Pridopidine

NAARDEN, The Netherlands & WALTHAM, Mass. & BARCELONA, Spain--(BUSINESS WIRE)--Prilenia Therapeutics B.V. and Ferrerii today announced the first enrollment in the pivotal, 500-participant, randomized, placebo-controlled Phase 3 study of pridopidine in people with rapidly progressive Amyotrophic Lateral Sclerosis (ALS) early in their disease course (“PREVAiLS”, NCT07322003). Enrolling the first participant in this confirmatory study is a milestone in our search for potential new therapeutic options that may help to slow disease progression, preserve function, maintain speech and prolong survival – key aims of early ALS therapy The first participant was enrolled at the at Mass General Brigham (MGB), under the supervision of Sabrina Paganoni, MD, PhD, Co-Director of the MGH Neurological Clinical Research Institute, and PREVAiLS principal investigator, who said: “Pridopidine is a sigma-1 receptor (S1R) agonist. The S1R has been shown to play a role in stimulating multiple neuroprotective pathways impaired in neurodegenerative diseases, such as ALS and Huntington’s disease (HD)iii. Enrolling the first participant in this confirmatory study is a milestone in our search for potential new therapeutic options that may help to slow disease progression, preserve function, maintain speech and prolong survival – key aims of early ALS therapy.” “The ALS community urgently needs new treatment options that can delay the disease’s relentless progression, and awaits the outcome of this study,” said Kuldip Dave, Ph.D. Senior Vice President of Research, ALS Association. “The earlier we can diagnose and treat ALS, the greater the potential to preserve function and maintain quality of life for longer, which are key to making ALS livable until we can cure it”. PREVAiLS is informed by peer-reviewed and published data from a subgroup analysis of similar participants with rapidly progressive ALS early in their disease course (pridopidine: n = 37; shared placebo: n = 35), from the randomized, double-blind, placebo-controlled Phase 2 HEALEY ALS Platform Trial. The HEALEY trial did not meet its primary or secondary endpoints in the full population; pre-specified and additional analyses showed effects in rapid progressive patients that we seek to confirm in PREVAiLS. The PREVAiLS study is set to take place in up to 60 leading ALS treatment centers across 13 countries. 11 sites are already, or will imminently be, initiated, with recruitment at additional sites in the US, Canada, EU, UK and Israel expected to commence in the coming weeks and months. More details on PREVAiLS can be found on ClinicalTrials.Gov (NCT07322003) / EU CT Number: 2025-524002-16-00. [This press release is intended for informational purposes only. Pridopidine is an investigational drug and is not approved for commercial use by any regulatory authority. Its safety and efficacy have not been established. Information contained herein does not constitute medical advice. Patients should consult their healthcare provider for guidance regarding diagnosis or treatment options. Local regulations may vary; this release is not intended to promote or advertise any product.] About PREVAiLS (Pridopidine Phase 3 Study to Evaluate Efficacy and Safety in ALS) PREVAiLS is a 48-week randomized (3:2 pridopidine:placebo), placebo-controlled study, with a 48-week open label extension phase to follow. The study seeks to enroll participants with definite or probable ALS (El Escorial Criteria) who are within 18 months from first onset of disease symptoms. The primary endpoint of PREVAiLS is the change from baseline in ALSFRS-R adjusted for mortality at 48 weeks. Secondary and exploratory endpoints include survival and measures of speech, respiratory function, bulbar function and quality of life, as well as patient-reported outcomes of communication and plasma biomarkersiv. More details on PREVAiLS can be found on ClinicalTrials.Gov (NCT07322003) / EU CT Number: 2025-524002-16-00. About pridopidine Pridopidine (45 mg twice daily) is an investigational selective, orally administered sigma-1 receptor (S1R) agonist. S1R has been shown to play a role in stimulating multiple neuroprotective pathways impaired in neurodegenerative diseases, such as ALS and Huntington’s disease (HD)iii. In clinical studies to date, it has demonstrated a favorable safety and tolerability profile, with data from more than 1,600 people (mostly from HD studies), some of whom have received active treatment for, up to seven yearsv. In addition to ALS, Prilenia and Ferrer are planning to initiate a potentially registrational pivotal Phase 3 study in HD. The study is expected to start recruitment in the first half of 2026. Pridopidine has Orphan Drug designation in HD and ALS in the US and EU, and FDA Fast Track designation for the treatment of HD. Pridopidine is an investigational drug not approved by any regulatory authority. Its role in ALS and other neurological conditions is currently under clinical investigation. About ALS Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease or often referred to as motor neuron disease (MND), is a progressive neurodegenerative disease, which means it is a chronic condition that gets worse over time as damage builds up in parts of the nervous systemvi. It affects a specific type of neurons – the motor neurons in the brain and spinal cord – and leads to a gradual loss of muscle function that eventually results in paralysis and deathvii. ALS affects approximately 500,000 people worldwideviii, and is more frequent in men than in womenix. The average survival is 2 to 5 yearsx. The exact cause of ALS is not fully understood, but it is believed to be a combination of genetic and environmental factors. ALS typically appears in individuals aged 40 to 70xi and presents a range of symptoms, including muscle weakness and atrophy, mobility issues such as lack of coordination and balance, muscle spasms, difficulty speaking clearly (dysarthria), trouble swallowing (dysphagia), fatigue, and emotional and cognitive changesxii. Symptoms worsen over time and significantly impact the quality of life of patients and their families by affecting their ability to perform daily activities independently. Current treatment options are limited. Dysfunction of the S1R has been associated with multiple forms of ALS, and maintaining S1R functionality may play a key role in protecting neuronal function. About Prilenia Prilenia is a private biopharmaceutical company driven by an unwavering commitment to scientific excellence and accelerating progress for people affected by HD, ALS and other neurodegenerative disorders. Our mission is simple but urgent: to develop and provide sustainable access to transformative medicines for people affected by devastating neurodegenerative diseases. The company is incorporated in the Netherlands and backed by leading life sciences investors. For more information, please visit www.prilenia.com, and connect with us on LinkedIn or X (Twitter). About Ferrer At Ferrer, we use business to fight for social justice. We have long been a company that wants to do things differently; instead of maximizing shareholder returns, we reinvest much of our profit in initiatives that give back to society. Back where it belongs. We go beyond compliance and are guided by the highest standards of sustainability, ethics and integrity. As such, since 2022, we are a B Corp. Founded in Barcelona in 1959, Ferrer offers transformative solutions for life-threatening diseases in more than one hundred countries. In line with our purpose, we have an increasing focus on pulmonary vascular and interstitial lung diseases and rare neurological disorders in adults and children. Our 1,800-strong team is driven by a clear conviction: our business is not an end in itself, but a way to change lives. We are Ferrer. Ferrer for good. www.ferrer.com i Geva, M., Goldberg, Y. P., Leitner, M. L., Cruz-Herranz, A., Hand, R., Chen, K., … Hayden, M. R. (2025). Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 1–13. https://doi.org/10.1080/21678421.2025.2597935 ii In April 2025, Prilenia and Ferrer signed a commercialization and co-development agreement for pridopidine. https://news.prilenia.com/press-releases/press-release-details/2025/Prilenia-Enters-into-a-Collaboration-and-License-Agreement-with-Ferrer-for-the-Commercialization-and-Co-Development-of-Pridopidine-in-Europe-and-Other-Select-Markets/default.aspx iii Lachance V, Bélanger S-M, Hay C, Le Corvec V, Banouvong V, Lapalme M, Tarmoun K, Beaucaire G, Lussier MP, Kourrich S. Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection. International Journal of Molecular Sciences. 2023; 24(3):1971. https://doi.org/10.3390/ijms24031971 iv van den Berg L, et al. A planned Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of pridopidine in participants with ALS 36th International Symposium on ALS/MND, San Diego, CA, USA, December 2025 v Goldberg YP, Navon-Perry L, Cruz-Herranz A, Chen K, Hecker-Barth G, Spiegel K, Cohen Y, Niethammer M, Tan AM, Schuring H, Geva M, Hayden MR. The Safety Profile of Pridopidine, a Novel Sigma-1 Receptor Agonist for the Treatment of Huntington's Disease. CNS Drugs. 2025 May;39(5):485-498. doi: 10.1007/s40263-025-01171-x. Epub 2025 Mar 7. PMID: 40055280; PMCID: PMC11982116. vi https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022#:~:text=ALS%2C%20is%20a%20nervous%20system,disease%20gets%20worse%20over%20time. vii Goutman SA, Hardiman O, Al-Chalabi A,et al. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):480-493. doi: 10.1016/S1474-4422(21)00465-8. viii Xu L, Liu T, Liu L, et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol. Apr 2020;267(4):944–953. doi:10.1007/s00415-019-09652-y ix Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918-1929. doi:10.1111/ene.14393 x Goutman SA, Hardiman O, Al-Chalabi A,et al. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):480-493. doi: 10.1016/S1474-4422(21)00465-8. xi https://www.als.org/understanding-als/who-gets-als xii Muscular Dystrophy Association. Amyotrophic Lateral Sclerosis (ALS). Signs and Symptoms [Internet]. MDA [Accessed October 18th, 2024]. Available from: https://www.mda.org/disease/amyotrophic-lateral-sclerosis/signs-and-symptoms

点击上方「蓝字」关注我们 引言 肌萎缩侧索硬化症（ALS）作为致命性神经退行性疾病，临床治疗始终缺乏突破性进展。sigma-1（σ1）受体曾被寄予厚望成为干预靶点，pridopidine 作为该受体激动剂，在前期研究中展现出潜在神经保护作用。然而，最新 HEALEY ALS 平台试验结果却令人意外，本文将从生物信息学与临床研究结合视角，深度解析这项关键研究的来龙去脉与科学启示。 核心观点概括 本研究通过 2/3 期多中心随机双盲平台试验，在 54 个美国研究中心纳入 163 名 ALS 患者，以 3:1 比例随机分配至 pridopidine（45mg 每日两次）组与安慰剂组，并纳入其他方案的 122 名安慰剂受试者进行联合分析。核心结论为：24 周干预后，pridopidine 在主要结局（疾病进展率比 DRR=0.99，95% CI 0.80-1.21）及关键次要结局中均未显示出显著疗效，但安全性良好，未出现严重不良事件差异。仅探索性分析发现其可能延缓说话速率和发音速率下降，但未达到临床核心获益标准。 文献解读 文章标题：普利多匹定治疗肌萎缩侧索硬化症：HEALEY ALS 平台试验 发表期刊：JAMA. 发表时间：2025年2月17日 影响因子：IF55.0/Q1 研究价值与意义 研究背景 1. ALS 病理特征：ALS 以运动神经元进行性丢失为核心，中位生存期仅 2-3 年，现有治疗手段有限，存在巨大未满足医疗需求。 2. σ1 受体的靶点合理性：σ1 受体在运动神经元高表达，功能缺失突变可导致青少年型 ALS，而药理激活可在 SOD1G93A 小鼠模型中延长生存期、改善运动功能。 3. Pridopidine 的前期基础：作为高选择性 σ1 受体激动剂，其在临床前研究中已证实可调控内质网 - 线粒体接触、钙稳态、自噬等多个 ALS 相关病理通路，且 45mg 每日两次剂量在 1700 余人的临床研究中显示良好耐受性。 价值意义 1. 为 σ1 受体靶向治疗提供高级别临床证据，明确该靶点在成人 ALS 中的实际干预效果。 2. 平台试验设计为 ALS 临床研究提供高效范式，通过安慰剂共享、多方案并行加速药物筛选。 3. 揭示 ALS 异质性对治疗效果的影响，为后续精准治疗方案设计提供关键参考。 研究路线和方法 研究设计 1. 试验类型：HEALEY ALS 平台试验的 D 方案，2/3 期、多中心、随机双盲、安慰剂对照。 2. 研究周期：2021 年 1 月 - 2022 年 7 月，干预 24 周，随访至 28 周。 3. 样本量：121 名 pridopidine 受试者 + 42 名同方案安慰剂受试者 + 122 名跨方案共享安慰剂受试者，共 369 人纳入分析。 核心方法 1. 入排标准：符合修订版 El Escorial 诊断标准、病程≤36 个月、预测肺活量≥50%、可吞咽药物，稳定使用或未使用利鲁唑 / 依达拉奉。 2. 随机化：按是否使用依达拉奉 / 利鲁唑分层，3:1 随机分配至治疗组与安慰剂组。 3. 结局评估： （1）主要结局：基于贝叶斯共享参数模型的疾病进展率比DRR，整合 ALSFRS-R 功能评分与生存期。 （2）次要结局：包括球部功能相关指标、肺活量下降速率、死亡或永久辅助通气时间等 5 项关键指标，及 63 项探索性结局。 （3）统计分析：采用贝叶斯共享参数模型、Cox 比例风险模型、线性混合模型等，控制基线症状持续时间、ALSFRS-R 基线斜率等协变量。 研究结果 （一）基线特征均衡性 治疗组与安慰剂组在性别（男性 60.0% vs 70.1%）、年龄平均 57.9 岁 vs 57.2 岁、病程（症状出现后平均 20.6 个月 vs 22.1 个月）、ALSFRS-R 总分（34.3 分 vs 35.1 分）等关键基线特征上无显著差异，保证了组间可比性。球部起病比例、King 分期分布、基础用药情况也基本一致，为结果可靠性奠定基础。 （表1：基线人口统计学特征） （二）主要结局无显著获益 ALSFRS-R 评分随时间下降趋势在 pridopidine 组与安慰剂组几乎重合，模型估计治疗组每月下降 0.99 分，安慰剂组下降 1.00 分，DRR=0.99（95% CI 0.80-1.21），DRR<1 的概率仅 0.55，无统计学意义。生存分析显示两组死亡率均为 0.012 / 人月，未体现生存获益。 （图1：24 周内通过修订版肌萎缩侧索硬化功能评定量表（ALSFRS-R）评分及生存期评估的疾病严重程度变化） （三）次要结局全面阴性 所有关键次要结局均未出现治疗组优势：球部功能障碍患者的肺活量下降速率（-1.83% vs -1.44%/ 月P=0.35）、ALSFRS-R 总分下降≥2 分的风险（HR=1.00，P=0.99）、死亡或永久辅助通气风险（HR=0.94，P=0.89）等均无显著差异。球部功能无恶化患者比例、球部域评分下降≥1 分的时间也未显示治疗获益。 （表2：关键次要结局指标的疗效分析） （四）探索性发现与安全性 1. 探索性结局：仅说话速率（P=0.03）和发音速率（P=0.01）两项语音指标显示治疗组下降更慢，可能与 σ1 受体在脑干语言相关区域高表达有关。 2. 安全性：最常见不良事件为跌倒（28.1% vs 29.3%）和肌肉无力（24.0% vs 31.7%），两组发生率相近；QTcF 间期无临床意义改变，未出现严重安全性信号。 研究不足与局限性 1. 受试者异质性：纳入了不同发病类型、分期的 ALS 患者，可能掩盖了药物对特定亚型的潜在疗效，尤其针对球部功能的干预效应易被稀释。 2. 干预时长不足：24 周可能短于 pridopidine 的起效周期，对于机制延迟的神经保护药物，短期干预难以显现临床获益。 3. 共享安慰剂偏倚：跨方案安慰剂受试者可能存在微小基线差异，虽通过统计模型调整，但仍可能影响结果准确性。 4. 缺失数据处理：连续结局分析中将死亡导致的缺失视为随机缺失，可能对部分指标的效应估计产生轻微影响。 未来研究改进建议 1. 精准筛选受试者：聚焦症状出现 18 个月内、快速进展型、球部起病或明确 σ1 受体相关基因型的 ALS 亚型，提高人群同质性。 2. 延长干预周期：设计 6-12 个月的长期试验，充分观察神经保护药物的累积效应。 3. 优化结局指标：增加语音功能、球部功能的客观量化指标，结合数字健康工具实现高频次居家评估，提高检测敏感性。 4. 联合治疗策略：探索 pridopidine 与现有药物（利鲁唑、依达拉奉）或其他靶点药物的联合应用，发挥协同效应。 5. 机制验证：结合生物标志物（如神经丝轻链 NfL），明确药物是否达到预期靶点调控效果，区分 "靶点无效" 与 "药物未达效应"。 引起的启示 1. 临床前与临床转化差距：动物模型中明确的 σ1 受体激活获益，在人类 ALS 中未完全重现，提示疾病复杂性与物种差异，需加强临床前模型的临床相关性验证。 2. ALS 的异质性是治疗失败的关键因素：传统 "一刀切" 的治疗模式难以应对 ALS 的遗传异质性、病理异质性和临床异质性，精准医学是未来核心方向。 3. 平台试验的高效性：HEALEY 平台通过共享对照组、灵活纳入多方案，显著提高了 ALS 药物研发效率，为罕见病临床试验提供了可复制的范式。 4. 安全性与收益的权衡：pridopidine 的良好安全性提示，即使未达主要疗效，仍可作为联合治疗候选药物进一步探索。 未来方向指引 1. 亚型特异性治疗：基于发病部位（球部 vs 肢体）、进展速率、遗传背景（如 SOD1、C9orf72 突变）进行分层临床试验，挖掘 pridopidine 在特定亚群中的潜在价值。 2. 靶点优化：开发更高选择性 σ1 受体激动剂，或联合调控 σ1 受体下游通路（如自噬、线粒体功能）的药物，增强治疗效应。 3. 生物标志物驱动的临床试验：将 NfL、脑成像、语音分析等生物标志物纳入富集策略或替代终点，加速药物筛选。 4. 跨疾病靶点验证：σ1 受体在亨廷顿病、阿尔茨海默病等神经退行性疾病中也有重要作用，可借鉴本研究经验开展跨疾病临床试验。 如何复刻? 1. 试验设计：采用平台试验框架，明确核心对照组与分层因素，降低样本量需求；优先选择已验证的结局指标（如 ALSFRS-R、肺活量）保证数据可比性。 2. 统计方法：学习贝叶斯共享参数模型的应用，整合功能与生存数据，提高稀疏结局的统计效能；借助 SAS、R、JAGS 等工具实现复杂模型拟合。 3. 数据管理：建立标准化数据采集流程，利用电子数据捕获系统如 PharmaEngine保证盲法完整性；规范不良事件与结局指标的定义与记录。 4. 合作网络：依托 ALS 协作联盟（如 NEALS Consortium）建立多中心研究网络，解决罕见病样本招募难题；加强与统计专家、靶点机制研究者的跨学科合作。 文章小结 本研究为 σ1 受体靶向治疗 ALS 提供了关键阴性证据，虽未达主要终点，但平台试验设计与亚型探索仍具重要价值。ALS 治疗的突破离不开对疾病异质性的深刻理解，你认为 pridopidine 在特定 ALS 亚型中是否仍有探索空间？欢迎在评论区分享你的观点，一起探讨神经退行性疾病的精准治疗之路！ 关注【生信地图】，生信不迷路。持续获取生信前沿研究解读、实用方案技术，科研路上，我们共同前行。 ·往期推荐· IF10.7一区！中国广州医科大学附属第一医院，从影像到分子：qCT 聚类解锁哮喘异质性的全新分型方案！ 国产生信太能打！华科大解锁糖尿病新思路，IF22.9 顶刊到手 IF15.7分神刊突破！运动强度主导免疫调控：HIIE 引发千余免疫蛋白显著改变