Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a rare autosomal recessive lysosomal disorder characterized by deficient heparan-N-sulfatase (HNS) activity, and subsequent accumulation of heparan sulfate, especially in the central nervous system. The disease is associated with progressive neurodegeneration in early childhood. For this open-label extension study of a phase 2b clinical trial, we report on safety and cognitive decline in patients receiving intrathecal (IT) administration of recombinant human HNS (rhHNS). Of 21 patients who completed the phase 2b study, 17 continued in the open-label extension. Patients receiving rhHNS IT 45 mg continued to receive the same treatment regimen (i.e., every 2 weeks or every 4 weeks) throughout the extension. Patients receiving no treatment in the phase 2b study were re-randomized to the treatment groups. Neurocognition was assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (BSID-III). Adverse events were recorded over the duration of the treatment period. Cognitive decline was observed in most patients in both treatment groups; however, improvements in BSID-III development quotient score were observed for two patients, in receptive and expressive communication scores for three patients each, in fine motor skills for one patient, and in gross motor skills for six patients. Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. The extension study was terminated early as the primary endpoints of the phase 2b study were not met, and no statistical analyses were carried out. Although cognitive decline was apparent in most patients, improvements were observed in a small group of patients. Greater declines were observed in patients at the higher end of the age range, suggesting earlier intervention may increase the possibility of a response to treatment. rhHNS IT treatment remained generally well tolerated up to 96 weeks.

Sanfilippo 综合征 A 型（粘多糖贮积症 IIIA 型）是一种罕见的常染色体隐性溶酶体疾病，其特征是乙酰肝素-N-硫酸酯酶 (HNS) 活性不足，随后硫酸乙酰肝素积累，尤其是在中枢神经系统中。该疾病与儿童早期进行性神经退行性变有关。对于这项 2b 期临床试验的开放标签扩展研究，我们报告了接受鞘内 (IT) 给予重组人 HNS (rhHNS) 的患者的安全性和认知能力下降。在完成 2b 期研究的 21 名患者中，17 名继续进行开放标签扩展。接受 rhHNS IT 45 mg 的患者在整个延长期内继续接受相同的治疗方案（即每 2 周或每 4 周）。在 2b 期研究中未接受治疗的患者被重新随机分配到治疗组。使用贝利婴幼儿发展量表®，第三版 (BSID-III) 评估神经认知。在治疗期间记​​录不良事件。两个治疗组的大多数患者都观察到认知能力下降；然而，在 2 名患者中观察到 BSID-III 发育商分数有所提高，在接受和表达交流评分中各有 3 名患者，1 名患者在精细运动技能方面，6 名患者在粗大运动技能方面有所改善。rhHNS IT 发生的治疗中出现的不良事件大多是轻微的，没有导致研究中止，也没有死亡。由于未达到 2b 期研究的主要终点，扩展研究提前终止，并且没有进行统计分析。尽管大多数患者的认知能力下降很明显，但在一小部分患者中观察到了改善。在较高年龄范围的患者中观察到更大的下降，这表明早期干预可能会增加对治疗产生反应的可能性。rhHNS IT 治疗在 96 周内通常保持良好的耐受性。