Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St Louis, MO, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St Louis, MO, USA.
Vanderbilt University Medical Center, Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
Lancet Diabetes Endocrinol. 2019 Feb;7(2):93-105. doi: 10.1016/S2213-8587(18)30307-3. Epub 2018 Dec 14.
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.
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.
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).
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.
Alexion Pharmaceuticals, Inc.
我们之前进行的一项针对 11 名患有危及生命的围产期或婴儿期低磷酸血症的婴儿和幼儿的 II 期、开放性研究显示，使用酶替代疗法阿法特酶治疗具有 1 年的安全性和疗效。我们旨在报告大约 7 年治疗后的长期结果。
我们对我们的单臂、开放性 II 期试验进行了预先设定的、研究结束时的 7 年随访，该试验招募了来自十家医院（美国六家、英国两家、加拿大一家和阿拉伯联合酋长国一家）的患有危及生命的围产期或婴儿期低磷酸血症的 3 岁或 3 岁以下的儿童。患者接受阿法特酶（每周三次皮下注射 1mg/kg，需要时调整为每周三次 3mg/kg）治疗，最长可达 7 年（主要治疗期加延长期）或直至产品上市；每次就诊时根据患者体重的变化调整剂量。该扩展研究的主要目的是评估阿法特酶的长期耐受性，定义为出现一种或多种治疗后出现的不良事件的患者数量，以及与低磷酸血症相关的骨骼表现，使用放射学整体变化印象（RGI-C）量表评估（-3 表示严重恶化，+3 表示完全或接近完全愈合）。还评估了呼吸支持、生长以及认知和运动功能。所有疗效和安全性分析均在接受任何阿法特酶治疗的所有患者中进行（全分析人群）。这项研究和扩展阶段在 ClinicalTrials.gov 上注册，编号为 NCT01205152，在 EudraCT 上注册，编号为 2009-009369-32。
2008 年 10 月 6 日至 2009 年 12 月 4 日期间招募了 11 名参与者。10 名患者完成了 6 个月的治疗期并进入了延长阶段；9 名患者接受了至少 6 年的阿法特酶治疗并完成了研究，其中 4 名患者的治疗时间超过 7 年。骨骼愈合在 7 年的治疗中得以维持；所有可评估的患者在第 6 年（n=9；中位数评分+2.0[范围 2.0-3.0]）和第 7 年（n=7；中位数评分+2.3[2.0-3.0]）的 RGI-C 评分至少为+2。完成研究的患者在第 4 年后不再需要呼吸支持。体重 Z 评分从第 3 年到研究结束时恢复到正常范围；长度或身高 Z 评分有所改善，但仍低于正常水平。贝利婴幼儿发育量表的粗大运动、精细运动和认知分量表的年龄当量评分也有所提高。11 名患者均至少出现了一次治疗后出现的不良事件。最常见的不良事件是发热（11 名患者中的 8 名[73%]）、上呼吸道感染（8 名[73%]）、颅缝早闭（7 名[64%]）和肺炎（7 名[64%]）。与阿法特酶相关的严重不良事件发生在 3 名（27%）患者中（慢性肝炎；中度即刻注射反应；颅缝早闭伴严重传导性耳聋）。
接受阿法特酶治疗长达 7 年的围产期或婴儿期低磷酸血症患者的骨骼矿化情况出现了早期、持续的改善。呼吸功能、生长以及认知和运动功能也得到了改善，阿法特酶通常具有良好的耐受性。
Alexion 制药公司。
