Setmelanotide for the Treatment of Acquired Hypothalamic Obesity.

Methods

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.

我们进行了一项3期试验，其中参与者以2:1的比例随机分配接受setmelanotide（剂量为1.5至3.0毫克）或安慰剂，通过皮下注射每日一次，持续52周，经过剂量递增期后。

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.

年龄至少为4岁的个体如果患有获得性下丘脑性肥胖，且符合以下标准，则有资格参与试验：体重指数（BMI；以公斤为单位的体重除以米为单位的身高的平方）至少为同年龄和性别的第95百分位数（对于<18岁的参与者）或至少为30（对于≥18岁的参与者），以及有下丘脑肿瘤、病变或损伤的病史。

The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period.

主要终点是剂量递增期结束后52周时BMI从基线开始的平均百分比变化。

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.

次要终点包括至少12岁参与者每周平均最大每日饥饿评分的平均变化（范围为0至10，分数越高表示饥饿程度越严重）。

Results

From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants).

从2023年4月26日至2025年3月18日，共有120名参与者被分配接受setmelanotide治疗（81名参与者）或安慰剂（39名参与者）。

The mean (±SD) age was 19.9±13.8 years (range, 4 to 66).

平均年龄为19.9±13.8岁（范围，4至66岁）。

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.

在18岁或以上的参与者中，平均体重指数（BMI）为41.2±9.7；在18岁以下的参与者中，平均BMI z分数为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).

在52周时，使用setmelanotide的患者的体重指数（BMI）的最小二乘平均（LSM）变化为-16.5%（95%置信区间[CI]，-19.3至-13.8），而安慰剂组为3.3%（95% CI，-0.6至7.2）（P<0.001），并且setmelanotide组的每周平均最大每日饥饿评分的LSM变化为-2.73（95% CI，-3.28至-2.18），安慰剂组为-1.45（95% CI，-2.23至-0.67）（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.

setmelanotide组的参与者中有100%报告了不良事件，而安慰剂组为90%，严重不良事件分别报告了28%和8%。

The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache.

使用赛特美拉肽最常见的不良事件包括皮肤色素沉着、恶心、呕吐和头痛。

Conclusions

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.

在4至66岁的获得性下丘脑肥胖患者中，与安慰剂相比，赛特美拉肽在52周时显著降低了BMI和饥饿感。

(Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).

(由Rhythm Pharmaceuticals资助; TRANSCEND临床试验注册号, NCT05774756。)