An Intermediate-Size Expanded Access Protocol for Amyotrophic Lateral Sclerosis with Pridopidine

Sigma 1受体（S1 R）已经成为ALS中有吸引力的治疗靶点。 S1 R突变是ALS的病因，S1 R蛋白功能丧失的程度 决定了发病年龄S1 R敲低可加重ALS小鼠模型的表型， S1 R激活影响已知与ALS有关的途径，即，核质 转运、蛋白质质量控制、内质网（ER）应激、线粒体功能，以及 自噬阿曲唑、依达拉奉和PB-TURSO，目前用于治疗的标准治疗药物， 在美国，ALS仅提供适度的临床益处，并且不知道通过S1 R起作用。 Nuedexta是一种非选择性S1 R激动剂，被批准用于治疗假性延髓情感， 已被证明可以改善ALS患者的延髓功能。 普利多匹定（Prilenia Therapeutics）是一种有效的和高选择性的小分子S1 R 激动剂S1 R在整个脑中显示高表达，特别是在脑干运动神经元中。 原子核。在G93 A SOD 1 ALS小鼠模型中，普利多匹定改变了疾病进展。 普利多匹定的安全性和有效性目前正在HEALEY ALS平台上进行测试 审判试验设计包括一项疗效随机对照试验（RCT），随后是一项开放性试验。 标签扩展（OLE）。普利多匹定方案的RCT部分招募了162名ALS参与者。 虽然它没有达到主要终点，但它显示了以下有益效果的趋势： 普利多匹定对几个结果的措施，与最大的可识别的影响，功能 评分、定量运动语言和神经丝光水平在早期和快速进展中 参与者OLE正在进行中。第二项针对选定人群的疗效试验 正在规划中。不幸的是，现实世界中的ALS人群中有很大一部分不会 由于限制性合格性标准，有资格入组第二项疗效研究。 目前的提议是2000年普多比啶的扩展访问协议（EAP）。 没有资格参加临床试验的ALS患者。与会者将收到 普多比啶长达24个月，而OLE和计划的第二次疗效试验正在进行中。 本研究将通过评价药物在人群中的作用提供真实的世界数据 这比疗效试验中包括的范围更广，通过收集安全性，临床， 以及长期暴露的生物学结果。

The Sigma 1 Receptor (S1R) has emerged as an attractive therapeutic target in ALS. Mutations in the S1R are causative of ALS and the degree of loss of function in S1R protein determines age of onset. S1R knock-down exacerbates phenotypes in ALS mouse models, and S1R activation impacts pathways that are known to be implicated in ALS, i.e., nucleocytoplasmic transport, protein quality control, endoplasmic reticulum (ER) stress, mitochondrial function, and autophagy. Riluzole, edaravone, and PB-TURSO, the current standard-of-care medications for ALS in the US, offer only modest clinical benefit and are not known to act through the S1R. Nuedexta, a non-selective S1R agonist, is approved for the treatment of pseudobulbar affect and has been shown to improve bulbar function in a subset of people living with ALS. Pridopidine (Prilenia Therapeutics) is a potent and highly selective small molecule S1R agonist. The S1R shows high expression throughout the brain, particularly in brainstem motor nuclei. In the G93A SOD1 ALS mouse model, pridopidine modified disease progression. The safety and efficacy of pridopidine are currently being tested inthe HEALEY ALS Platform Trial. The trial design includes an efficacy randomized controlled trial (RCT) followed by an open label extension (OLE). The RCT portion of the pridopidine regimen enrolled 162 ALS participants. While it did not reach the primary endpoint, it showed trends toward beneficial effects of pridopidine on several outcome measures, with the greatest identifiable effect on functional scores, quantitative motor speech, and neurofilament light levels in early and faster progressing participants. The OLE is ongoing. A second efficacy trial targeting a selected population of people with ALS is being planned. Unfortunately, a large segment of the real-world ALS population won’t be eligible to enroll in this second efficacy study due to the restrictive eligibility criteria. The current proposal is an expanded access protocol (EAP) of pridopidine in 200 individuals with ALS who are ineligible for clinical trials. Participants would receive pridopidine for up to 24 months, while the OLE and the planned second efficacy trial are ongoing. This study will provide real- world data by evaluating the effects of the drug in a population that is broader than the one included in the efficacy trials and by collecting safety, clinical, and biological outcomes over longer term exposure.