Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial
Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial
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DOI：
10.1016/s2213-8587(18)30307-3
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发表时间：
2019-02-01
影响因子：
44.5
通讯作者：
McAlister, William H.
中科院分区：
文献类型：
--
作者：
Whyte, Michael P.;Simmons, Jill H.;McAlister, William H.
背景：我们之前的第二阶段，开放式研究，对11名患有危及生命的围产期或婴儿低磷血症的婴幼儿进行的研究表明，酶替代疗法asfotase alfa一年来的安全性和有效性。我们的目标是报告在大约7年的治疗期间的长期结果。方法我们对我们的单臂开放标签2期试验进行了预先指定的、研究结束时的7年随访，在该试验中，来自10家医院(6家在美国，2家在英国，1家在加拿大，1家在阿拉伯联合酋长国)招募了3岁或更小的患有危及生命的围产期或婴儿低磷症的儿童。患者接受阿司福酶阿尔法(每周3次皮下注射1毫克/公斤，如果需要每周3次调整为3毫克/公斤)长达7年(初级治疗期加推广阶段)或直到产品上市；每次就诊时根据患者体重的变化调整剂量。这项扩展研究的主要目标是评估阿斯福酶α的长期耐受性，定义为有一个或多个治疗紧急不良事件以及与低磷相关的骨骼表现的患者的数量，使用放射学全球变化印象(RGI-C)量表进行评估(-3表示严重恶化，+3表示完全或接近完全愈合)。呼吸支持、生长发育、认知和运动功能也被评估。所有的有效性和安全性分析都是在所有接受阿司匹林(全分析人群)治疗的患者中进行的。这项研究和推广阶段在ClinicalTrials.gov和EudraCT注册，编号NCT01205152和EudraCT，编号2009-009369-32。10名患者完成了6个月的疗程，进入了延长期；9名患者接受了至少6年的阿司匹林治疗，并完成了这项研究，其中4名患者正在接受超过7年的治疗。骨性愈合持续超过7年；所有可评估的患者在第6年(n=9；中位数评分+2.0[2.0-3.0])和第7年(n=7；中位数分数+2.3[2.0-3.0])至少有+2分。完成研究的患者在第4年后都不需要呼吸支持。从第3年到研究结束，体重Z评分改善到正常范围；长度或身高Z评分有所改善，但仍低于正常。贝利婴幼儿发育量表中与年龄相当的粗大运动、精细运动和认知分量表的分数也有所改善。所有11名患者都至少有一次治疗-紧急不良事件。最常见的不良反应是发热(8例[73%])、上呼吸道感染(8例[73%])、颅缝早闭(7例[%])和肺炎(7例[%])。3名(27%)患者发生了与阿斯福酶相关的严重不良事件(重度慢性肝炎；中度注射后反应；重度颅缝融合伴严重传导性耳聋)。使用阿斯福酶治疗围产期或婴儿低磷症长达7年的解释患者显示出早期、持续的骨骼矿化改善。呼吸功能、生长发育、认知和运动功能也有所改善，阿司匹林一般耐受性良好。版权所有(C)2018爱思唯尔有限公司。保留所有权利。
Background Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment.Methods We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (-3 indicating severe worsening, and + 3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and EudraCT, number 2009-009369-32.Findings 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least + 2 at year 6 (n=9; median score + 2.0 [range 2.0-3.0]) and year 7 (n=7; median score + 2.3 [2.0-3.0]). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness).Interpretation Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated. Copyright (c) 2018 Elsevier Ltd. All rights reserved.