TRANSCEND
This phase 3 trial showed that a daily injection which turns the brain's fullness signal back on cut body-mass index by about a sixth, and reduced hunger, in children and adults whose weight gain followed damage to the hypothalamus from a tumour or its treatment, while people on placebo gained weight; it supported the March 2026 US approval of Imcivree for that use.
Overview
TRANSCEND (NCT05774756; organisation id RM-493-040; US Imcivree label Trial 1) was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial of setmelanotide, a melanocortin-4 receptor agonist, in acquired hypothalamic obesity. Participants were at least 4 years old with 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. They were assigned 2:1 to setmelanotide 1.5 to 3.0 mg or placebo, injected subcutaneously once daily for 52 weeks after a dose-escalation period.
The primary endpoint was the mean percent change in body-mass index from baseline to 52 weeks after the end of dose escalation. In the NEJM 2026 report, 120 participants (81 setmelanotide, 39 placebo; mean age 19.9 years, range 4 to 66) were assigned between April 2023 and March 2025. The least-squares mean change in body-mass index was minus 16.5 percent (95 percent CI minus 19.3 to minus 13.8) with setmelanotide and plus 3.3 percent (minus 0.6 to 7.2) with placebo (P less than 0.001). Among participants aged 12 and older, the least-squares mean change in the weekly average of maximal daily hunger scores (0 to 10) was minus 2.73 versus minus 1.45 (P = 0.009). Adverse events occurred in 100 percent of the setmelanotide group and 90 percent of the placebo group, serious adverse events in 28 percent and 8 percent; skin hyperpigmentation, nausea, vomiting and headache were the commonest events with setmelanotide.
The FDA approved the acquired hypothalamic obesity indication for patients aged 4 years and older on 19 March 2026 (Drugs@FDA supplement 9). The registry lists the trial as active, not recruiting, with completion expected in 2027, and its condition is hypothalamic obesity rather than a corpus cancer, which is why the automated pass never attached it to the setmelanotide record.
- -16.5 vs 3.3 out of 100 reached this endpoint with Setmelanotide 1.5 to 3.0 mg daily compared with Placebo; 19.8 fewer per 100.
- On this measure the first group did worse, not better.
- The p-value (<0.001) says a difference this large would rarely happen by chance; it does not say how large or how useful the difference is.
- Setmelanotide 1.5 to 3.0 mg daily: -2.7 points; Placebo: -1.4 points.
- The p-value (0.009) says a difference this large would rarely happen by chance; it does not say how large or how useful the difference is.
- Least-squares mean; 95% CI -3.28 to -2.18; the abstract does not give the subgroup size.
- This endpoint is not one of the standard survival or response measures; read it alongside the trial's primary result.
- These results apply to the people the trial enrolled: Acquired hypothalamic obesity after a hypothalamic tumour, lesion or injury in people aged 4 years and older: setmelanotide 1.5 to 3.0 mg versus placebo, injected under the skin once daily for 52 weeks after dose escalation. People in a different situation may not see the same effect.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
120 analysed.
Least-squares mean; 95% CI -19.3 to -13.8 · Least-squares mean; 95% CI -0.6 to 7.2
SourceLeast-squares mean; 95% CI -3.28 to -2.18; the abstract does not give the subgroup size · Least-squares mean; 95% CI -2.23 to -0.67
Source| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Mean percent change in body-mass index at 52 weeks after dose escalation (pivotal cohort)primary | Setmelanotide 1.5 to 3.0 mg daily | 81 | -16.5% | - | <0.001 | link |
| Placebo | 39 | 3.3% | ||||
| Change in the weekly average of maximal daily hunger score at 52 weeks (participants aged 12 and older; scale 0 to 10) | Setmelanotide 1.5 to 3.0 mg daily | - | -2.73 points | - | 0.009 | link |
| Placebo | - | -1.45 points |