A new therapy helps achieve a healthier BMI in people whose weight has become dysregulated following treatment for a brain tumor, a clinical trial has found. The results of the trial have been published today in the prestigious New England Journal of Medicine. The new drug, setmelanotide, offers hope for improved health and quality of life for children and adults with hormonal and metabolic dysfunction caused by a brain tumor.
A tumor in the hypothalamus – the brain's control center for hormone regulation – is usually treatable. Each year, approximately 25 children and 50 adults in the Netherlands are diagnosed with a tumor in this region.
Although tumors affecting the brain's hormone center are often benign and can be removed safely, many patients continue to suffer from severe long-term consequences caused by damage to the hypothalamus. For some, these complications can even be life-threatening.
Damage to the hypothalamus can disrupt an important signaling pathway in the brain. The resulting loss of control over satiety, metabolism and impulse regulation can lead to uncontrolled eating and obesity. Until now, there has been no effective treatment for this condition.
In a clinical trial led by Rhythm Pharmaceuticals, Seattle Children's Research Institute, and the University of Florida, scientists studied the effects of setmelanotide*, a drug that restores signaling related to satiety and energy expenditure in the brain.
The study enrolled 120 children and adults with severe obesity caused by hypothalamic damage. For most people taking part, the condition resulted from a brain tumor or its treatment. The average BMI among participants aged 18 years and older was 41.8**.
Of the participants, 81 received a weekly injection of setmelanotide for one year. The remaining 39 participants were assigned – without the knowledge of either the participants or the researchers – to a control group and received a saline placebo throughout the study.
After one year, BMI had decreased by an average of 17% among people receiving setmelanotide. In the placebo group, BMI increased by an average of 3%, which was expected given their continued experience of excessive hunger and reduced metabolism.
The overall net effect of setmelanotide was a 20% reduction in BMI. For someone with an average starting BMI of 41.8, this means their BMI decreased to 33.44. For a person who is 170 cm (5 ft 7 in) tall, that would mean a net weight loss of approximately 24 kilograms (53 pounds) – from a total weight of 121 kilograms (267 pounds) to 97 kilograms (214 pounds).
The results of the clinical trial are published today (Wednesday) in the leading medical journal The New England Journal of Medicine. The study was funded by Rhythm Pharmaceuticals, the manufacturer of setmelanotide.
Most people who received setmelanotide (88%) experienced side effects. These included skin darkening or pigmentation changes, as well as headaches and gastrointestinal symptoms. Even so, 95% of people who took part in the trial chose to continue taking the medication after the trial ended – or chose to start it if they had been assigned to the placebo group. The researchers expect BMI to decrease further in people who continue treatment for longer than one year.
A reduction in BMI provides substantial health benefits, both in the short and long term. It lowers the risk of cardiovascular disease and obesity-related metabolic complications.
A total of 31 participants had previously been treated, before and/or during the study, with obesity medications targeting the GLP-1 pathway, such as Ozempic. People for whom these treatments had not been sufficiently effective and who remained obese were eligible to take part in this trial.
Based on the results of this clinical trial, the new therapy has now been approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)***. The researchers hope that all children and adults living with hypothalamic damage will eventually have access to setmelanotide.
As a next step, the research team plans to investigate the potential effects of setmelanotide when administered immediately after – or even before – surgery. This approach could potentially prevent obesity from developing. In the future, it may also allow surgeons to safely remove more tumor tissue, reducing the risk of the tumor growing back.
The researchers also suspect that hypothalamic obesity is underdiagnosed in adults. They believe that better methods are needed to pick out people with hypothalamic obesity, as setmelanotide may also offer benefits to this population.
Because setmelanotide specifically targets a brain receptor involved in the regulation of satiety and energy balance, the drug is not effective for all forms of obesity. It is intended only for people whose satiety signaling pathway has been disrupted.
Dr. Christian Roth, a pediatric endocrinologist and principal investigator of the Norcliffe Foundation Center for Integrative Brain Research at Seattle Children's Research Institute who served as senior author and was instrumental in the trial's planning, said:
"Our findings represent a major breakthrough for children and adults living with acquired hypothalamic obesity. We designed this study to directly target the deficient MC4R pathway (neural circuit in the brain that regulates hunger), which we believed was central to the disease. The results exceeded expectations: setmelanotide achieved clinically meaningful reductions in BMI and had profound, transformative improvements in hunger and quality of life. By significantly reducing extreme hunger, this treatment allows patients and their families to shift their focus away from food and back to life."
Prof. Hanneke van Santen, MD, pediatric endocrinologist at the Princess Máxima Center for Pediatric Oncology and Wilhelmina Children's Hospital, who led the Dutch arm of the clinical trial, said:
"Until now, there was very little we could do for children with acquired hypothalamic obesity. We could help them manage the consequences, but the condition often turned the lives of both children and their families upside down. From the moment a child wakes up at five in the morning, they experience overwhelming food cravings. They live with a constant sensation of hunger that they cannot control and that isn't relieved by eating. Combined with reduced impulse control and loss of initiative, this often creates extremely difficult situations at home.
"Our clinical trial looking at the benefit of setmelanotide gives children with hypothalamic obesity and their families new hope. The drug's effect was remarkable. Children who previously struggled not only with obesity but also with lethargy, emotional outbursts, and many other obesity-related problems truly seemed to come back to life. And alongside that, there was the tangible and impressive weight loss.
"The results of our clinical trial are so compelling that I hope setmelanotide will soon be reimbursed for this patient group. That is essential if we want to offer setmelanotide to all children living with obesity caused by hypothalamic damage."
Edward Nieuwenhuis, MD, PhD, Chief Medical Officer of the Princess Máxima Center for Pediatric Oncology, said:
"Surgery to remove a brain tumor can result in damage to the hypothalamus, with enormous consequences for quality of life. Among other challenges, children may develop an uncontrollable appetite.
"It is wonderful to see a medication that appears to work so well for children with acquired hypothalamic obesity. Through this study, the Princess Máxima Center has made a significant contribution to improving the quality of life of children affected by brain tumors."
Roan (aged 14) has hypothalamic obesity following treatment for a craniopharyngioma – a tumor affecting his hypothalamus, the brain's hormone control center. Aside from the problems with weight regulation, his vision was reduced to less than 10% and he has memory problems. He says:
"The hunger is the hardest part. I'm hungry almost all day long. It's especially difficult when I'm home alone or in the evenings, because it's hard not to keep thinking about food. At school, I eat in a quieter area so I'm not constantly surrounded by temptation. My doctor told me about the new medication, and I really hope I'll be able to get it. Even if the hunger went away, every day would still be a challenge. But it would make a huge difference."
