Abstract：
The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA\'s proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.
摘要：
肌萎缩侧索硬化症（ALS）缺乏明确的治疗方法强调了探索这种致命疾病的新的和改进的治疗方法的迫切需要。进步,和致残神经退行性疾病。截至2023年底，五种治疗方法-利鲁唑，依达拉奉,氢溴酸右美沙芬+硫酸奎尼丁(DHQ)，托费森,和苯丁酸钠-牛磺熊去氧胆酸（PB-TUDCA）-被FDA批准用于治疗ALS患者。其中PB-TUDCA已被证明会影响DNA加工损伤，线粒体功能障碍，内质网应激,氧化应激，和病理性折叠蛋白聚集缺陷，与ALS病理生理学有关。CENTAUR2期试验表明PB-TUDCA对ALS功能评定量表修订（ALSFRS-R）死亡风险的显著影响，住院治疗,以及基于事后分析的ALS患者需要气管造口术或永久辅助通气。最近,与CENTAUR试验结果相比，PHOENIX3期试验(NCT05021536)结果显示,48周时ALSFRS-R总评分无变化.因此,赞助商公司启动了与美国FDA和加拿大卫生部自愿撤销PB-TUDCA上市许可的程序.在本文中,我们回顾了ALS的病理生理学，重点关注PB-TUDCA提出的作用机制和最近的临床试验结果，并讨论ALS和其他神经系统疾病相互矛盾的试验数据的含义。
