Introduction

Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). Intravenously-administered enzyme replacement therapies, while effective in other forms of MPS without neurological involvement, have not been successful in patients with MPS IIIA, as they are unable to cross the blood-brain barrier to improve neurological symptoms. We evaluated the long-term safety, tolerability, and clinical outcomes of recombinant human heparan-N-sulfatase (rhHNS) administered intrathecally (IT) in children with MPS IIIA in a phase 1/2 extension study.

Methods

Patients aged ≥3 years with MPS IIIA who had previously completed a phase 1/2 study and received ≥5 of the 6 planned rhHNS infusions via IT administration, were eligible for inclusion. Patients who received 10 mg in the phase 1/2 study had their dose increased to 45 mg. Patients who were treated with 45 mg or 90 mg rhHNS IT in the phase 1/2 study remained on this monthly dose in the extension study. rhHNS was administered via an intrathecal drug delivery device (IDDD). Primary endpoints included the type and severity of adverse events, presence of anti-rhHNS antibodies in the CSF and serum, and changes in laboratory values. Secondary endpoints included standardized neurocognitive assessments and brain magnetic resonance imaging.

Results

In the extension study, 12 patients with a mean (SD) age of 9.6 (7.3) years continued treatment with rhHNS IT for a median of 264.4 weeks. Ten of 12 patients completed the extension study. rhHNS IT was generally well-tolerated. All patients experienced at least one treatment-emergent adverse event (TEAE), most being mild or moderate in severity. No serious adverse events (SAEs) were considered related to the study drug, and no deaths occurred. Most SAEs were related to malfunctions of the IDDD. Declines from baseline in Bayley Scales of Infant Development, Third Edition or Kaufman Assessment Battery for Children, Second Edition, Nonverbal Index developmental quotient scores were evident at all rhHNS dosing groups: −17.97%, −18.99%, and −12.12% in the 10/45, 45, and 90 mg groups, respectively, at Month 54.

Conclusions

Overall, rhHNS IT was well tolerated in the extension study. However, rhHNS IT was unable to slow the neurocognitive decline of patients with MPS IIIA. This study was subsequently terminated early because pre-specified efficacy criteria were not met, and the study did not yield clinical proof of concept. (Clinicaltrials.gov Identifier NCT01299727).

中文翻译：

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Sanfilippo综合征A型患者鞘内注射乙酰肝素-N-硫酸酯酶的长期安全性和临床结果

介绍

目前，粘多糖贮积症IIIA（MPS IIIA）没有有效的治疗方法。静脉内给药的酶替代疗法虽然对其他形式的 MPS 有效，但不涉及神经系统，但在 MPS IIIA 患者中并不成功，因为它们无法穿过血脑屏障以改善神经系统症状。我们在一项 1/2 期扩展研究中评估了鞘内 (IT) 给予 MPS IIIA 儿童的重组人乙酰肝素-N-硫酸酯酶 (rhHNS) 的长期安全性、耐受性和临床结果。

方法

年龄≥3 岁的 MPS IIIA 患者之前完成了 1/2 期研究并通过 IT 管理接受了 6 次计划 rhHNS 输注中的≥5 次，有资格入选。在 1/2 期研究中接受 10 mg 的患者的剂量增加到 45 mg。在 1/2 期研究中接受 45 mg 或 90 mg rhHNS IT 治疗的患者在扩展研究中仍保持每月剂量。rhHNS 通过鞘内给药装置 (IDDD) 给药。主要终点包括不良事件的类型和严重程度、脑脊液和血清中抗 rhHNS 抗体的存在以及实验室值的变化。次要终点包括标准化的神经认知评估和脑磁共振成像。

结果

在扩展研究中，12 名平均 (SD) 年龄为 9.6 (7.3) 岁的患者继续接受 rhHNS IT 治疗，中位时间为 264.4 周。12 名患者中有 10 名完成了扩展研究。rhHNS IT 通常耐受性良好。所有患者都经历了至少一种治疗中出现的不良事件 (TEAE)，大多数患者的严重程度为轻度或中度。没有严重不良事件（SAE）被认为与研究药物有关，并且没有发生死亡。大多数 SAE 与 IDDD 的故障有关。贝利婴儿发育量表第三版或考夫曼儿童评估电池第二版中的基线下降，非语言指数发育商分数在所有 rhHNS 给药组中都很明显：-17.97%、-18.99% 和 -12.12% 在 10在第 54 个月时，分别为 45、45 和 90 mg 组。

结论

总体而言，rhHNS IT 在扩展研究中具有良好的耐受性。然而，rhHNS IT 无法减缓 MPS IIIA 患者的神经认知能力下降。该研究随后提前终止，因为未达到预先指定的疗效标准，并且该研究没有产生临床概念证明。（Clinicaltrials.gov 标识符 NCT01299727）。