Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Amsterdam, the Netherlands.
Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust (MFT), University of Manchester, United Kingdom.
Mol Genet Metab. 2021 Dec;134(4):317-322. doi: 10.1016/j.ymgme.2021.09.003. Epub 2021 Sep 14.
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.
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.
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.
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).
目前，尚无治疗黏多糖贮积症 IIIA（MPS IIIA）的有效方法。虽然静脉给予酶替代疗法在无神经受累的其他形式的 MPS 中有效，但在 MPS IIIA 患者中却无法成功，因为它们无法穿过血脑屏障来改善神经症状。我们在一项 1/2 期扩展研究中评估了重组人硫酸乙酰肝素-N-脱硫酸酶（rhHNS）鞘内（IT）给药在 MPS IIIA 儿童中的长期安全性、耐受性和临床结局。
先前完成过 1/2 期研究并接受了 6 次 IT 给药计划中的至少 5 次 rhHNS 输注的年龄≥3 岁的 MPS IIIA 患者有资格入组。1/2 期研究中接受 10mg 剂量的患者将其剂量增加至 45mg。1/2 期研究中接受 45mg 或 90mg rhHNS IT 治疗的患者在扩展研究中继续接受该每月剂量。rhHNS 通过鞘内药物输送装置（IDDD）给药。主要终点包括不良事件的类型和严重程度、CSF 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神经认知评估和脑磁共振成像。
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 通常具有良好的耐受性。所有患者均经历了至少一次治疗出现的不良事件（TEAE），大多数为轻度或中度严重程度。无严重不良事件（SAE）被认为与研究药物有关，且无死亡发生。大多数 SAE 与 IDDD 故障有关。在所有 rhHNS 给药组中，Bayley 婴儿发育量表，第三版或 Kaufman 儿童评估成套测验，第二版非言语指数发育商数评分均从基线下降：分别为 -17.97%、-18.99%和-12.12%在 10/45、45 和 90mg 组中，分别在第 54 个月。
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 患者的神经认知衰退。由于未达到预先规定的疗效标准，并且该研究未产生治疗 MPS IIIA 的临床概念验证，因此该研究提前终止。（临床试验.gov 标识符 NCT01299727）。
