Background

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2–5 years with POMC or LEPR deficiency or BBS.

Methods

This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2–5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete.

Findings

Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7–99·8). The mean percent change in BMI from baseline at week 52 was −18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was −26% (SD 11) in patients with POMC or LEPR deficiency and −10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported.

Interpretation

To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population.

Funding

Rhythm Pharmaceuticals.

中文翻译：

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Setmelanotide 治疗 2-5 岁罕见 MC4R 通路相关肥胖症 （VENTURE） 患者：一项为期 1 年、开放标签、多中心、3 期试验

 背景

Setmelanotide 是一种黑皮质素-4 受体 （MC4R） 激动剂，已被证明可以减轻 6 岁及以上患有黑皮质素原 （POMC） 缺乏症（包括前蛋白转化酶枯草杆菌蛋白酶/kexin 1 型 [PCSK1] 的双等位基因变异）、瘦素受体 （LEPR） 缺乏症或 Bardet-Biedl 综合征 （BBS） 患者的饥饿感和体重。目前尚无批准用于 6 岁以下患者的疗法。3 期、开放标签 VENTURE 试验旨在评估 setmelanotide 在 2-5 岁 POMC 或 LEPR 缺陷或 BBS 患者中的疗效和安全性。

 方法

这项 3 期、开放标签、多中心试验在美国、英国、西班牙和澳大利亚的六个地点进行，招募了 2-5 岁因双等位基因 POMC（包括 PCSK1）或 LEPR 变异或基因证实的 BBS 而出现食欲亢进和肥胖的符合条件的患者。开放标签皮下注射 setmelanotide 每天给药一次，持续 52 周，从 0·5 mg 开始，剂量每 2 周增加一次，增量为 0·5 mg，直到达到基于体重的最大剂量。第 52 周的共同主要终点是 BMI Z 评分（一种用于评估儿科患者 BMI 的统计量度，考虑患者的 BMI 并将其与相同年龄和性别的参考值进行比较）和平均百分比变化。其他终点测量了安全性、饥饿、体重相关结局和照顾者负担。该研究于 ClinicalTrials.gov （NCT04966741） 注册并已完成。

 发现

2022 年 3 月 8 日至 2023 年 9 月 18 日期间，在 6 个地点筛选了 13 名患者，并招募了 12 名患者（7 名 POMC 或 LEPR 患者，5 名 BBS 患者）;1 例 BBS 患者被排除在外，因为他们的 BMI 不在第 97 个百分位数或以上。在入组的 12 名患者中，大多数为男性 （7 [58%] vs 女性 5 [42%]），平均年龄为 3·6 岁 （SD 0·9）。11 例患者完成了试验。根据 WHO 方法，12 名参与者中有 10 名 （83%） 在第 52 周时达到 BMI Z 评分降低 0·2 分或更多（95% CI 58·7-99·8）。在第 52 周时，总体安全人群中 BMI 相对于基线的平均百分比变化为 -18% （SD 13）。POMC 或 LEPR 缺乏症患者第 52 周时 BMI 的平均百分比变化为 -26% （SD 11），BBS 患者为 -10% （9）。第 52 周时，BMI Z 评分 （3·4 [2·5]） 和 BMI 第 95 个百分位数的百分比 （32·5 [22·9]） 的次要终点平均降低。91% 的护理人员报告说，患者的饥饿感低于基线时。所有不良事件均为轻度或中度;皮肤色素沉着过度、呕吐、鼻咽炎、上呼吸道感染和注射部位反应最常见。未报告严重不良事件或导致研究中止或死亡的不良事件。

 解释

据我们所知，这是 setmelanotide 在 6 岁以下患者中的首次试验。这些结果支持该药物作为管理该人群肥胖的早期干预措施的好处。

 资金

 Rhythm 制药公司。