Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.
Setmelanotide resulted in a significant reduction in BMI and hunger scores over 52 weeks in participants with acquired hypothalamic obesity, but the long-term implications and safety profile require further investigation.
Where it sits
this study against the rest of the setmelanotide corpusSummary and findings
This phase 3 trial evaluated the effects of setmelanotide on body mass index (BMI) and hunger in participants aged 4 to 66 years with acquired hypothalamic obesity. Participants received either setmelanotide (1.5 to 3.0 mg) or placebo daily for 52 weeks. The study reported significant changes in BMI and hunger scores favoring setmelanotide over placebo.
Abstract
<h4>Background</h4>A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed.<h4>Methods</h4>We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age.<h4>Results</h4>From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache.<h4>Conclusions</h4>Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).
Background
This study addresses the efficacy of setmelanotide, a melanocortin-4 receptor agonist, in treating acquired hypothalamic obesity, a condition characterized by significant weight gain due to hypothalamic damage. Prior studies indicated potential weight loss benefits, but further data were necessary to establish its effectiveness and safety in a larger cohort. The significance of this trial lies in its phase 3 design, which aims to provide more robust evidence regarding the treatment's impact on BMI and hunger.
Methods
The study was a phase 3 randomized controlled trial with a total of 120 participants assigned in a 2:1 ratio to receive either setmelanotide (1.5 to 3.0 mg) or placebo subcutaneously once daily for 52 weeks following a dose-escalation period. Participants were eligible if they had acquired hypothalamic obesity defined by specific BMI criteria and a history of hypothalamic tumor, lesion, or injury. The primary endpoint was the mean percent change in BMI from baseline to 52 weeks, while secondary endpoints included changes in hunger scores.
Results
The primary endpoint demonstrated a least-squares mean (LSM) change in BMI of -16.5% (95% CI, -19.3 to -13.8) for the setmelanotide group compared to 3.3% (95% CI, -0.6 to 7.2) for the placebo group, with a statistically significant difference (P<0.001). Additionally, the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) for setmelanotide versus -1.45 (95% CI, -2.23 to -0.67) for placebo (P=0.009).
Interpretation
The results indicate a statistically significant reduction in BMI and hunger scores with setmelanotide compared to placebo. However, while the effect on BMI is statistically significant, the clinical significance may be questioned, particularly given the high baseline BMI and the potential for small effect sizes in the context of obesity treatment. The study's limitations, including industry funding and the relatively short follow-up period, necessitate caution in interpreting these findings and their applicability to broader populations.
Key findings
- LSM change in BMI at 52 weeks was -16.5% (95% CI, -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001)
- LSM change in weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P=0.009)
- Adverse events reported in 100% of participants in the setmelanotide group and in 90% of those in the placebo group
- Serious adverse events reported in 28% of the setmelanotide group and 8% of the placebo group
- Mean age of participants was 19.9±13.8 years (range, 4 to 66)
- Mean BMI among participants 18 years or older was 41.2±9.7
Limitations
- Industry-funded study, potential for bias
- Short follow-up of 52 weeks may not capture long-term effects
- Small sample size with n=120 participants
- Single-site trial limits generalizability
- Participants had a high baseline BMI, which may affect outcomes