Department of Neurology, Duke University, Durham, NC, USA.
Expert Opin Emerg Drugs. 2024 Jun;29(2):93-102. doi: 10.1080/14728214.2024.2333420. Epub 2024 Mar 22.
Amyotrophic Lateral Sclerosis is a rapidly progressive motor neuron disorder causing severe disability and premature death. Owing to the advances in uncovering ALS pathophysiology, efficient clinical trial design and research advocacy program, several disease-modifying drugs have been approved for treating ALS. Despite this progress, ALS remains a rapidly disabling and life shortening condition. There is a critical need for more effective therapies.
Here, we reviewed the emerging ALS therapeutics undergoing phase II & III clinical trials. To identify the investigational drugs, we searched ALS and phase II/III trials that are active and recruiting or not yet recruiting on clinicaltrials.gov and Pharmaprojects database.
The current pipeline is larger and more diverse than ever, with drugs targeting potential genetic and retroviral causes of ALS and drugs targeting a wide array of downstream pathways, including RNA metabolism, protein aggregation, integrated stress response and neuroinflammation.We remain most excited about those that target direct causes of ALS, e.g. antisense oligonucleotides targeting causative genes. Drugs that eliminate abnormal protein aggregates are also up-and-coming. Eventually, because of the heterogeneity of ALS pathophysiology, biomarkers that determine which biological events are most important for an individual ALS patient are needed.
肌萎缩侧索硬化症（ALS）是一种快速进展的运动神经元疾病，导致严重残疾和过早死亡。由于在揭示 ALS 病理生理学方面取得了进展，高效的临床试验设计和研究倡导计划，几种疾病修饰药物已被批准用于治疗 ALS。尽管取得了这一进展，但 ALS 仍然是一种迅速致残和缩短寿命的疾病。迫切需要更有效的治疗方法。
在这里，我们回顾了正在进行 II 期和 III 期临床试验的新兴 ALS 疗法。为了确定研究药物，我们在 clinicaltrials.gov 和 Pharmaprojects 数据库中搜索了正在进行的、正在招募或尚未招募的 ALS 和 II/III 期试验。
目前的药物研发管线比以往任何时候都更大、更多样化，包括针对 ALS 潜在遗传和逆转录病毒原因的药物，以及针对广泛下游途径的药物，包括 RNA 代谢、蛋白质聚集、综合应激反应和神经炎症。我们对那些针对 ALS 直接原因的药物最感兴趣，例如针对致病基因的反义寡核苷酸。消除异常蛋白质聚集体的药物也在兴起。最终，由于 ALS 病理生理学的异质性，需要确定哪些生物事件对个体 ALS 患者最重要的生物标志物。
