Kitaoka Taichi, Tajima Toshihiro, Nagasaki Keisuke, Kikuchi Toru, Yamamoto Katsusuke, Michigami Toshimi, Okada Satoshi, Fujiwara Ikuma, Kokaji Masayuki, Mochizuki Hiroshi, Ogata Tsutomu, Tatebayashi Koji, Watanabe Atsushi, Yatsuga Shuichi, Kubota Takuo, Ozono Keiichi
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
Clin Endocrinol (Oxf). 2017 Jul;87(1):10-19. doi: 10.1111/cen.13343. Epub 2017 May 2.
Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan.
Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015.
Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1).
Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development.
Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved.
Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.
低磷酸酯酶症（HPP）是一种罕见的骨骼疾病，其特征为矿化不足和碱性磷酸酶活性降低。阿法骨化醇（AA）最近已被开发用于治疗HPP并发症。本研究评估了其在日本的安全性和疗效。
开放标签、多中心、前瞻性试验。2014年6月至2015年7月期间，11家医院招募了患者。
13例患者（9例女性，4例男性），基线年龄从0天至34岁，入组并接受AA治疗（除1例患者外，所有患者均为每周皮下注射3次，每次2mg/kg）。所有患者均有ALPL基因突变。HPP的类型包括围生期（n = 6）、婴儿期（n = 5）、儿童期（n = 1）和成人期（n = 1）。
主要结局指标是根据不良事件（AE）和实验室数据确定的安全性。作为次要结局指标，从总生存期、呼吸状况、佝偻病严重程度和粗大运动发育方面评估疗效。
注射部位反应是最常见的AE。围生期型患者中观察到1例可能与治疗相关的严重AE为惊厥和低钙血症。此外，婴儿期型的3例患者出现高钙血症和/或高磷血症，并给予这些患者低钙和/或低磷配方。关于疗效，所有患者均存活，影像学表现、发育里程碑和呼吸功能均有改善。
阿法骨化醇治疗改善了HPP患者的骨骼、呼吸和身体症状，且严重AE较少。我们的结果为AA治疗HPP患者的安全性和疗效提供了支持。
