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Abstract：
BACKGROUND: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China.
METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit.
RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses.
CONCLUSIONS: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA.
BACKGROUND: ClinicalTrials.gov identifier, NCT04419233.
METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit.
RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses.
CONCLUSIONS: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA.
BACKGROUND: ClinicalTrials.gov identifier, NCT04419233.
摘要：
背景：脊髓性肌萎缩症（SMA）是一种罕见的，常染色体隐性遗传,导致进行性肌肉无力和萎缩的神经肌肉疾病。Nusinersen,反义寡核苷酸，于2019年2月在中国批准SMA。我们报告了上市后监测第4阶段研究的中期结果，熊猫(NCT04419233),收集安全数据，功效,Nusinersen在中国常规临床实践中在SMA患儿中的药代动力学。
方法：参加PANDA的参与者将在nusinersen治疗开始后观察2年。主要终点是治疗期间不良事件(AE)/严重AE(SAE)的发生率。疗效评估包括世界卫生组织（WHO）运动里程碑评估，哈默史密斯婴儿神经检查（HINE），和通风支持。在每次剂量访问时测量nusinersen的血浆和脑脊液(CSF)浓度。
结果：截至2023年1月4日，50名参与者入组，数据截止：10名婴儿发病（≤6个月），40名后期发病（>6个月）SMA。所有50名参与者都接受了至少一个剂量的nusinersen;6已经完成了研究。45名（90％）参与者经历了AE，并且大多是轻度/中度；没有AE导致nusinersen停药或停药。11名参与者经历了严重不良事件，最常见的肺炎(n=9);没有一个被认为与研究治疗有关。在整个研究中，两个亚组均观察到WHO运动里程碑的稳定性或增益，平均HINE-2评分均得到改善。无严重呼吸事件发生,研究期间未启动永久性通气支持.给药前nusinersenCSF浓度在整个负荷剂量期间稳定增加，多剂量后血浆中没有积累。
结论：Nusinersen总体耐受性良好，总体安全性可接受，与nusinersen已知的安全性一致。功效,安全,和nusinersen暴露与先前的观察结果一致。这些结果支持持续的PANDA和对中国SMA参与者的nusinersen的评估。
背景：ClinicalTrials.gov标识符，NCT04419233。
方法：参加PANDA的参与者将在nusinersen治疗开始后观察2年。主要终点是治疗期间不良事件(AE)/严重AE(SAE)的发生率。疗效评估包括世界卫生组织（WHO）运动里程碑评估，哈默史密斯婴儿神经检查（HINE），和通风支持。在每次剂量访问时测量nusinersen的血浆和脑脊液(CSF)浓度。
结果：截至2023年1月4日，50名参与者入组，数据截止：10名婴儿发病（≤6个月），40名后期发病（>6个月）SMA。所有50名参与者都接受了至少一个剂量的nusinersen;6已经完成了研究。45名（90％）参与者经历了AE，并且大多是轻度/中度；没有AE导致nusinersen停药或停药。11名参与者经历了严重不良事件，最常见的肺炎(n=9);没有一个被认为与研究治疗有关。在整个研究中，两个亚组均观察到WHO运动里程碑的稳定性或增益，平均HINE-2评分均得到改善。无严重呼吸事件发生,研究期间未启动永久性通气支持.给药前nusinersenCSF浓度在整个负荷剂量期间稳定增加，多剂量后血浆中没有积累。
结论：Nusinersen总体耐受性良好，总体安全性可接受，与nusinersen已知的安全性一致。功效,安全,和nusinersen暴露与先前的观察结果一致。这些结果支持持续的PANDA和对中国SMA参与者的nusinersen的评估。
背景：ClinicalTrials.gov标识符，NCT04419233。
