Setmelanotide lowers BMI in patients with acquired hypothalamic obesity

Treatment with setmelanotide results in significant BMI reductions in individuals with acquired hypothalamic obesity compared with placebo, with an acceptable safety profile, as shown by the results of a phase III study presented at ENDO 2025.

“In the largest randomized, placebo-controlled trial in acquired hypothalamic obesity to date, setmelanotide demonstrated significant effects over placebo in the primary and all key secondary efficacy endpoints at 52 weeks, with no new safety signals,” said lead author Dr Susan A. Phillips, Pediatric Endocrinology, University of California San Diego, San Diego, California, US.

“Setmelanotide may represent an important treatment option for patients with acquired hypothalamic obesity aged ≥4 years, for which there are no currently approved treatments,” she added.

Overall, 120 patients aged 4 ≥years with BMI ≥95th percentile (4‒<18 years) or ≥30 kg/m² (≥18 years) and acquired hypothalamic obesity following hypothalamic tumour, lesion, or injury were included. They were randomized to receive either setmelanotide (n=81) 0.5 mg subcutaneously once daily (QD), titrated up to 1.5‒3.0 mg QD based on age, weight, and tolerability, or placebo (n=39) for up to 60 weeks.

BMI reduction

Of the participants (mean age 19.9 years), 60.0 percent were female. The BMI in patients aged ≥18 years was 41.2 kg/m², while the BMI Z score in those aged <18 years was 3.61. Fourteen patients ceased treatment prior to end of trial (withdrew: four with setmelanotide vs three with placebo; due to adverse events [AEs]: seven with setmelanotide vs two with placebo). [ENDO 2025, abstract OR11-01]

Participants met the primary endpoint of a modified intent-to-treat (mITT) analysis of the percentage change in BMI at 52 weeks. The mean change in BMI was ‒16.5 percent in the setmelanotide arm compared with 3.3 percent in the placebo arm, with a significant placebo adjusted difference of ‒19.8 percent (95 percent confidence interval [CI], ‒24.6 to ‒15.1; p<0.0001).

With regard to the secondary endpoint, a significantly greater proportion of patients treated with setmelanotide than placebo achieved a BMI reduction of ≥5 percent (79.5 percent vs 10.4 percent), ≥10 percent (63.0 percent vs 5.2 percent), ≥15 percent (50.6 percent vs 2.6 percent), and ≥20 percent (43.2 percent vs 0 percent; p<0.0001 for all).

Phillips and her team also noted a higher mean change in the weekly average of the maximal daily hunger score (≥12 years) among patients who received setmelanotide than those on placebo (‒2.68 vs ‒1.24; p=0.0030).

Safety profile

In terms of safety, all 81 patients in the setmelanotide arm experienced AEs compared with 35 in the placebo arm (100 percent vs 89.7 percent). Skin hyperpigmentation (55.6 percent vs 7.7 percent) was the most common AE, followed by nausea (50.6 percent vs 30.8 percent), vomiting (39.5 percent vs 17.9 percent), and headache (38.3 percent vs 30.8 percent).

Furthermore, one serious treatment-related AE, which is hypernatremia due to vomiting and an inability to tolerate their desmopressin, occurred in the setmelanotide arm.

Setmelanotide was reinitiated after 2 days upon hospital discharge. Notably, one patient with a history of seizure disorder in the setmelanotide cohort died due to seizures. However, this was deemed unrelated to treatment.

“Hypothalamic melanocortin-4 receptor signalling plays a critical role in the regulation of hunger, satiety, and energy expenditure,” Phillips said. “Hypothalamic injury from a tumour or its treatment, or following traumatic brain injury, can lead to hyperphagia and acquired hypothalamic obesity, for which there are no approved treatments.”