印第安纳大学医学院Erik A Imel研究小组开展了布罗沙单抗与传统治疗儿童x-连锁低磷血症疗法的比较研究。 该项研究成果发表在2019年5月16日出版的《柳叶刀》上。

该研究组比较了由口服磷酸盐和活性维生素D组成的常规持续治疗与改用burosumab(一种针对FGF23的全人单克隆抗体)治疗儿童x相关性低磷酸盐血症的疗效和安全性。 在16个临床点的随机、主动对照、开放标签的3期试验中，课题组登记了1-12岁的x -连锁低磷血症儿童。 主要合格标准为:总佝偻病严重程度评分至少为2·0分，空腹血清磷低于0·97 mmol/L(3·0 mg/dL)，确诊为PHEX(磷酸盐调节肽酶同源物，x连锁)突变或变异，在患者或具有适当x连锁显性遗传的家庭成员中具有未知意义，三岁以下儿童接受至少连续六个月的常规治疗或三岁以上儿童接受至少连续十二个月的常规治疗。 将符合条件的患者随机分配(1:1)，每2周接受0·8 mg/kg皮下布洛单抗治疗(布洛单抗组)或研究人员规定的常规治疗(常规治疗组)。 两次干预都持续了64周。 主要终点是第40周佝偻病严重程度的变化，通过x线片全球变化印象评分评估。 所有接受至少一剂治疗的患者均纳入初级和安全性分析。 该试验在ClinicalTrials.gov上注册，编号为NCT02915705。招聘发现时间为2016年8月3日至2017年5月8日。 在122例评估患者中，有61例纳入研究。 其中，32名(18名女孩，14名男孩)被随机分配继续接受常规治疗，29名(16名女孩，13名男孩)接受布洛舒单抗治疗。 对于第40周的主要终点，burosumab组患者的影像学整体评分改变的整体印象明显优于常规治疗组(burosumab组与常规治疗组相比，最小二乘平均值+1·9 [SE 0·1]与+0·8[0·1];差值1·1,95% CI 0·8-1·5;术;0·0001)。 治疗-研究人员认为可能、可能或肯定与治疗有关的紧急不良事件在布罗沙单抗组中发生率更高(29例布罗沙单抗患者中有17例[59%]，而在常规治疗组中有32例患者中有7例[22%])。 每组发生3例严重不良事件，均被认为与治疗无关并已解决。与传统治疗方法相比，布罗沙单抗治疗x -连锁低磷血症儿童佝偻病的严重程度、生长和生物化学特性均有显著改善。

研究人员表示，儿童x -连锁低磷血症的特点是血清成纤维细胞生长因子23 (FGF23)、低磷血症、佝偻病、下肢弯曲和生长障碍浓度升高。

附：英文原文

Title: Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial

Author: Erik A Imel, Francis H Glorieux, Michael P Whyte,et al

Issue&Volume: May 16, 2019

Summary

Background

X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods

In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1–12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings

Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8–1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation

Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

DOI: https://doi.org/10.1016/S0140-6736(19)30654-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30654-3/fulltext