A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Pridopidine in Participants With Huntington's Disease (HD)

The goal of this clinical trial is to learn if pridopidine can slow the clinical decline of Huntington's Disease (HD) in adult participants. It will also inform about the safety of pridopidine.
The main questions the study aims to answer are:
Does pridopidine slow the overall worsening of HD over 1 year? Does pridopidine slow the worsening of specific aspects of HD over 1 year, namely the clinical progression, the ability to perform daily life activities (functional capacity), the mind's ability to process information (cognition), working of the muscles (motor function), and quality of life?
Researchers will compare the drug pridopidine to a placebo (a look-alike substance that contains no drug) to see if pridopidine works better than placebo to treat HD. During the first year of the study, participants will have the same chance to receive either pridopidine or placebo.
Participants will:
Take 1 pridopidine or placebo capsule twice daily for 12 months. Visit the clinic 6 times within 1 year for checkups and tests.
All participants who complete this 1-year placebo-controlled study period will roll over into an additional 2-year study period during which all participants will receive pridopidine treatment, including participants who had received placebo during the first year. During this additional 2-year treatment period participants will visit the clinic a total of 6 times for checkups and tests.

开始日期2026-06-01

申办/合作机构

Prilenia Therapeutics BV

[+1]

CTIS2025-524002-16-00

/ Recruiting临床3期

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Pridopidine in Participants with Amyotrophic Lateral Sclerosis

开始日期2026-05-12

申办/合作机构

Ferrer Internacional SA

NCT07322003

/ Recruiting临床3期

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Pridopidine in Participants With Amyotrophic Lateral Sclerosis

The goal of this clinical trial is to learn if the drug pridopidine works to treat amyotrophic lateral sclerosis in adults. It will also help to learn about the safety of pridopidine. The main question it aims to answer is:
Does pridopidine slow disease progression of ALS?
Researchers will compare pridopidine to a placebo (a look-alike substance that contains no drug) to see if pridopidine works to treat ALS.
Participants will:
Take pridopidine or a placebo by mouth every day for 48 weeks. Afterwards, all participants will take pridopidine for another 48 weeks.
Visit the clinic once every 1-3 months for checkups and tests

开始日期2026-02-01

申办/合作机构

Prilenia Therapeutics BV

[+1]

100 项与普利多匹定相关的临床结果

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100 项与普利多匹定相关的转化医学

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100 项与普利多匹定相关的专利（医药）

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117

项与普利多匹定相关的文献（医药）

2026-06-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Beyond motor symptoms: efficacy of pharmacotherapies on motor, functional, and cognitive domains in Huntington's disease - a systematic review

Review

作者: Teixeira, Amanda Gomes ; Wiprich, Melissa Talita ; Colonetti, Tamy ; Endler, Ana Thereza ; Rosa, Maria Inês da ; Bonan, Carla Denise ; Pereira, Wuesllen Dondossola ; Lodetti, Guilherme ; Rico, Eduardo Pacheco ; Pacagnan, Lucas de Oliveira ; Redivo, Henrique

INTRODUCTION:

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, neuropsychiatric, cognitive, and peripheral alterations impairing functional capacity and quality of life (QoL). Pharmacotherapies, including dopaminergic and glutamatergic drugs, primarily target motor symptoms, while cholinergic modulators address cognitive decline. However, the literature lacks comprehensive reviews evaluating the combination of these three drug classes across a broad spectrum of clinical outcomes, extending beyond the total motor score (TMS).

OBJECTIVE:

This systematic review aimed to assess the efficacy of dopaminergic, glutamatergic, and cholinergic drugs on motor, functional, cognitive decline, and QoL in HD patients.

METHODOLOGY:

Following PRISMA guidelines, searches were performed in MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library until October 2025. Randomized clinical trials evaluating these three classes of drugs in adults with genetically confirmed HD were included. Primary outcomes were Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), Total Functional Capacity (TFC), and cognitive performance. Secondary outcomes included the Independence Scale (IS) and QoL. Risk of bias was assessed using the Cochrane RoB 2 tool. Due to substantial heterogeneity, results were synthesized descriptively.

RESULTS:

From 32,746 studies, 15 were included in the final analysis. Findings showed that UHDRS TMS was improved with dopaminergics (tetrabenazine, deutetrabenazine, and pridopidine) and glutamatergic (riluzole) drugs. Only pridopidine treatment exhibited efficacy on UHDRS TFC, subsequently improving UHDRS IS. For QoL, deutetrabenazine treatment proved effective. In the UHDRS cognitive domain, tetrabenazine improved performance in the Stroop Color and Word test, while rivastigmine (cholinergic) improved verbal fluency.

CONCLUSION:

Dopaminergic, glutamatergic, and cholinergic drugs exhibit distinct efficacy profiles across various motor and non-motor UHDRS components. This positions them as therapeutic options for attenuating both the motor and non-motor symptoms in HD.

2026-04-03·Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

Article

作者: Macklin, Eric A. ; Tan, Andrew M. ; Cruz-Herranz, Andres ; Hand, Randal ; Gershoni Emek, Noga ; Geva, Michal ; Goldberg, Y. Paul ; Paganoni, Sabrina ; Berry, James D. ; Cudkowicz, Merit E. ; Hayden, Michael R. ; Leitner, Melanie L. ; Shefner, Jeremy M. ; Chen, Kelly

Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.

2026-04-01·EUROPEAN NEUROPSYCHOPHARMACOLOGY

Emerging neurobiological targets in psychiatric treatment

Review

作者: Berk, Michael ; Govinnage, Janani ; Giorlando, Frank ; De Zoysa, Agampodi Ishan ; Narayanaswamy, J C ; Dodd, Seetal

Despite significant advancements in psychopharmacology, there are inadequate treatment options for many psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorders. This review explores emerging neurobiological targets beyond conventional monoaminergic approaches, focusing on sodium channels, Neuropeptide Y (NPY), Neurokinin 1 (NK1) receptors, P2 × 7 purinergic receptors, Sigma-1 receptors, and Orexin. Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission. NPY-based therapies have potential in stress-related disorders, foreshadowing rapid anxiolytic and antidepressant effects through modulation of the stress response. NK1 receptor antagonists, although inconsistent in mood disorders, show promise in addiction treatment by reducing substance cravings. The P2 × 7 receptor, a key regulator of neuroinflammation, has been implicated in mood disorders, and its pharmacological inhibition may provide neuroprotective benefits. Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system. While these emerging therapeutic targets hold promise, challenges remain in translating preclinical findings into effective clinical applications. Large-scale, placebo-controlled trials are necessary to establish their efficacy and safety. The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness.

项与普利多匹定相关的新闻（医药）

2026-06-30

·拓麦Neurol

期刊精要 | 亨廷顿病药物研发十年全景：从症状控制到疾病修饰的范式转移

点击蓝字关注“拓麦Neurol” 亨廷顿病（HD）是一种罕见的遗传性神经退行性疾病，长期以来缺乏有效的疾病修饰治疗手段。近日，发表于Movement Disorders的一项系统综述全面梳理了2014年至2025年HD药物研发管线的演变，揭示了这一领域正在发生的深刻变革。 1 研发管线概览：来自欧洲亨廷顿病网络（EHDN）、CHDI基金会等机构的研究团队，对clinicaltrials.gov和WHO国际临床试验注册平台的数据进行了系统分析。截至2025年11月13日的索引日期，共识别出165项HD注册临床研究，累计需要7501名参与者。研究构成如下： ▸ 观察性研究：54项（32.1%），包括自然史研究、生物标志物研究等 ▸ 干预性试验：111项（67.9%），其中药理学试验69项，非药理学试验33项，生物标志物效用评估9项在69项药理学试验中，54.9%已完成，10.8%已终止，39.2%仍处于活跃状态。11年间共测试了50种不同的药物，目前有21种药物正在评估中。 2 范式转移：从症状治疗到疾病修饰这是过去十年HD研发最显著的变化。研究发现，HD药物研发管线经历了清晰的战略转向： ▸ 2014-2019年：症状治疗药物占主导地位。2017年新进入管线的药物中83.3%为症状治疗，2019年这一比例为80%。 ▸ 2021年起：疾病修饰疗法（Disease-Modifying Therapy, DMT）开始占据主流。 ▸ 2022-2025年：所有新进入管线的药物均为DMT。目前，DMT在各期试验中的占比已达到： ▸ 1期试验：90.5% ▸ 2期试验：61.8% ▸ 3期试验：55.6% 这一趋势与阿尔茨海默病领域相似，后者目前78%的在研药物为DMT。 3 作用机制：HTT降低策略异军突起基于改良的CADRO（Common Alzheimer's and Related Dementias Research Ontology）分类系统，50种药物覆盖了8大生物学过程类别，加上独立的亨廷顿蛋白（HTT）降低类别。两大主流方向： ▸ 神经递质受体靶向：12种药物，主要用于症状治疗 ▸ HTT降低策略：12种药物，是DMT的核心方向 HTT降低疗法的丰富管线，反映了20多年来对HTT mRNA和蛋白质结构、功能及病理效应研究的厚积薄发。目前管线中有11项试验评估8种HTT降低药物，其中仅3种（VO659、WVE-003、RG6496）为等位基因选择性/偏好性寡核苷酸，其余均同时靶向野生型和突变型HTT。其他机制还包括：炎症调节、氧化应激、代谢与生物能量学、细胞死亡、生长因子与激素、突触可塑性/神经保护、表观遗传调控、细胞替代疗法等。 4 药物类型：新兴疗法崭露头角研发管线呈现出多元化的技术平台格局：值得注意的是，在50种管线药物中，仅12种（24.5%）是专为HD设计的，其余多为其他适应症开发的药物的再利用。 5 研发挑战：成功率仅3% HD药物开发面临着严峻的转化挑战：从1期到获批的整体成功率约为3%，显著低于其他神经退行性疾病： ▸ 阿尔茨海默病：19% ▸ 帕金森病：15% ▸ 肌萎缩侧索硬化（ALS）：4%-12% 过去10年中，仅有两种药物获得批准： ▸ Deutetrabenazine（美国、以色列、澳大利亚） ▸ Valbenazine（美国）两者均为舞蹈症症状治疗药物，目前尚无获批的HD疾病修饰疗法。从2期推进到3期的药物仅有4种（8.2%）： tominersen、NestaCell、pridopidine和SAGE-718。其中，tominersen的3期试验因安全性问题终止，SAGE-718项目已停止，NestaCell的3期试验尚未启动。 6 试验设计变迁：更早、更准、更长目标人群前移： ▸ 93.8%的试验在临床运动诊断后的患者中进行 ▸ 仅6.2%的试验明确纳入运动诊断前参与者 ▸ 但DMT试验正越来越多地聚焦于疾病早期阶段（HD-ISS 2期）试验周期延长： ▸ HD药物平均需要9.8年完成1-3期临床试验 ▸ 先进疗法的1/2期试验持续时间几乎是其他类型的3倍（85个月 vs 30.5个月） ▸ 2期试验平均持续147.2周，3期试验平均150.8周生物标志物应用不足： ▸ 仅26.2%的药理学试验将生物标志物作为药效学终点 ▸ 而其他神经退行性疾病这一比例为54% ▸ 最常用的生物标志物：HTT蛋白水平、神经丝轻链（NfL）、尾状核体积 7 地理与资金：欧美主导，产业驱动地理分布： ▸ 86.1%的试验在北美和/或欧洲进行 ▸ 1期试验：欧洲38%，北美19% ▸ 3期试验：北美占46% ▸ 南美地区试验极少，尽管委内瑞拉、哥伦比亚等国HD患病率较高资金来源： ▸ 72.5%的药理学试验由行业资助 ▸ 这一比例较1999-2017年的60%显著提升 ▸ 目前与阿尔茨海默病（78%行业资助）已相当 8 当前管线：21项活跃试验蓄势待发截至索引日期，共有21项正在进行和计划中的试验，评估17种化合物，其中15项在过去2年内启动。这些试验共需要1968名参与者。亮点药物： ▸ AMT-130（AAV基因治疗）：1/2期3年数据显示，与倾向匹配的Enroll-HD对照相比，UHDRS综合评分下降减少75%，NfL表现良好 ▸ PTC518（Votoplam）：剪接调节剂，PIVOT-HD研究达到主要终点 ▸ Pridopidine：Sigma-1受体激动剂，是HD中患者暴露年数最多的在研药物结语过去十年，HD药物研发管线经历了从症状治疗到疾病修饰的深刻转型。HTT降低策略、基因治疗、细胞治疗等新兴技术平台的涌入，为这个长期缺乏有效治疗的领域带来了新的希望。然而，3%的整体成功率、生物标志物应用不足、试验周期漫长等挑战依然严峻。随着HD综合分期系统（HD-ISS）的推广应用、Enroll-HD等研究平台的持续赋能，以及生物标志物检测技术的进步，HD药物研发有望进入更精准、更高效的新阶段。对于HD患者和家属而言，这是一个充满挑战但也孕育希望的时代。 1 END 1 供稿：Meredith 校对：Jaya 排版：Meredith / Vanessa 声明：编辑部对刊载内容进行仔细审阅以尽力保持其准确性，但对稿件的使用或其中的任何错误、遗漏或不准确之处等均不承担任何责任。文中所表达的任何观点不代表编辑部的观点，文中提及或排除任何方法或药物并不构成对其使用的提倡、建议或拒绝，因此在为本文中提及的任何产品开处方前，请查阅生产商的最新处方信息。内容仅限医疗卫生专业人士学习交流使用，非医疗卫生专业人士请主动退出浏览与阅读，否则由此产生的相关风险与后果应自行承担。在未获得正式授权前，所有转载及使用文中内容均为侵权。原文来自： Konstantinova P, Townhill J, Bronzova J, Andreeva V, Sathe S, Sampaio C. Systematic Review of the Huntington's Disease Drug Development Pipeline, 2014 to 2025. Mov Disord. Published online June 1, 2026. doi:10.1002/mds.70361. 作者未参与本精要的编写。 #HD：Huntington Disease，亨廷顿病/亨廷顿舞蹈病点击查看原文链接 ↓↓↓

2026-06-09

·生物通

综述：抑郁中靶向神经炎症：Sigma

抑郁症是全球致残的主要原因，但传统单胺能抗抑郁药（monoaminergic antidepressants）治疗不足，因其起效延迟、疗效不一且副作用显著。累积的证据将神经炎症（neuroinflammation）――由胶质细胞功能障碍、外周-中枢免疫串扰及相关细胞应激通路驱动――定位为抑郁症发病机制中的关键上游机制，导致神经递质失调和突触可塑性受损。本综述考察了Sigma-1受体（Sigma-1 receptor, Sig-1R）的整合作用，该受体是一种主要定位于线粒体相关内质网膜（mitochondria-associated endoplasmic reticulum membrane, MAM）的配体操作分子伴侣，作为减轻这种神经炎症级联反应的有前景的治疗靶点。研究人员系统地综合了临床前证据，证明Sig-1R的药理学激活产生广泛的抗神经炎症效应，包括促进小胶质细胞稳态并转向抗炎表型、减弱反应性星形胶质细胞增生、抑制关键促炎信号枢纽如核因子κB（NF-κB）和NLRP3炎症小体，以及减轻少突胶质细胞功能障碍。除免疫调节外，Sig-1R激活缓解内质网应激、增强自噬和线粒体自噬清除、支持线粒体生物能量学并加强内源性抗氧化防御。这些作用共同打断了连接细胞应激、炎症和突触损伤的恶性循环。研究人员还评估了代表性Sig-1R激动剂的进展并回顾了现有临床试验数据，包括新型多靶点药物AXS-05的结果。遗传和药理学功能缺失研究进一步强调了Sig-1R在情绪调节和应激韧性中的关键作用。总之，Sigma-1受体是细胞稳态和适应的关键调节因子。其激动剂代表了一种有前景的治疗策略，超越了症状性单胺能调节，从机制上靶向抑郁症中核心的炎症和蛋白稳态紊乱，具有改善治疗效果的潜力。**3 The Sig-1R: Molecular Properties, Distribution, and Core Functions****3.1 Structure of Sig-1R** Sigma-1受体（Sig-1R）是一种配体操作的分子伴侣，主要定位于线粒体相关内质网膜（mitochondria-associated endoplasmic reticulum membrane, MAM）。晶体学研究表明，Sig-1R含有一个位于蛋白中部的单次跨膜结构域，其N端配体结合域朝向内质网（ER）腔，C端固醇结合域位于胞质侧。Sig-1R可呈现单体与寡聚体两种构象，激动剂（如(+)-戊唑辛）结合可稳定受体并促进其分子伴侣功能，促使Sig-1R与结合伴侣BiP解离，并转运至ER-线粒体接触位点，进而稳定离子通道与受体，调节钙稳态与神经元兴奋性。拮抗剂则稳定另一种构象，打断这些功能相互作用。**3.2 Expression Pattern: Beyond Neurons** Sig-1R在CNS中广泛表达，尤其在情绪调节相关脑区（海马、前额叶皮层、杏仁核、下丘脑和脑干单胺能核团）高度富集。除神经元外，Sig-1R在小胶质细胞、星形胶质细胞和少突胶质细胞（OLs）中也有功能性表达，提示其在胶质细胞中介导不同细胞类型特异性作用。在星形胶质细胞中，Sig-1R调节反应性、增强谷氨酸清除并促进营养因子释放；在少突胶质细胞中可能参与髓鞘形成；在内皮细胞中支持血脑屏障完整性。转录组分析表明Sig-1R mRNA在不同CNS细胞类型中表达比例与水平存在差异，但蛋白表达定量受抗体特异性限制。**3.3 Sig-1R: Core Physiological Functions** Sig-1R作为多能分子伴侣，在细胞应激下通过整合机制维持神经元与免疫稳态。其主要通过伴侣活性结合并稳定多种客户蛋白，包括离子通道（如NMDA受体、电压门控钙通道、钾通道Kv1.2）、G蛋白偶联受体（如μ-阿片受体、5-HT受体）和神经递质转运体（如SERT、DAT）。这些相互作用支撑其神经保护与抗应激效应：例如，稳定NMDA受体增强突触可塑性与BDNF依赖的促存活信号，同时防止兴奋毒性损伤；特异性调节5-HT1A受体介导快速抗抑郁样作用。**4 Role of Sig-1R in Modulating Neuroinflammation****4.1 Modulating Microglia Phenotype** Sig-1R激动剂通过促进小胶质细胞从促炎表型（CD11b、iNOS、IL-1β、TNF-α）向抗炎修复表型（CD68、CD206、Arg1、IL-10、TGF-β）转变发挥抗炎作用。该效应在LPS刺激和慢性应激模型中一致观察到。机制上，Sig-1R激活抑制TLR4/MyD88驱动的NF-κB活化（稳定IκBα，阻止NF-κB二聚体核转位）及MAPK通路（p38、JNK）。不同激动剂（如SKF83959与(+)-戊唑辛）可能通过不同MAPK通路发挥效应，提示变构调节剂与经典激动剂机制存在差异。**4.2 Modulating Astrocyte Reactivity and Supportive Functions** Sig-1R激动剂通过抑制NF-κB信号通路，减少反应性星形胶质细胞分泌促炎介质（IL-6、TNF-α），并降低趋化作用以限制外周免疫细胞浸润。同时，Sig-1R激活增强星形胶质细胞的关键稳态功能：上调兴奋性氨基酸转运体2（EAAT2）增强谷氨酸摄取，减轻兴奋毒性；促进BDNF释放（如LS-1-137、氟哌啶醇代谢物及SKF83959）。Sig-1R对星形胶质细胞呈现双重有益效应：抑制有害促炎信号同时增强营养支持。**4.3 Modulating Glial Crosstalk: Oligodendrocyte Dysfunction** Sig-1R调节少突胶质细胞分化和髓鞘形成。Sig-1R在少突胶质细胞成熟过程中表达显著上调，过表达促进少突胶质前体细胞（OPCs）分化，而siRNA敲低则抑制该过程。在病理条件下，反应性星形胶质细胞释放TNF-α可刺激OL分化，但IL-1β可能诱导OL凋亡和低髓鞘化。小胶质细胞-OL轴通过调节OPC增殖和分化促进髓鞘修复。Sig-1R激动剂可能通过调节小胶质细胞功能减轻OL损伤和抑郁样行为。**4.4 Regulation of Monocyte-Driven Neuroinflammation** Sig-1R通过周细胞激活调节单核细胞跨BBB浸润：在可卡因作用下，Sig-1R从ER脂滴转位至周细胞质膜脂筏，与c-Src激酶相互作用，触发PDGFR-β磷酸化和NF-κB核转位，上调趋化因子CXCL10，促进单核细胞迁移。Sig-1R敲除或药理学抑制可阻断该级联反应。在HIV感染巨噬细胞中，Sig-1R激活增加病毒复制和cathepsin B分泌，而拮抗剂BD-1047通过上调线粒体和ER伴侣蛋白维持溶酶体完整性。此外，Sig-1R以Rac1依赖性方式支持巨噬细胞胞葬作用，在树突状细胞中抑制促炎细胞因子并增强IL-10分泌，调节Th1/Th17极化。**4.5 Modulating Endoplasmic Reticulum Stress and Protein Misfolding** Sig-1R作为动态调节器，通过抑制过度UPR激活打破ER应激与神经炎症的恶性循环。激动剂（如氟伏沙明）可降低ER应激标志物（GRP78/BiP、CHOP、磷酸化PERK、IRE1、eIF2α）。分子层面，配体结合后的Sig-1R与BiP/GRP78相互作用，促进BiP从IRE1和PERK的管腔域解离，减弱其激活。IRE1激活减弱降低XBP1s产生和JNK通路激活；PERK抑制减少eIF2α磷酸化和ATF4/CHOP表达，从而阻止线粒体凋亡和炎症反应。**4.6 Enhancing Autophagy/Mitophagy and Mitochondrial Biogenesis** Sig-1R激活通过稳定电子传递链组分和电压依赖性阴离子通道减少线粒体ROS生成，并上调Nrf2依赖性抗氧化酶（超氧化物歧化酶、谷胱甘肽）。慢性不可预测温和应激模型显示Sig-1R激活增强自噬流（增加LC3-II、Beclin1，降低p62/SQSTM1），促进受损线粒体的线粒体自噬清除，减少NLRP3炎症小体激活。此外，Sig-1R通过ERK1/2信号增强CD38表达，促进星形胶质细胞向神经元的线粒体转移，支持神经突生长和神经元存活。合成激动剂普利多匹定（pridopidine）在慢性应激动物中上调自噬标志物，并伴随NLRP3炎症小体活化和神经炎症减轻。**4.7 Sig-1R-Modulated Microbiota in Depressive Pathophysiology** 肠脑轴通过肠道上皮屏障、HPA轴及微生物代谢产物（如短链脂肪酸SCFAs）调节抑郁病理。Sig-1R激动剂氟伏沙明可恢复甲基苯丙胺诱导的肠道菌群失调并激活海马BDNF/TrkB信号通路。Sig-1R敲除小鼠出现显著抑郁样行为，伴随肠道菌群组成改变（Alistipes、Alloprevotella、Libiksteris相对丰度降低）。将Sig-1R敲除小鼠的粪便微生物移植至野生型受体小鼠，可复现肠道菌群失调和抑郁样表型，证明Sig-1R调节的肠道菌群在抑郁病理中的因果作用。**5 Sig-1R-Mediated Anti-Neuroinflammatory Effects Translate to Antidepressant Outcomes****5.1 Specificity of Sig-1R Agonist Actions in Producing Antidepressant-Like Effects** 多种选择性Sig-1R激动剂在啮齿类抑郁模型中产生显著抗抑郁样效应，并伴随抗神经炎症作用。PRE-084在CUMS、社会挫败和LPS模型中降低强迫游泳实验（FST）和悬尾实验（TST）不动时间，增加蔗糖偏好（SPT），同时降低促炎细胞因子（IL-1β、TNF-α、IL-6）、抑制小胶质细胞激活、下调NLRP3炎症小体组分、减轻内质网应激，并上调BDNF。SA-4503（Cutamesine）增强海马BDNF表达，通过形成Sig-1R/5-HT1A受体复合物、恢复GluN1水平和改善LTP发挥效应；但其II期临床试验（NCT00551109）结果未发表。Igmesine在临床前和开放标签试验中显示疗效，但多中心安慰剂对照研究仅在英国亚组中显示显著改善。YL-0919通过促进神经元重塑、恢复线粒体功能、抑制NF-κB驱动神经炎症发挥多模式效应，并在小胶质细胞缺失模型中部分恢复小胶质细胞数量。性别因素影响Sig-1R功能：敲除小鼠中抑郁样行为仅出现在雄性，雌性在卵巢切除后表型显现，雌激素可能补偿受体缺失。**5.2 Interaction of Antidepressant Drugs at Sig-1Rs** 多种临床抗抑郁药（三环类、MAOIs、SSRIs等）对Sig-1R具有显著亲和力。人脑PET研究使用[11C]SA4503证实，高亲和力配体氟伏沙明可在活体人脑中取代示踪剂，而低亲和力SSRI帕罗西汀则不能。神经类固醇（DHEA、孕烯醇酮）和快速起效抗抑郁药氯胺酮也报道与Sig-1R相互作用。SSRI（特别是氟伏沙明）对脓毒症和COVID-19的保护作用可能部分通过Sig-1R激活介导，而非完全依赖5-羟色胺增强。**5.3 Sig-1R in Depression: Complementary Evidence From Genetic Studies** Sig-1R敲除小鼠表现出基线焦虑和抑郁样行为，伴随神经炎症信号增强（促炎细胞因子升高、小胶质细胞激活）以及突触可塑性和海马神经发生缺陷。药理学拮抗剂可阻断Sig-1R激动剂的行为和细胞效应。然而，组成型敲除模型存在发育性代偿改变，如饮酒表型在敲除小鼠与药理学抑制间存在差异，表明药理学干预更能揭示受体的急性调节作用。综合而言，Sig-1R功能缺失促进神经炎症、神经可塑性受损和应激易感性增加。**5.4 Recent Clinical Trial Evidence** 氟伏沙明在抑郁症患者中减轻抑郁症状并降低IL-6水平，部分通过Sig-1R介导。AXS-05（右美沙芬-安非他酮）作为Sig-1R激动剂，III期试验中6周治疗在MADRS评分上优于安慰剂，39.5%参与者达到缓解，且优于安非他酮单药。IIa期试验中右美沙芬-奎尼丁组合使MADRS和QIDS-SR评分分别降低13.0和5.9分。这些结果支持多靶点治疗策略中纳入Sig-1R调节的前景。**6 Summary and Outlook** Sig-1R激活调节多条影响细胞健康与存活的信号通路，使其成为神经炎症相关神经疾病（如抑郁）的引人注目的治疗靶点。临床前、转化、药理学和临床证据一致表明Sig-1R在维持神经元和细胞稳态、可塑性和功能中的整合作用。受体调节单胺类、谷氨酸和炎症细胞因子等多种介质。NMDA受体拮抗剂/Sig-1R激动剂联合（右美沙芬-安非他酮）获FDA批准用于成人重性抑郁障碍，为Sig-1R靶向策略提供了临床先例。然而，既往选择性Sig-1R激动剂的转化失败提示仍需关注脱靶效应、细胞类型特异性信号和配体选择性。Sigma-2受体与Sig-1R共享类似配体结合谱，增加了药物设计复杂性。未来需开展基于生物标志物（外周或中枢炎症标志物）的患者分层临床试验，使用选择性PET示踪剂评估靶点占据，探索Sig-1R激动剂与传统抗抑郁药、抗细胞因子生物制剂或神经保护剂的协同方案，并验证反映中枢神经炎症消退的可靠标志物。这些努力将有助于阐明Sig-1R在抑郁中减轻神经炎症的作用，并推动机制指导的个性化抗抑郁策略发展。

2026-05-26

·Business Wire

Prilenia Donates Clinical Trial Datasets to CHDI Foundation to Advance Huntington's Disease Research

NAARDEN, The Netherlands & WALTHAM, Mass.--(BUSINESS WIRE)--Prilenia Therapeutics B.V. today announced a Data Use Agreement (DUA) under which Prilenia will provide CHDI with clinical data from the placebo arms of its PRIDE and PROOF studies for the purpose of advancing research into treatments for Huntington's disease (HD). “Patients are at the center of this initiative; it is vital to foster an ecosystem where we can all work together to fully utilize high-quality data to enable future innovation for the benefit of people living with HD.” “Collaboration which balances scientific rigor with data openness is an ethical and scientific imperative. Sharing data is key to accelerating and advancing knowledge and understanding and accelerates progress aimed at the development of much needed treatments capable of diminishing the effect of intractable diseases such as HD,” said Dr. Michael R. Hayden, Prilenia’s Chief Executive Officer. “Patients are at the center of this initiative; it is vital to foster an ecosystem where we can all work together to fully utilize high-quality data to enable future innovation for the benefit of people living with HD.” Robi Blumenstein, the president of CHDI Management, the company that manages the scientific activities of CHDI Foundation, remarked: “Prilenia’s gifting of these data will help us better understand how placebo-related effects influence clinical trial outcomes, which could improve the design and interpretation of future trials and ultimately support the development of more effective approaches to slow the progression of this devastating disease. A better understanding of placebo effects could also help strengthen the validation of external comparator approaches, including those derived from the Enroll-HD dataset.” Under the terms of the agreement, CHDI receives a worldwide, non-exclusive license to use the individual patient level data for the placebo patients from the two studies, full ownership of any research results it generates using the data, and the option to also make the data available to qualified third-party research institutions and companies. Prilenia retains ownership of the underlying data itself, and all data remains securely coded and anonymized to protect the identity of study participants. Any publications arising from the research may include a Prilenia author and will acknowledge Prilenia as the source of the data. About Huntington’s Disease Huntington’s disease (HD) is a rare, inherited, autosomal dominant, neurodegenerative disease that results in functional, motor, cognitive and behavioral symptoms, and ultimately leads to death. HD is caused by a mutation in the huntingtin genei, and each child of a parent with HD has a 50 percent chance of developing the diseaseii. Across the world an estimated 100,000 people have HDiii,iv, with an additional 300,000 people at risk of developing HDv,vi. It is usually diagnosed between the ages of 30 and 50, although HD can occur at any age, including in children and young adults (known as juvenile onset HD or JHD). The disease progresses slowly over 15 to 20 years, with patients slowly losing their ability to work, communicate, manage day-to-day life and take care of themselves. This increasing disability leads to full reliance on a caregiver and, ultimately, death. The only currently available treatments for HD focus on symptomatic relief and palliative care, with nothing impacting measures of overall progression. A potential registrational Phase 3 study of pridopidine in early to mid-stage HD is planned to commence in the second quarter of 2026. About Prilenia Prilenia is a private biopharmaceutical company driven by an unwavering commitment to scientific excellence and accelerating progress for people affected by Huntington’s disease (HD), amyotrophic lateral sclerosis (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. Prilenia is partnered with Ferrer for the commercialization and co-development of pridopidine. 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 CHDI Foundation, Inc. CHDI Foundation is a privately-funded, nonprofit biomedical research organization devoted to a single disease – Huntington’s disease (HD). Its mission is to collaboratively develop therapeutics that will provide meaningful clinical benefit to patients as quickly as possible. To achieve this CHDI manages a diverse portfolio of research projects through a novel virtual model that encourages scientific collaboration to more directly connect innovative research, drug discovery, and clinical development. This helps bridge the translational gap that often exists between academic and industrial research pursuits, and which adds costly delays to therapeutic development. CHDI’s activities extend from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery and development to clinical studies and trials. i Eddings, C. R., Arbez, N., Akimov, S., Geva, M., Hayden, M. R., & Ross, C. A. (2019). Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiology of disease, 129, 118–129. https://doi.org/10.1016/j.nbd.2019.05.009 ii Myers RH. Huntington's disease genetics. NeuroRx. 2004 Apr;1(2):255-62. doi: 10.1602/neurorx.1.2.255. PMID: 15717026; PMCID: PMC534940.) iii https://medically.roche.com/global/en/medical-material/HSG-2019-poster-yohrling-prevalence-of-huntington-s-disease-in-the-US-pdf.html iv Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord. 2012 Aug;27(9):1083-91. doi: 10.1002/mds.25075. Epub 2012 Jun 12. PMID: 22692795. v Medina et al., Prevalence and Incidence of Huntington's Disease: An Updated Systematic Review and Meta-Analysis. Mov Disord. 2022 Dec;37(12):2327-2335. vi Jiang, A., Handley, R. R., Lehnert, K., & Snell, R. G. (2023). From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research. International Journal of Molecular Sciences, 24(16), 13021. https://doi.org/10.3390/ijms241613021

引进/卖出临床3期

100 项与普利多匹定相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09953	普利多匹定	-	DB11947

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
亨廷顿舞蹈病	申请上市	欧盟	Prilenia Therapeutics BV	2024-09-03
肌萎缩侧索硬化	临床3期	美国	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	比利时	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	加拿大	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	法国	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	德国	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	以色列	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	意大利	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	荷兰	Prilenia Therapeutics BV	2026-02-01
肌萎缩侧索硬化	临床3期	波兰	Prilenia Therapeutics BV	2026-02-01

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04556656 (PROOF-HD, Company_Website) 人工标引	临床3期	亨廷顿舞蹈病	-	Pridopidine	憲餘憲鹹糧願鹹鹹壓獵(獵窪願襯範窪窪衊鹽築) = Compared to natural history cohort from ENROLL-HD, data at 2 years shows slowing of disease progression by 65% for TFC (p = <0.0001) for pridopidine-treated patients off ADMs. Similar results were seen compared to history cohort TRACK-HD. 顧繭齋選觸餘範網顧餘 (鏇構鹹範網壓遞醖艱構 ) 更多	积极	2025-10-10
NCT04556656 (PROOF-HD, Pubmed \| Nat Med) 人工标引	临床3期	亨廷顿舞蹈病	-	Pridopidine (45 mg)	憲醖鏇襯窪構壓觸遞膚(鹹鏇願艱網淵積艱獵餘) = Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC. 顧獵網築壓糧構繭鏇糧 (繭範範齋觸衊餘醖觸餘 ) 未达到更多	积极	2025-09-05
				Placebo
NCT04297683 \| NCT04615923 (HEALEY ALS Platform Trial, Pubmed \| JAMA)	临床2/3期	肌萎缩侧索硬化 sigma-1 (σ1) receptor	163	Pridopidine 45 mg twice daily	壓鹹鹽選繭範齋淵顧構(獵顧衊鑰淵齋鏇觸選鏇): DRR = 0.99 (95% CI, 0.8 ~ 1.21) 更多	不佳	2025-04-01
				Placebo
NCT04556656 (PROOF-HD, CTgov)	临床3期	亨廷顿舞蹈病	499	Pridopidine (Pridopidine)	鏇衊憲願鹽糧壓醖築製(構壓構觸廠構獵膚窪齋) = 膚淵餘夢鏇夢膚壓鹹鬱遞鑰構鏇積壓鹹觸襯鬱 (鑰襯蓋壓築淵構膚醖憲, 0.119) 更多	-	2025-03-12
				Placebo (Placebo)	鏇衊憲願鹽糧壓醖築製(構壓構觸廠構獵膚窪齋) = 齋願網製構夢蓋繭窪壓遞鑰構鏇積壓鹹觸襯鬱 (鑰襯蓋壓築淵構膚醖憲, 0.119) 更多
NCT00724048 (HART, CTgov)	临床2期	亨廷顿舞蹈病	227	Placebo (Placebo)	艱鑰網壓願醖廠蓋廠憲(鹹繭簾鹽鑰鹽醖選糧壓) = 觸憲衊淵範膚衊簾壓膚積構鹹醖積繭簾衊憲鏇 (艱範壓夢夢衊遞鏇鑰齋, 3.72) 更多	-	2023-08-31
				ACR16 (ACR16 10 mg BID)	艱鑰網壓願醖廠蓋廠憲(鹹繭簾鹽鑰鹽醖選糧壓) = 鬱範選憲鑰範壓壓憲鹹積構鹹醖積繭簾衊憲鏇 (艱範壓夢夢衊遞鏇鑰齋, 3.33) 更多
NCT04615923 (HEALEY ALS Platform Trial, CTgov)	临床2/3期	肌萎缩侧索硬化	163	Pridopidine (Pridopidine)	壓築齋願鑰獵餘夢廠網(鏇淵繭糧製鹹繭壓淵鏇) = 鹹鹹憲範夢窪網顧糧壓顧繭淵壓鹹壓廠窪積蓋 (餘衊製憲廠齋夢簾鏇鹹, 0.077) 更多	-	2023-08-23
				Matching Placebo (Matching Placebo)	壓築齋願鑰獵餘夢廠網(鏇淵繭糧製鹹繭壓淵鏇) = 築憲糧繭觸製憲鬱鹽餘顧繭淵壓鹹壓廠窪積蓋 (餘衊製憲廠齋夢簾鏇鹹, 0.070) 更多
NCT04615923 (HEALEY ALS Platform, NEWS) 人工标引	临床2期	肌萎缩侧索硬化 Nfl	-	Pridopidine	襯範衊積鹹艱構餘觸醖(鬱艱鹹壓網齋獵獵觸襯) = 齋鬱憲觸醖餘鏇願鑰鹽鬱簾齋淵夢構願築餘網 (淵壓餘鬱醖艱淵範鹹選 )	积极	2023-02-23
				Placebo	襯範衊積鹹艱構餘觸醖(鬱艱鹹壓網齋獵獵觸襯) = 鏇齋範鑰遞簾遞製鹽淵鬱簾齋淵夢構願築餘網 (淵壓餘鬱醖艱淵範鹹選 )
NCT00724048 \| EUCTR2007-004988-22-AT \| NCT02006472 \| NCT00665223 \| EUCTR2013-001888-23-AT (PRIDE-HD, Pubmed)	临床2期	亨廷顿舞蹈病	402	Pridopidine 45 mg bid	積築鹹繭構齋窪夢鹽廠(鏇願襯獵築糧繭醖鑰膚) = 糧網壓淵餘蓋餘壓獵製觸餘廠夢鹹顧鹽糧構鹹 (夢製鏇鬱獵鏇襯網網簾, 8.0)	-	2023-02-22
NCT03922711 (CTgov)	临床2期	药物性运动障碍 \| 帕金森病	23	Placebo	觸鬱範鏇構餘衊獵積構(願鏇衊齋範遞艱膚鬱鑰) = 夢窪構鹹鹽積範衊鑰憲醖構顧廠選衊淵鹽鹹鹹 (鏇製獵構蓋糧餘齋繭範, 6.44) 更多	-	2022-07-01
NCT01306929 (Open-HART, CTgov)	临床2期	亨廷顿舞蹈病	134	pridopidine	簾繭鹹襯壓鏇範鬱觸製 = 窪構窪顧積窪繭構餘選積遞壓憲蓋憲鑰齋繭窪 (構鬱繭醖蓋艱積糧憲廠, 膚觸範範廠獵獵鏇衊築 ~ 築願繭繭築蓋醖鹹繭襯) 更多	-	2022-02-09