Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease
Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease
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DOI：
10.1212/01.wnl.0000277648.63931.c0
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发表时间：
2007-10-09
期刊：
影响因子：
9.9
通讯作者：
Seibyl, John
中科院分区：
文献类型：
--
作者：
Shoulson, Ira;Schwid, Steven;Seibyl, John
背景：CEP-1347 抑制混合谱系激酶，这些激酶激活与帕金森病 (PD) 发病机制有关的细胞凋亡途径。 CEP-1347 可提高多种非临床模型中神经元的存活率，并且被发现在 PD 患者的 4 周内是安全的且耐受性良好。我们进行了 CEP-1347 试验的帕金森研究检查 (PRECEPT)，以评估其在早期 PD 中改善疾病的潜力。方法：同意但尚未需要多巴胺能治疗的 PD 患者 (n = 806) 被随机随机分配至 CEP-1347，剂量为 10 mg BID、25 mg BID 或 50 mg BID，或匹配安慰剂，并进行盲法和前瞻性评估。主要临床终点是出现需要多巴胺能治疗的残疾的时间。次要终点包括统一帕金森病评定量表 (UPDRS) 的变化和纹状体多巴胺转运蛋白的 beta-CIT SPECT 成像。 结果：在平均 21.4 个月的随访后，该研究提前结束，当时计划的中期分析表明继续实验性治疗是徒劳的。当时，与活性 CEP-1347 相比，随机接受安慰剂的 191 名受试者中有 108 名 (57%) 达到了需要多巴胺能治疗的残疾主要终点：205 名受试者中的 133 名 (65%) 接受 10 mg BID，212 名受试者中的 126 名 (59%) 接受 25 mg BID，198 名受试者中的 127 名 (64%) 接受 50 mg BID毫克 BID。 UPDRS 评分和 beta-CIT 成像的变化显示出相似的模式。结论：与预测有利的疾病缓解结果的动物模型研究相反，我们发现 CEP-1347 对早期帕金森病的治疗无效。
Background: CEP-1347 inhibits mixed lineage kinases that activate apoptotic pathways implicated in the pathogenesis of Parkinson disease ( PD). CEP-1347 enhances neuronal survival in a variety of nonclinical models and was found to be safe and well tolerated during 4 weeks in PD patients. We conducted the Parkinson Research Examination of CEP-1347 Trial ( PRECEPT) to assess its disease-modifying potential in early PD.Methods: Consenting PD patients not yet requiring dopaminergic therapy ( n = 806) were randomized equally to CEP-1347 in dosages of 10 mg BID, 25 mg BID, or 50 mg BID, or matching placebo, and were evaluated blindly and prospectively. The primary clinical end point was time to the development of disability requiring dopaminergic therapy. Secondary end points included changes in the Unified Parkinson's Disease Rating Scale ( UPDRS) and beta-CIT SPECT imaging of striatal dopamine transporters.Results: The study was concluded early, after an average of 21.4 months of follow-up, when a planned interim analysis demonstrated that it would be futile to continue experimental treatment. At that time, 108 of 191 subjects randomized to placebo ( 57%) had reached the primary end point of disability requiring dopaminergic therapy compared with active CEP-1347: 133 of 205 ( 65%) on 10 mg BID, 126 of 212 ( 59%) on 25 mg BID, and 127 of 198 ( 64%) on 50 mg BID. Changes in UPDRS scores and beta-CIT imaging showed similar patterns.Conclusions: In contrast to research in animal models that predicted favorable disease-modifying outcomes, we found CEP-1347 to be an ineffective treatment in early Parkinson disease.