study. Among adults, mean body weight declined by 6% at 16 weeks.
Maximal daily hunger scores were reported by participants aged 12 years and older on a scale of 0 to 10, with a higher score indicating more hunger. Hunger scores declined at 1 week of treatment and remained lower than baseline through the end of the study. At 16 weeks, mean maximal hunger scores were 2.9 points lower compared with baseline.
All participants reported at least one treatment-emergent adverse event during the study, with all but one event being mild or moderate in severity. The most frequent adverse events were nausea, vomiting and skin hyperpigmentation. One participant discontinued the study due to hyperpigmentation and another discontinued due to increased levels of liver transaminases. Both events were related to setmelanotide and moderate in severity.
‘Encouraging’ long-term weight loss
Twelve participants continued receiving setmelanotide as part of a long-term extension trial. Those participants had a 26% decline in BMI from baseline to 1 year. Of the most frequent adverse events reported in the main trial, only vomiting was reported during the long-term extension.
“The sustained and deepened weight loss at 1 year of setmelanotide therapy ... was especially encouraging to see,” Roth said. “Eleven of those patients improved by one or more overweight classes, and three pediatric patients achieved normal weight.”
Setmelanotide is now being investigated in an ongoing 52-week, phase 3, placebo-controlled trial, according to Roth. Topline data from the trial is expected in the first half of 2025.
For more information:
Christian L. Roth, MD, can be reached at christian.roth@seattlechildrens.org.
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