Gene Therapy Center, University of Minnesota, Minneapolis, MN, USA.
Birmingham Children's Hospital, Birmingham, UK.
Mol Genet Metab. 2019 Feb;126(2):131-138. doi: 10.1016/j.ymgme.2018.12.003. Epub 2018 Dec 6.
Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.
III 型黏多糖贮积症是由于 N-乙酰-α-葡糖胺糖苷酶（NAGLU）酶活性显著降低，导致硫酸乙酰肝素在关键器官中积累，进行性脑萎缩和神经认知能力下降。在这项开放标签研究中，11 名符合条件的 2 至<12 岁（发育年龄≥1 岁）的患者按顺序分为 3 个递增剂量组（0.3mg/kg[3 例]、1.0mg/kg[4 例]或 3.0mg/kg[4 例]），通过静脉输注，每 2 周 1 次，共 24 周，然后中断 4 周（A 部分），从第 28 周开始，每 2 周以 1.0 和/或 3.0mg/kg 进行治疗（B 部分），然后在研究中大约 2 年进行每 2 周 5.0 或 10.0mg/kg 的治疗（C 部分）。该研究的主要目的是评估安全性和耐受性；次要目的包括评估 SBC-103 对脑脊液（CSF）中总硫酸乙酰肝素水平、脑结构磁共振成像（皮质灰质体积）和神经认知状态（年龄当量/发育商）的影响。在研究期间，3 名患者出现了 13 次治疗中出现的严重不良事件（SAE）；8 名患者出现了 32 次与输注相关的反应（IAR）。大多数不良反应为轻度，静脉内使用 SBC-103 耐受性良好。在 C 部分第 52 周时，分别为 5.0 和 10.0mg/kg 剂量的平均（SD）变化为：CSF 中硫酸乙酰肝素水平分别为-4.7%（8.3）和-4.7%（14.7），皮质灰质体积分别为-8.1%（3.5）和-10.3%（9.4），认知年龄当量分别为+2.3（6.9）分和+1.0（9.2）分，发育商分别为-8.9（10.2）分和-14.4（9.2）分。总之，SBC-103 通常具有良好的耐受性。CSF 中硫酸乙酰肝素水平的变化较小，并且不能从早期研究时间点维持，在研究的较高剂量下，没有总体上有临床意义的神经认知功能改善的明确证据，并且没有观察到剂量依赖性效应。
