Neurology Clinical Trial Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Nat Med. 2011 Nov 20;17(12):1652-6. doi: 10.1038/nm.2579.
Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d(-1)) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d(-1) or 300 mg d(-1) as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant (P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.
肌萎缩侧索硬化症（ALS）的特征是上下运动神经元功能障碍和丧失，肌肉迅速无力、萎缩和死亡。许多因素，包括线粒体功能障碍，可能导致 ALS 的发病机制。利鲁唑仅在一定程度上延长了生存时间，但对肌肉力量或功能没有影响，是唯一批准用于治疗 ALS 的药物。我们在一项两部分、双盲安全性和耐受性研究中，在肌萎缩侧索硬化症患者中测试了假定的线粒体调节剂右苯哌甲酯（KNS-760704；（6R）-4,5,6,7-四氢-N6-丙基-2,6-苯并噻唑二胺），初步评估了其对功能下降和死亡率的影响。在第 1 部分中，评估了右苯哌甲酯（50、150 或 300mg/d）与安慰剂相比在 12 周内的效果。在第 2 部分中，经过 4 周的单盲安慰剂洗脱期后，继续接受治疗的患者被重新随机分为右苯哌甲酯 50mg/d 或 300mg/d 作为双盲活性治疗，持续 24 周。右苯哌甲酯安全且耐受性良好。第 1 部分中 ALS 功能评定量表修订版（ALSFRS-R）的斜率下降趋势显示出剂量依赖性衰减，第 2 部分中 ALSFRS-R 从基线的变化和死亡率的联合等级检验显示出组间有统计学意义的差异（P=0.046），这强烈支持进一步研究右苯哌甲酯在 ALS 中的应用。
