背景:脂化酶α的酶替代疗法,重组人酸性鞘磷脂酶(rhASM),适用于儿童和成人中酸性鞘磷脂酶缺乏症(ASMD)的非中枢神经系统表现。一个持续的,开放标签,长期研究(NCT02004704)评估了5例成人ASMD患者使用脂化酶α的安全性和有效性.
结果:经过6.5年的治疗,没有中断,无与糖脂酶相关的严重不良事件,与早期评估相比,没有新的安全信号。大多数因治疗引起的不良事件强度为轻度(1742/1766,98.6%)。在治疗相关的不良事件中(n=657),超过一半被认为是输液相关反应(n=403,61.3%),如头痛,恶心,腹痛,关节痛,发热,和疲劳。没有患者产生针对细胞摄取的中和抗药物抗体,并且生命体征没有临床上明显的不良变化,血液学,或心脏安全参数。脾脏和肝脏体积的改善(减少)持续了6.5年(从基线的平均变化为-59.5%和-43.7%,分别)。肺对一氧化碳的扩散能力从基线平均增加55.3%,伴随间质性肺病参数的改善。基线时的血脂谱表明血脂异常。所有患者在脂凝酶α治疗后,促动脉粥样硬化脂质水平持续下降,抗动脉粥样硬化脂质水平升高。
结论:Alfa寡核苷酸酶是ASMD的第一种疾病特异性治疗方法。这项研究表明,用脂酶α的长期治疗具有良好的耐受性,并且与相关疾病临床措施的持续改善有关。NCT02004704注册2013年11月26日,https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1。
Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD.
After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment.
Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .