1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
2 Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA.
Neurorehabil Neural Repair. 2018 Jun;32(6-7):578-589. doi: 10.1177/1545968318776371. Epub 2018 Jun 5.
Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery.
This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia.
Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks).
ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia.
ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.
中和中枢神经系统神经突生长抑制因子，例如 Nogo-A，是改善脊髓损伤（SCI）后恢复的一种很有前途的方法。在动物 SCI 模型中，鞘内给予抗 Nogo-A 抗体可促进再生神经突生长和功能恢复。
这项首次人体研究评估了鞘内给予人抗 Nogo-A 抗体 ATI355 在急性完全性外伤性截瘫和四肢瘫患者中的可行性、安全性、耐受性、药代动力学和初步疗效。
患者（N=52）在损伤后 4 至 60 天开始治疗。4 个连续剂量递增队列接受 5 至 30 mg/2.5 mL/天连续鞘内 ATI355 输注 24 小时至 28 天。进行药代动力学评估后，另外 2 个队列接受推注方案（分别在 4 周内进行 6 次鞘内注射 22.5 和 45 mg/3 mL）。
ATI355 在 1 年随访时耐受性良好。所有患者均经历了≥1 次不良事件（AE）。共报告了 581 次不良事件，大多数为轻度，与急性 SCI 后预期的情况相符。15 名患者报告了 16 例严重不良事件，均与 ATI355 无关；1 例细菌性脑膜炎病例被认为与鞘内给药有关。ATI355 血清水平呈剂量依赖性，输注和推注后脑脊液水平个体间差异很大。1 名截瘫患者的运动评分提高了 8 分。四肢瘫患者的总运动评分均有提高，19 名患者中有 3 名增加了>10 分，1 名增加了 27 分，均在第 48 周。19 名四肢瘫患者中有 7 例从完全性 SCI 转变为不完全性 SCI。
ATI335 在人体中耐受性良好；可能需要考虑使用鞘内抗体给药进行急性 SCI 的疗效试验。
