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

使用普利多匹定治疗肌萎缩侧索硬化症的中型扩展治疗方案

• 批准号: 10835282
• 负责人: Suma Babu
• 金额: $ 1013.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10835282
• 关键词: ALS patients; Affect; Age of Onset; Agonist; Amyotrophic Lateral Sclerosis; Autophagocytosis; Biological; Biological Markers; Brain; Brain Stem; Cell Nucleus; Clinical; Clinical Data; Clinical Trials; Data; Disease; Disease Progression; Dose; Double-Blind Method; Eligibility Determination; Endoplasmic Reticulum; Enrollment; Ensure; Enteral Feeding; FDA approved; Genetic Polymorphism; Geography; Goals; Human; Huntington Disease; Individual; Light; Measures; Membrane; Methods; Mitochondria; Modeling; Molecular; Motor; Motor Neurons; Mutation; Neuronal Injury; Oral; Oral Administration; Oral cavity; Outcome; Outcome Measure; Participant; Pathway interactions; Patient Outcomes Assessments; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Physical Function; Placebo Control; Population; Property; Proteins; Protocols documentation; Psychometrics; Quality Control; Quality of Life Assessment; Randomized; Randomized, Controlled Trials; Receptor Activation; Receptor Gene; Regimen; Research; Respiratory physiology; Riluzole; Running; Safety; Serum; Signal Transduction; Site; Speech; Testing; Therapeutic; Vital capacity; clinical efficacy; design; disability; efficacy clinical trial; efficacy study; efficacy trial; endoplasmic reticulum stress; genetic analysis; healthy volunteer; improved; knock-down; longitudinal dataset; loss of function; mouse model; neurofilament; neuroimaging; novel; nucleocytoplasmic transport; open label; patient oriented; phenylmethylpyrazolone; primary endpoint; randomized, clinical trials; receptor; receptor function; remote assessment; research clinical testing; sigma-1 receptor; small molecule; smartphone application; standard of care; superoxide dismutase 1; therapeutic target; trend; trial design

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.

Sigma 1 受体 (S1R) 已成为 ALS 中有吸引力的治疗靶点。 S1R 突变是 ALS 的病因以及 S1R 蛋白功能丧失的程度 决定发病年龄。 S1R 敲低加剧了 ALS 小鼠模型的表型，并且 S1R 激活影响已知与 ALS 相关的途径，即核细胞质 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，目前的标准治疗药物 在美国，ALS 仅提供有限的临床益处，并且不知道通过 S1R 发挥作用。 Nuedexta 是一种非选择性 S1R 激动剂，被批准用于治疗假性延髓情感和 已被证明可以改善部分 ALS 患者的延髓功能。 普利多匹定 (Prilenia Therapeutics) 是一种有效且高度选择性的小分子 S1R 激动剂。 S1R 在整个大脑中表现出高表达，特别是在脑干运动中 原子核。在 G93A SOD1 ALS 小鼠模型中，普利多匹定可改变疾病进展。 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。试验设计包括功效随机对照试验 (RCT)，然后是开放性试验 标签扩展（OLE）。普利多匹定方案的随机对照试验部分招募了 162 名 ALS 参与者。 虽然它没有达到主要终点，但它显示了以下趋势： 普利多匹定对多项结果指标的影响最大，其中对功能的影响最大 早期和快速进展中的分数、定量运动言语和神经丝光水平 参与者。 OLE 正在进行中。针对选定人群的第二次功效试验 ALS 正在计划中。不幸的是，现实世界中的 ALS 人群中很大一部分人不会 由于限制性资格标准，有资格参加第二次功效研究。 目前的提案是200年普利多匹定的扩展访问协议（EAP） 不符合临床试验资格的 ALS 患者。参与者将收到 普利多匹定治疗长达 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作用来提供真实世界的数据 这比功效试验中包含的范围更广泛，并通过收集安全性、临床、 以及长期暴露的生物学结果。