Setmelanotide, a melanocortin-4 receptor agonist, significantly reduced body mass index (BMI) and signs of hunger in patients with acquired hypothalamic obesity, according to findings from the phase III TRANSCEND trial published in The New England Journal of Medicine. Although focused primarily on patients with craniopharyngioma, this study addresses a clinically important survivorship issue: the management of severe hypothalamic obesity that can develop after treatment for tumors involving the hypothalamus.
“Our findings represent a major breakthrough for children and adults living with acquired hypothalamic obesity,” said senior author Christian L. Roth, MD, a pediatric endocrinologist and principal investigator of the Norcliffe Foundation Center for Integrative Brain Research at Seattle Children’s Research Institute. “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.”
Following the results of the TRANSCEND study, the U.S. Food and Drug Administration as well as the European Medicines Agency approved an expanded indication of setmelanotide for chronic weight management in adults and pediatric patients aged 4 years and older with acquired hypothalamic obesity.
Background and Study Methods
Following a successful phase II trial for setmelanotide, a melanocortin-4 receptor agonist, for weight loss in patients with acquired hypothalamic obesity, researchers conducted a randomized phase III trial to further explore the benefit of the agent. TRANSCEND enrolled patients aged 4 years or older who had acquired hypothalamic obesity, defined as a BMI at or above the 95th percentile for age and sex, or a BMI of at least 30 for adult patients (18 years and older) with a history of a hypothalamic tumor, lesion, or injury. Patients were randomly assigned 2:1 to receive either setmelanotide at a dose of 1.5 to 3.0 mg or placebo, administered subcutaneously once daily for 52 weeks, after a dose-escalation period.
The primary endpoint was the mean percent change in BMI over 52 weeks.
A total of 120 patients were enrolled in the setmelanotide (n = 81) and placebo (n = 39) arms. Patients had a mean age of 19.9 years (range = 4–66 years).
Among adult patients, the mean BMI was 41.2 ± 9.7, and the mean BMI for younger patients was 3.61 ±1.66
At 52 weeks, the least-squares mean change in BMI was –16.5% (95% confidence interval [CI] = –19.3 to –13.8) for setmelanotide and 3.3% (95% CI = –0.6% to 7.2%) with placebo (P < .001).
The least-squares mean change in the weekly average of maximal daily hunger scores, a secondary endpoint, was –2.73 (95% CI = –3.28 to –2.18) and –1.45 (95% CI = –2.23 to –0.67) for the setmelanotide and placebo arms, respectively (P = .009).
All patients in the investigational arm experienced an adverse event, compared with 90% of patients in the placebo arm, with the most common events in the setmelanotide arm being skin hyperpigmentation, nausea, vomiting, and headache. Serious adverse events were observed in 28% of patients in the investigational arm and in 8% of patients in the control arm.
“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,” said study author Hanneke van Santen, MD, a pediatric endocrinologist at the Princess Máxima Center for Pediatric Oncology and Wilhelmina Children’s Hospital, who led the Dutch arm of the clinical trial.
For oncology clinicians, the findings highlight the importance of addressing chronic treatment-related complications in patients with hypothalamic tumors, in addition to managing the underlying disease
DISCLOSURES:The study was supported by Rhythm Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.
