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

Sigma-1受体(S1R)已成为ALS治疗的重要靶点。 S1R基因突变是ALS和S1R蛋白功能丧失程度的原因 决定发病年龄。S1R基因敲除加剧了ALS小鼠模型的表型，并且 S1R激活影响已知的与ALS有关的通路，即核质 运输、蛋白质质量控制、内质网(ER)应激、线粒体功能和 自噬。利鲁唑、依达拉奉和PB-Turso，目前的标准护理药物 在美国，肌萎缩侧索硬化症只提供温和的临床益处，并不知道通过S1R起作用。 NUEDEXTA是一种非选择性S1R激动剂，被批准用于治疗假性延髓影响和 已被证明可以改善部分ALS患者的延髓功能。 普里多巴定(Prilenia Treeutics)是一种高效、高选择性的小分子S1R 激动剂。S1R在整个大脑中都有高表达，特别是在脑干运动中 原子核。在G93A SOD1ALS小鼠模型中，普里多巴定改善了疾病进展。 普立多巴胺的安全性和有效性目前正在Healey ALS平台上进行测试 审判。试验设计包括一项有效性随机对照试验(RCT)，随后是一项开放试验 标签扩展(OLE)。普立多巴定方案的RCT部分招募了162名ALS参与者。 虽然它没有达到主要终点，但它显示出以下有益效果的趋势 普鲁多巴定在几个结果指标上，对功能的影响最大 早期和较快进展的分数、量化运动语言和神经细丝光照水平 参与者。OLE正在进行中。针对选定人群的第二次疗效试验 与肌萎缩侧索硬化症的关系正在计划之中。不幸的是，现实世界中的很大一部分ALS人群不会 由于严格的资格标准，有资格参加这项第二次疗效研究。 目前的建议是200中的普立多巴胺的扩展访问协议(EAP) 没有资格参加临床试验的肌萎缩侧索硬化患者。参与者将收到 最长可达24个月，而OLE和计划中的第二次疗效试验正在进行中。 这项研究将通过评估药物在人群中的效果来提供真实世界的数据 这比包括在疗效试验中的数据更广泛，通过收集安全性、临床和 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.