- In a randomized phase III trial, the MC4R agonist setmelanotide achieved substantial reductions in BMI and hunger scores in patients with acquired hypothalamic obesity.
- At one year, participants receiving setmelanotide lost a mean of 36.4 lb, whereas the placebo group gained 5.3 lb.
- These results supported the recent regulatory approval expanding setmelanotide’s label for this indication.
Treatment with setmelanotide (Imcivree), a melanocortin-4 receptor (MC4R) agonist, produced significant reductions in body mass index (BMI) and hunger in individuals with acquired hypothalamic obesity, according to the phase III TRANSCEND trial.
By week 52, adults and pediatric patients as young as 4 years old treated with setmelanotide experienced a mean BMI reduction of 16.5%, compared with a 3.3% increase in the placebo group (P<0.001), reported Christian Roth, MD, of Seattle Children’s Research Institute in Washington, and colleagues.
This translated to a mean weight loss of 36.4 lb with setmelanotide versus a 5.3 lb gain with placebo. Therapy also lowered the weekly average of maximum daily hunger scores (−2.73 vs −1.45 points, P=0.009), the authors wrote in the New England Journal of Medicine.
Based on these data, the once-daily injection received approval earlier this year as the first therapy specifically indicated for acquired hypothalamic obesity in patients aged 4 years and older.
Acquired hypothalamic obesity is a rare condition characterized by rapid, intractable weight gain following hypothalamic damage caused by tumors, surgery, head trauma, or inflammation. This damage precipitates a constellation of symptoms including hyperphagia, hormone deficiencies, severe fatigue, sleep and thermoregulatory disturbances, and a slowed metabolism.
“Patients with acquired hypothalamic obesity and their families face an urgent need for effective treatment options,” Roth stated in a release from the drug manufacturer.
Current options remain limited. Standard obesity management strategies, such as GLP-1 receptor agonists or bariatric surgery, do not directly target the underlying hypothalamic dysfunction driving the condition, often yielding variable results.
Setmelanotide functions as a synthetic analogue of the endogenous α-MSH hormone, bypassing the hypothalamic lesion to restore impaired MC4R signaling. The MC4R pathway is central to the homeostatic regulation of body weight, modulating hunger, satiety, food intake, and energy expenditure.
In an accompanying editorial, I. Sadaf Farooqi, MBChB, PhD, of the University of Cambridge in England, observed that structural hypothalamic damage might reasonably have been predicted to render setmelanotide ineffective.
“Had the investigators not carried out this trial, patients with a complex condition for which no other therapies exist would have been denied the opportunity to benefit from an effective drug,” she wrote.
Farooqi noted that the efficacy of GLP-1 receptor agonists in individuals with MC4R mutations suggests the two drug classes act via largely independent neural pathways, raising the possibility that patients could benefit from combination therapy with setmelanotide and a GLP-1 agent.
“It is a salutary reminder to physicians, researchers, and regulators that experimental medicine studies and early-phase clinical trials are sometimes the only means by which we can test hypotheses and ask critical questions about disease mechanisms to advance knowledge and transform human health,” she wrote. “There is little doubt that the results of this trial will do exactly that.”
Setmelanotide also holds indications for Bardet-Biedl syndrome and for genetic obesity resulting from mutations in the POMC, LEPR, or PCSK1 genes.
In the double-blind TRANSCEND trial, researchers randomized 120 patients in a 2:1 ratio across 29 global sites, including the U.S., between April 2023 and March 2025. Participants assigned to the active arm received a daily dose of 1.5 to 3.0 mg following a dose-escalation period.
Enrollees ranged from 4 to 66 years of age (mean age 19.9), all with obesity and a history of hypothalamic injury. The majority (78%) had sustained damage from a craniopharyngioma tumor.
Adverse events were generally mild to moderate. The most common side effects included skin hyperpigmentation (56% vs 8% with placebo), nausea (51% vs 31%), vomiting (40% vs 18%), and headache (38% vs 31%). The authors noted that while setmelanotide selectively targets MC4Rs, it can also activate melanocortin-1 receptors, accounting for the high rates of skin hyperpigmentation.
A higher incidence of melanocytic nevi was also observed with the study drug (17% vs 5%). One serious adverse event was attributed to setmelanotide: a participant experienced severe drug-induced nausea and vomiting that prevented oral desmopressin administration, leading to hypernatremia and hospitalization.
The investigators acknowledged that while a significant decrease in hunger was demonstrated, the trial was not designed to assess changes in energy expenditure. A long-term extension trial is ongoing to evaluate the safety and efficacy of treatment beyond one year.
