Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury
Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury
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DOI：
10.1089/neu.2011.1765
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发表时间：
2011-05-01
影响因子：
4.2
通讯作者：
McKerracher, Lisa
中科院分区：
文献类型：
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作者：
Fehlings, Michael G.;Theodore, Nicholas;McKerracher, Lisa
多种证据已经证实Rho通路在中枢神经系统（CNS）损伤后控制神经元对生长抑制蛋白的反应中是重要的。一种名为BA-210（商标为Cethrin（R））的药物阻断了Rho的激活，并在临床前动物研究中显示出用于治疗脊髓损伤（SCI）的前景。这是一份I/IIa期临床研究报告，旨在测试药物的安全性和耐受性，以及急性SCI手术期间单次给予BA-210后患者的神经系统状态。胸部（T2-T12）或颈部（C4-T1）SCI患者被依次招募参加该剂量范围（0.3 mg至9 mg Cethrin）的多中心研究，该研究包括48例具有完整美国脊髓损伤协会评估（ASIA）A的患者。生命体征;临床实验室检查;在研究前和治疗后1年的随访期内进行脊柱、头部和腹部的计算机断层扫描（CT）;脊柱的磁共振成像（MRI）和ASIA评估。报告的治疗后出现的不良事件是急性SCI患者人群的典型事件，没有严重不良事件归因于药物。药代动力学分析显示，药物的全身暴露水平较低，患者间变异性较高。在所有剂量组中，胸椎患者的ASIA运动评分较基线的变化均较低（1.8 +/- 5.1），颈椎患者的ASIA运动评分较基线的变化较大（18.6 +/- 19.3）。在接受3 mg Cethrin治疗的宫颈患者中观察到运动评分的最大变化，在12个月时观察到ASIA运动评分改善27.3 +/- 13.3分。大约6%的胸椎患者从ASIA A转换为ASIA C或D，而宫颈患者为31%，3 mg宫颈队列为66%。虽然患者数量较少，但在这项开放标签试验中观察到的运动恢复表明BA-210可能会增加完全SCI后的神经恢复。计划在SCI患者中进行进一步的Cethrin临床试验，以建立疗效证据。
Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin (R)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8 +/- 5.1) and larger in cervical patients (18.6 +/- 19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3 +/- 13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.