Setmelanotide was associated with greater reductions in body mass index and participant-reported hunger scores than placebo among pediatric and adult patients with acquired hypothalamic obesity in the phase 3 TRANSCEND trial published in The New England Journal of Medicine.
The researchers conducted the phase 3, double-blind, randomized, placebo-controlled trial at 29 sites across six countries. Eligible patients were aged 4 years or older and had acquired hypothalamic obesity associated with craniopharyngioma, another hypothalamic lesion, or documented hypothalamic injury. For patients with craniopharyngioma or another hypothalamic lesion, surgery, chemotherapy, or radiation involving the hypothalamus had occurred at least 6 months before screening. Patients with documented hypothalamic injury also had to be at least 6 months beyond the injury.
Participants were randomly assigned 2:1 to receive once-daily subcutaneous setmelanotide or placebo. Setmelanotide was escalated from 0.5 mg to a therapeutic dose of 1.5 to 3 mg. The primary assessment occurred 52 weeks after completion of dose escalation, with total treatment lasting up to approximately 60 weeks.
The modified intention-to-treat analysis included 120 treated participants: 81 received setmelanotide and 39 received placebo. The mean age was 20 years, 59% were younger than 18 years, and 78% had craniopharyngioma. The primary analysis used an adjusted analysis-of-covariance model, and missing values were imputed using available placebo-group data.
At the primary assessment, the least-squares mean body mass index (BMI) change was a 17% reduction with setmelanotide and a 3% increase with placebo, an adjusted difference of approximately 20 percentage points.
A prespecified key secondary endpoint—defined as at least a 5% BMI reduction in adults or at least a 0.2-point BMI z score reduction in patients younger than 18 years—occurred in 83% of setmelanotide recipients and 21% of placebo recipients. Across the overall trial population, at least a 5% BMI reduction occurred in 80% of setmelanotide recipients and 10% of placebo recipients.
Among participants aged at least 12 years who were able to assess and report their own hunger, the weekly average of maximal daily hunger scores decreased by a least-squares mean of 2.7 points with setmelanotide and 1.5 points with placebo. These three key secondary outcomes were tested hierarchically; other secondary and subgroup findings were not adjusted for multiplicity.
Adverse events occurred in 100% of setmelanotide recipients and 90% of placebo recipients. Serious adverse events occurred in 28% and 8%, respectively. Common events with setmelanotide included skin hyperpigmentation, nausea, vomiting, and headache. One treatment-related serious adverse event involved hypernatremia and hospitalization in a patient who could not take oral desmopressin because of setmelanotide-associated nausea and vomiting.
The trial provided approximately 1 year of controlled data. Visible skin hyperpigmentation may have made treatment assignment apparent to some participants, potentially reducing the effectiveness of blinding. The study population also had a high prevalence of pituitary hormone deficiencies, with 66% having a reported history of secondary adrenal insufficiency and 81% having a reported history of arginine vasopressin deficiency.
The study was funded by Rhythm Pharmaceuticals. Researcher disclosures can be found in the published study.