Setmelanotide for the treatment of acquired hypothalamic obesity (TRANSCEND)
In children and adults whose severe weight gain followed damage to the hypothalamus, a year of daily setmelanotide injections cut body-mass index by 16.5 percent while placebo recipients gained 3.3 percent, and hunger fell more too.
Overview
Primary publication of TRANSCEND (NCT05774756). Participants aged 4 years and older with acquired hypothalamic obesity, defined by a body-mass index at or above the 95th percentile for age and sex (under 18) or at least 30 (18 and over) and a history of a hypothalamic tumour, lesion or injury, were randomly assigned 2:1 to setmelanotide 1.5 to 3.0 mg or placebo, given subcutaneously once daily for 52 weeks after dose escalation. The primary endpoint was the mean percent change in body-mass index from baseline to 52 weeks after the end of dose escalation; the weekly average of maximal daily hunger scores (0 to 10) in participants aged 12 and older was a secondary endpoint.
From 26 April 2023 to 18 March 2025, 120 participants were assigned to setmelanotide (81) or placebo (39); mean age 19.9 years (range 4 to 66). The least-squares mean change in body-mass index at 52 weeks was minus 16.5 percent (95 percent CI minus 19.3 to minus 13.8) with setmelanotide and 3.3 percent (minus 0.6 to 7.2) with placebo (P less than 0.001); the hunger score changed by minus 2.73 (minus 3.28 to minus 2.18) versus minus 1.45 (minus 2.23 to minus 0.67) (P = 0.009). Adverse events were reported in 100 percent and 90 percent of participants and serious adverse events in 28 percent and 8 percent; skin hyperpigmentation, nausea, vomiting and headache were the commonest events with setmelanotide.
- Least-squares mean change in body-mass index at 52 weeks: minus 16.5 percent with setmelanotide vs plus 3.3 percent with placebo (P<0.001).
- Hunger score (participants aged 12 and older): minus 2.73 vs minus 1.45 (P = 0.009).
- Serious adverse events in 28 percent vs 8 percent; skin hyperpigmentation, nausea, vomiting and headache were the commonest events with setmelanotide.
For survivors of craniopharyngioma and other hypothalamic injuries, whose weight gain has resisted diet and conventional drugs, this is the first randomised evidence of a treatment that works on the damaged satiety pathway itself. The FDA extended the Imcivree label to acquired hypothalamic obesity in March 2026 on this trial.
- One year of follow-up; durability beyond 52 weeks and effects on cardiometabolic outcomes are not yet reported.
- Serious adverse events were more than three times as frequent with setmelanotide (28 percent vs 8 percent).
- The abstract does not give the size of the age 12 and older subgroup used for the hunger endpoint.