Abstract：
Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores.
All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001).
Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 .
All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001).
Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 .
摘要：
背景：α寡核苷酸酶是一种重组人酸性鞘磷脂酶（ASM）酶替代疗法（ERT），用于酸性鞘磷脂酶缺乏症（ASMD）的非中枢神经系统表现。我们报告了20名儿童（4名青少年[12-17岁]，九个孩子[6-11岁]，和7名婴儿/早期儿童[1-5岁]）患有基线脾肿大和生长缺陷，他们完成了1年的ASCEND-Peds临床试验（NCT02292654），并在长期研究中继续接受脂化酶α（NCT02004704）。疗效终点包括脾脏和肝脏体积，肺对一氧化碳（DLCO）的扩散能力，高分辨率计算机断层扫描（HRCT）肺部成像，脂质分布，肝功能检查,和身高Z分数。
结果：所有20名前ASCEND-Peds患者均完成了至少2年的脂化酶α治疗。在治疗的第二年，没有患者停药，也没有出现新的安全问题；99%的不良事件是轻度或中度的。在第2年期间，一名患者有两个与治疗相关的严重事件超敏反应得以解决。脾脏和肝脏体积从基线平均减少61%和49%，在基线时进行检测的9例患者中,DLCO预测百分比分别(p<0.0001)和平均百分比增加46.6%(p<0.0001).通过1年改善或正常化的脂质分布和升高的肝转氨酶水平保持稳定。所有年龄组的平均身高Z评分均有所改善（从基线1.17的平均变化，P<0.0001）。
结论：在2年的治疗过程中，Olipudasealfa总体上耐受良好。在治疗的第一年期间观察到的临床相关疾病终点的改善在第二年得以维持或增强。试用注册NCT02004704注册2013年11月26日，https://clinicaltrials.gov/ct2/show/record/NCT02004704。
结果：所有20名前ASCEND-Peds患者均完成了至少2年的脂化酶α治疗。在治疗的第二年，没有患者停药，也没有出现新的安全问题；99%的不良事件是轻度或中度的。在第2年期间，一名患者有两个与治疗相关的严重事件超敏反应得以解决。脾脏和肝脏体积从基线平均减少61%和49%，在基线时进行检测的9例患者中,DLCO预测百分比分别(p<0.0001)和平均百分比增加46.6%(p<0.0001).通过1年改善或正常化的脂质分布和升高的肝转氨酶水平保持稳定。所有年龄组的平均身高Z评分均有所改善（从基线1.17的平均变化，P<0.0001）。
结论：在2年的治疗过程中，Olipudasealfa总体上耐受良好。在治疗的第一年期间观察到的临床相关疾病终点的改善在第二年得以维持或增强。试用注册NCT02004704注册2013年11月26日，https://clinicaltrials.gov/ct2/show/record/NCT02004704。
