medwireNews: The TRANSECEND trial confirms that the melanocortin-4 receptor (MC4R) agonist setmelanotide achieves a significantly greater reduction in BMI and hunger than placebo in children, adolescents and adults with acquired hypothalamic obesity.
The randomised phase 3 trial findings published in The New England Journal of Medicine confirm earlier phase 2 study findings, prompting the investigators to say that “[t]he consistent response to setmelanotide, an α-MSH [α-melanocyte-stimulating hormone] analogue, supports the hypothesis — although it is not yet fully proven — that impaired α-MSH signaling in the MC4R pathway may be a critical deficit in acquired hypothalamic obesity.”
Christian Roth (Seattle Children’s Research Institute, Washington, USA) and co-authors postulate that the MC4R agonist may reduce hunger and increase resting energy expenditure by restoring a deficiency in α-MSH, “similar to hormone-replacement therapies that many patients receive (such as lifelong growth hormone, thyroxine, and hydrocortisone substitution in patients with hypopituitarism).”
Setmelanotide dosing schedule
The study included 120 participants aged 4–66 years (mean 19.9 years, 59% <18 years) who had received surgery, chemotherapy or radiotherapy for craniopharyngioma (78%) or another type of lesion in the hypothalamic region at least 6 months earlier. Children were eligible for the trial if they had a BMI at or above the 95th percentile for age and sex (mean BMI z score=3.61), and adults if they had a BMI of 30 kg/m2 or above (mean BMI=41.2 kg/m2)
Patients were randomly assigned to receive once daily subcutaneous setmelanotide for 52 weeks following an initial dose-escalation period until a therapeutic dose was reached (n=81) or placebo (n=39). For children aged 4–6 years, the therapeutic dose was set at 1.5 mg for those weighing less than 20 kg, 2.0 mg for those weighing 20–24 kg, 2.5 mg for those weighing 25–29 kg, and 3.0 mg for those weighing 30 kg or more; the therapeutic dose was fixed at 3.0 mg for participants aged 6 years and older.
Of note, 66% of the participants also had secondary adrenal insufficiency (adrenal or adrenocortical insufficiency or adrenocorticotropic hormone deficiency), 81% had arginine vasopressin deficiency, and 83% were receiving desmopressin during the trial.
Significant BMI benefits of setmelanotide
After 52 weeks of treatment at the therapeutic dose, the primary endpoint of least squares mean change in BMI in the full study population was –16.5% with setmelanotide versus 3.3% with placebo, a significant difference.
All three key secondary efficacy endpoints also significantly favored setmelanotide therapy, Roth et al report.
Namely, a BMI z score reduction of at least 0.2 points in children or a 5% BMI reduction in adults (83 vs 21%); a BMI reduction of 5% or greater in all patients (80 vs 10%), and a change in the maximal daily hunger score of all participants aged 12 years or older (–2.73 vs –1.45 points).
Other secondary and exploratory analyses were “generally supportive of the primary and key secondary endpoints,” the investigators say, such as the change in BMI z score for children (–1.47 vs –0.12 points) and change in the percentage of children in the 95th percentile for BMI (–26.3 vs –0.1 percentage points).
There was also a greater change in the Symptoms of Hyperphagia composite score with setmelanotide versus placebo as rated by caregivers for children younger than 12 years (–0.65 vs –0.24 out of 0–2 points) and by participants aged 12 years or older (–0.30 vs –0.14 points).
AEs and limitations
Patients given setmelanotide were more likely than those given placebo to experience one or more adverse events (AEs, 100 vs 90%), most commonly skin hyperpigmentation (56 vs 8%), nausea (51 vs 31%), vomiting (40 vs 18%) and headache (38 vs 31%). While AEs were generally mild to moderate, 28% of setmelanotide-treated patients experienced serious AEs, as did 8% of controls.
One serious AE was attributed to trial treatment by the investigators; a patient given setmelanotide who experienced hypernatremia from drug-induced vomiting and inability to take desmopressin, leading to elevated blood sodium – the participant was able to restart treatment after a 2-day pause during hospitalisation.
Setmelanotide was discontinued by six (7%) patients due to AEs, two of whom had multiple side effects. These included hyperpigmentation, gastroesophageal reflux, injection site pruritus, muscle spasms, rhinorrhea, nausea and vomiting, and seizure. Three (8%) patients given placebo also discontinued the trial due to dyspnoea, hypersensitivity or injection site reactions.
The researchers highlight that multiple pituitary hormone deficiencies were common in the trial participants. “Because hunger was generally reduced in participants who received setmelanotide, decreased food and fluid intake may have exacerbated fluid and electrolyte imbalances in this population,” they write.
For example, the team comments, “participants with worsening adrenal insufficiency, nausea and vomiting may have been interpreted as adverse events occurring during the treatment period rather than as symptoms of adrenal insufficiency, which potentially delayed the initiation or escalation of [glucocorticoid] therapy.”
Roth and co-authors note that the trial findings are also limited by “the relatively short duration […] for a disease in which long-term treatment is expected owing to the permanence of hypothalamic injury.”
A long-term extension study beyond 1 year of treatment is ongoing, they say.
By Lynda Williams
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