维索利肽治疗儿童低软骨发育不全：一项2期试验。
Vosoritide treatment for children with hypochondroplasia: a phase 2 trial.
作者信息
Dauber Andrew, Zhang Anqing, Kanakatti Shankar Roopa, Boucher Kimberly, McCarthy Tara, Shafaei Niusha, Seaforth Raheem, Castro Meryll Grace, Dham Niti, Merchant Nadia
机构信息
Division of Endocrinology, Children's National Hospital, Washington, DC 20010, USA.
Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
出版信息
EClinicalMedicine. 2024 Apr 11;71:102591. doi: 10.1016/j.eclinm.2024.102591. eCollection 2024 May.
BACKGROUND
Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in . It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia.
METHODS
We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 μg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007).
FINDINGS
Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity.
INTERPRETATION
Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia.
FUNDING
This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.
背景
软骨发育不全是一种罕见的常染色体显性骨骼发育不良，由……中的激活变异引起。其表现为身材不成比例矮小，临床严重程度范围广泛。目前尚无批准用于治疗软骨发育不全儿童身材矮小的药物。沃索瑞肽是一种C型利钠肽类似物，最近被批准用于改善软骨发育不全儿童的生长。我们旨在评估沃索瑞肽在软骨发育不全儿童中的安全性和有效性。
方法
我们在美国的一个中心进行了一项单臂、2期、开放标签试验，招募了26名软骨发育不全儿童。该试验包括一个6个月的观察期，以确定基线年化生长速度，随后是一个12个月的干预期，在此期间，沃索瑞肽通过皮下注射每日给药，剂量为15μg/kg/天。试验的共同主要终点包括不良事件的发生率以及治疗12个月后年龄-性别标准化年化生长速度和身高标准化偏差评分（SDS）相对于基线的变化。该试验已在ClinicalTrials.gov注册（NCT04219007）。
结果
24名平均年龄为5.86岁的参与者接受了沃索瑞肽治疗。第一名参与者于2020年8月4日入组，最后一名参与者于2023年9月8日完成了为期18个月的试验。沃索瑞肽耐受性良好，未出现与治疗相关的严重不良事件。83.3%的参与者出现注射部位反应。没有参与者因不良事件而停止治疗。与观察期相比，治疗期间年化生长速度增加了2.26标准差（SD），身高SDS增加了0.36 SD。软骨发育不全特异性身高SDS增加了0.38 SD。绝对年化生长速度每年增加1.81厘米。
解读
沃索瑞肽在增加软骨发育不全儿童生长速度方面是安全有效的。疗效与软骨发育不全儿童的报道相似。
资助
本研究由BioMarin制药公司的一项研究者发起的赠款支持。
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