阿糖苷酶α酶替代疗法治疗酸性鞘磷脂酶缺乏症（ASMD）：成人治疗 6.5 年后临床结局持续改善。

Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults.

机构信息

National Hospital for Neurology, University College London Hospitals, London, UK.

Icahn School of Medicine at Mount Sinai, New York, NY, US.

出版信息

Orphanet J Rare Dis. 2023 Apr 25;18(1):94. doi: 10.1186/s13023-023-02700-x.

BACKGROUND

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.

RESULTS

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.

CONCLUSIONS

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 .

背景

奥昔拉肽酶阿尔法是一种重组人酸性鞘磷脂酶（rhASM），用于治疗非中枢神经系统酸性鞘磷脂酶缺乏症（ASMD）的儿童和成人患者。一项正在进行的、开放性、长期研究（NCT02004704）评估了奥昔拉肽酶阿尔法在 5 名 ASMD 成人患者中的安全性和疗效。

结果

经过 6.5 年的治疗，与早期评估相比，没有停药、奥昔拉肽酶阿尔法相关的严重不良事件，也没有新的安全信号。大多数治疗中出现的不良事件为轻度（1742/1766，98.6%）。在与治疗相关的不良事件（n=657）中，超过一半被认为是输注相关反应（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性抗药物抗体，生命体征、血液学或心脏安全性参数也没有临床意义上的不良变化。脾脏和肝脏体积的改善（减少）在 6.5 年内持续进展（分别从基线减少 59.5%和 43.7%的平均值变化）。从基线开始，一氧化碳弥散能力的平均值增加了 55.3%，同时间质性肺病参数也得到了改善。基线时的血脂谱表明存在血脂异常。所有患者在接受奥昔拉肽酶阿尔法治疗后，都持续降低了致动脉粥样硬化的脂质水平，并增加了抗动脉粥样硬化的脂质水平。

结论

奥昔拉肽酶阿尔法是治疗 ASMD 的第一种针对特定疾病的治疗方法。本研究表明，长期使用奥昔拉肽酶阿尔法治疗具有良好的耐受性，并与相关疾病临床指标的持续改善相关。NCT02004704 于 2013 年 11 月 26 日注册，网址为 https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 。