Shriners Hospital for Children, St Louis, MO, USA.
Yale University School of Medicine, New Haven, CT, USA.
Lancet Diabetes Endocrinol. 2019 Mar;7(3):189-199. doi: 10.1016/S2213-8587(18)30338-3. Epub 2019 Jan 9.
Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia.
In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 μmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing.
Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64.
Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia.
Ultragenyx Pharmaceutical and Kyowa Kirin International.
患有 X 连锁低磷血症的儿童血液中循环的磷激素成纤维细胞生长因子 23（FGF23）浓度较高，这会导致肾脏磷丢失和低磷血症、佝偻病、骨骼畸形和生长受损。Burosumab 是一种针对 FGF23 的人源单克隆抗体，可改善 5-12 岁 X 连锁低磷血症儿童的磷稳态和佝偻病。我们旨在评估在 X 连锁低磷血症的幼儿中使用 burosumab 的安全性和疗效。
在美国的三家医院进行的这项开放标签、2 期试验中，1-4 岁的 X 连锁低磷血症儿童（年龄）接受皮下注射每两周一次的 burosumab（0.8mg/kg），共 64 周。如果连续两次的空腹血清磷浓度低于 1.03mmol/L（3.2mg/dL），血清磷从基线增加了小于 0.16mmol/L（0.5mg/dL），并且错过了 burosumab 的剂量，则将剂量增加至 1.2mg/kg。在扩展期内，参与者可以继续接受最多另外 96 周的 burosumab 治疗。主要纳入标准为：知情同意时年龄为 1-4 岁；空腹血清磷浓度小于 0.97mmol/L（3.0mg/dL）；血清肌酐 8.8-35.4μmol/L（0.1-0.4mg/dL）；放射性佝偻病证据（至少需要 5 名参与者在膝关节处的 Thacher 佝偻病严重程度评分≥1.5）；患者或直接亲属中存在 PHEX 突变或意义不明的变异，且也患有 X 连锁低磷血症。入组时停止常规治疗。主要终点是安全性和空腹血清磷浓度从基线到第 40 周的变化。从基线到第 40 周和第 64 周（使用 Thacher 佝偻病严重程度评分和改良的放射学总体变化印象进行评估）以及卧位长度或站立高度的佝偻病严重程度变化为关键次要结局。这项试验在 ClinicalTrials.gov 注册，编号为 NCT02750618，正在进行中。
2016 年 5 月 16 日至 6 月 10 日，我们招募了 13 名 X 连锁低磷血症儿童。所有 13 名儿童均完成了 64 周的治疗并纳入疗效和安全性分析；在分析时，没有超过 70 周的治疗。从基线到第 40 周治疗的血清磷最小二乘均值增加了 0.31mmol/L（SE 0.04；95%CI 0.24-0.39；0.96mg/dL[SE 0.12]；p<0.0001）。所有患者均至少发生过一次不良事件。5 名儿童发生了 14 次与治疗相关的不良事件，大多为注射部位反应。一名儿童发生了 1 例严重不良事件（牙脓肿），认为与治疗无关。其他所有不良事件均为轻度至中度，除了认为与治疗无关的严重食物过敏外。没有出现肾钙质沉着症或常规安全性化学面板结果的显著变化。总 Thacher 佝偻病严重程度评分从基线到第 40 周下降了 1.7（SE 0.1；p<0.0001），从第 64 周下降了 2.0（SE 0.1；p<0.0001）。放射学总体变化印象评分也表明有显著改善，第 40 周和第 64 周的最小二乘均值评分分别为+2.3（SE 0.1）和+2.2（SE 0.1）（均 p<0.0001）。平均卧位或站立身高 Z 评分从基线到第 64 周保持不变。
Burosumab 具有良好的安全性，可提高血清磷水平，并改善佝偻病，防止 X 连锁低磷血症幼儿的生长早期下降。这些发现可能会极大地改变 X 连锁低磷血症幼儿的治疗方法。
Ultragenyx Pharmaceutical 和 Kyowa Kirin International。
