Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of Oral Verdiperstat (BHV-3241) in Patients With Semantic Variant Primary Progressive Aphasia (svPPA) Due to TDP-43 Pathology

The purpose of the study is to test the safety and tolerability of twice daily Verdiperstat in patients with semantic variant primary progressive aphasia (svPPA) due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Three-fourths of the participants will receive Verdiperstat and one-fourth will receive Placebo during the 24-week treatment duration.

开始日期2022-04-14

申办/合作机构

The University of California, San Francisco

[+3]

NCT04616456

/ Completed早期临床1期IIT

Effect of Verdiperstat on Microglial Activation in Well-characterized MSA Patients

This study will comprise of two phases, an observational phase and a treatment phase.
In the observational phase the specific aims are: 1. To determine the presence and regional distribution of microglial activation, as assessed by 18F-PBR06 PET, in subjects with MSA as compared to healthy controls, at baseline and at 6-9 months' follow-up.
2. To assess the relationship between microglial activation and clinical progression at baseline and follow-up.
In the treatment phase the specific aims of the study are:
The specific aims of the study are:
1. To assess whether verdiperstat (BHV-3241) reduces 18F-PBR06 PET signal, and thus microglial activation and inflammation, in well-characterized MSA patients.
2. To assess the relationship between PET changes and clinical progression at baseline and follow-up in patients treated with verdiperstat.
3. To assess the relationship between PET changes and volumetric brain MRI at baseline and follow-up in patients treated with verdiperstat.
Currently there is no known disease modifying therapy for MSA. Recently, the drug verdiperstat (BHV-3241) has appeared in the investigational arena specifically for the indication of Multiple System Atrophy. Verdiperstat (BHV-3241) is currently being used in a phase 3 active drug trial at Massachusetts Hospital. Verdiperstat (BHV-3241) is known to target Myeloperoxidase, an enzyme implicated in neuroinflammation, a major driver in disease pathogenesis. Our previous study (IRB protocol #2016P002373) demonstrated that applying TSPO (translator protein) PET imaging enabled us to track changes in neuroinflammation and thus provide a viable biomarker for disease progression.
In this pilot study, the investigators aim to assess the effect of an investigational drug, verdiperstat (BHV-3241) on microglial activation in MSA patients using [F-18]PBR06 and to link it with clinical and morphometric MRI brain changes following treatment.

开始日期2020-12-30

申办/合作机构

The Brigham & Women's Hospital, Inc.

[+1]

NCT04436510

/ Completed临床2/3期IIT

HEALEY ALS Platform Trial - Regimen B Verdiperstat

The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.
Regimen B will evaluate the safety and efficacy of a single study drug, verdiperstat, in participants with ALS.

开始日期2020-07-28

申办/合作机构

The Massachusetts General Hospital

[+1]

100 项与 Verdiperstat 相关的临床结果

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100 项与 Verdiperstat 相关的转化医学

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100 项与 Verdiperstat 相关的专利（医药）

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项与 Verdiperstat 相关的文献（医药）

2025-06-27·BIOSCIENCE REPORTS

The PAD4 inhibitor GSK484 diminishes neutrophil extracellular trap in the colon mucosa but fails to improve inflammatory biomarkers in experimental colitis

Article

作者: Ahmad, Gulfam ; Lee, Aaron ; Ortiz-Cerda, Tamara ; Hunter, Jordan ; Xie, Kangzhe ; Witting, Paul K.

Inflammatory bowel disease (IBD) is a gastrointestinal disorder characterised by elevated colonic neutrophil extracellular traps (NETs), which are associated with disease severity. Formation of NETs is primarily driven by peptidyl arginine deaminase IV (PAD4) and other enzymes including myeloperoxidase (MPO) and neutrophil elastase. The present study evaluated the effect of MPO and PAD4 inhibition in dextran sodium sulfate (DSS)-induced colitis. Experimental colitis was induced in male C57BL/6 mice by 2% w/v DSS in drinking water ad libitum. Treatment groups received daily oral administration of MPO inhibitor (AZD3241; 30 mg/kg) and/or intraperitoneal injection of PAD4 inhibitor (GSK484; 4 mg/kg) 4 times over 9 days. Inhibition of PAD4 significantly diminished NET density in the colonic mucosa of mice insulted with DSS, reaching levels similar to that detected in control mice. Both inhibitors offered limited improvement in disease-activity-index, a scoring system that considers the extent of weight loss, stool consistency and rectal bleeding. Histology showed that MPO and/or PAD4 inhibition did not recover DSS-induced colon histoarchitectural damage whilst Alcian blue staining demonstrated that PAD4 failed to reduce goblet cell loss. The selected dosage of PAD4 inhibition also yielded no effect on inflammatory markers and antioxidant protein levels. These data sets suggest that other mechanisms may be involved in the pathogenesis of IBD, and the appropriate dosage of GSK484 requires thorough investigation.

2025-04-01·JAMA Neurology

Verdiperstat in Amyotrophic Lateral Sclerosis

Article

Importance:

Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

Objective:

To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Design, Settings, and Participants:

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

Interventions:

Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

Main Outcomes and Measures:

The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

Results:

A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

Conclusions and Relevance:

Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

Trial Registration:

Clinical Trial Identifiers: NCT04297683 and NCT04436510

2025-03-01·EXPERIMENTAL NEUROLOGY

Microglial suppression by myeloperoxidase inhibitor does not delay neurodegeneration in a mouse model of progressive multiple sclerosis

Article

作者: Pistolesi, Alessandra ; Chiarugi, Alberto ; Guasti, Daniele ; Ranieri, Giuseppe ; Buonvicino, Daniela ; Calvani, Maura

Drugs able to efficiently counteract the progression of multiple sclerosis (MS) are still an unmet need. Numerous preclinical evidence indicates that reactive oxygen-generating enzyme myeloperoxidase (MPO), expressed by neutrophils and microglia, might play a key role in neurodegenerative disorders. Then, the MPO inhibition has been evaluated in clinical trials in Parkinson's and multiple system atrophy patients, and a clinical trial for the treatment of amyotrophic lateral sclerosis is underway. The effects of MPO inhibition on MS patients have not yet been explored. In the present study, by adopting the NOD mouse model of progressive MS (PMS), we evaluated the pharmacological effects of the MPO inhibitor verdiperstat (also known as AZD3241) on functional, immune, and mitochondrial parameters during disease evolution. We found that daily treatment with verdiperstat did not affect the pattern of progression as well as survival, despite its ability to reduce mitochondrial reactive oxygen species and microglia activation in the spinal cord of immunized mice. Remarkably, verdiperstat did not affect adaptive immunity, neutrophils invasion as well as mitochondrial derangement in the spinal cords of immunized mice. Data suggest that microglia suppression is not sufficient to prevent disease evolution, corroborating the hypothesis that immune-independent components drive neurodegeneration in progressive MS.

项与 Verdiperstat 相关的新闻（医药）

2025-06-02

·药学进展

独家原创 | 廖红研究员：神经炎症在肌萎缩侧索硬化中的作用及相关药物研发进展

“点击蓝字关注我们廖红博士，中国药科大学多靶标天然药物全国重点实验室、江苏省药效研究与评价服务中心、新药筛选中心研究员及博士生导师。主要从事神经生物学和神经药理学方面的研究。曾作为研究科学家在新加坡中央医院临床部门神经生物学研究室工作3年。主持多项国家自然科学基金项目、江苏省自然科学项目、江苏省国际合作项目、教育部博士点基金项目；作为主要参与者参与科技部“十一五”重大新药创制项目2项；开展与制药企业横向合作。目前与德国萨尔大学和澳大利亚南澳大学开展国际合作。曾为中国药科大学学术委员会委员， J Neurochem,Neuroscience,Neurochem Int,Int J Exp Pathol等多个期刊的审稿人。现已发表文章100篇左右，其中SCI文章60篇左右。获教育部科学技术进步奖二等奖，排名第3；江苏医科科技进步奖一等奖，排名第4。神经炎症在肌萎缩侧索硬化中的作用及相关药物研发进展 PPS 胡孟秋，何梅俊，廖红*（中国药科大学多靶标天然药物全国重点实验室新药筛选与药效评价中心，江苏南京210009）[摘要]肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）是一种以大脑和脊髓运动神经元进行性丢失为特征的致死性神经退行性疾病，其发病机制尚未完全阐明。越来越多的证据表明，神经炎症在ALS的病理进程中发挥着重要作用。综述了小胶质细胞、星形胶质细胞和外周免疫细胞等参与神经炎症的关键细胞在ALS疾病进程中的作用，并总结了靶向ALS神经炎症的药物临床研发进展，以期为ALS的病理研究和相关药物研发提供新的方向。肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）是一种罕见的致死性神经退行性疾病，其通常累及运动皮层、脑干和脊髓的上下运动神经元（motor neurons，MNs），致使患者出现进行性、无痛性肌肉无力症状，最终在3~5年内因呼吸衰竭而死亡[1]。根据ALS患病率（prevalence rate，即新旧病例的总和占总人群比例）和发病率（incidence rate，即新发病例占可能发生该疾病人群的比例）研究数据所进行的Meta分析估计，2020年全球ALS的患病率和发病率分别为每10万人4.42例（95%置信区间为3.92~4.96）和每年每10万人1.59例（95%置信区间为1.39~1.81）[2]。研究发现，ALS的患病率和发病率也与性别和年龄相关：男性的患病率和发病率高于女性，且ALS患病率随年龄的增长而上升[3]。根据2012—2016年中国人口普查数据粗略估算，2016年中国ALS患病率和发病率约为每10万人2.97例（95%置信区间为2.91~3.03）和每年每10万人1.62例（95%置信区间为1.58~1.67），且发病率呈逐年升高趋势[4-5]。ALS通常分为家族性ALS（familial amyotrophic lateral sclerosis，fALS）和散发性ALS（sporadic amyotrophic lateral sclerosis，sALS）。fALS指具有ALS家族史的病例，约占ALS病例的10%~15%，目前约70%的fALS病例已明确其突变基因[1]。现已发现与ALS相关的基因约有50个，常见的包括超氧化物歧化酶1基因（superoxide dismutase 1 gene，SOD1）、9号染色体开放阅读框72基因（chromosome 9 open reading frame 72，C9orf72）、肉瘤融合基因（fused in sarcoma，FUS）和交互反应DNA结合蛋白43基因（TAR DNA-binding protein 43 gene，TDP-43）等[6]。sALS指没有ALS家族史的病例，约占ALS病例的85%。研究发现，约15%的sALS患者也存在ALS相关基因的致病突变，但这种突变位点较为罕见，且仅发生在单独个体，无家族史，因此绝大部分sALS病因尚不明确[1]。目前的研究已提出多种ALS可能的发病机制，但确切致病机制仍不明确。这些机制包括DNA修复损伤、RNA代谢紊乱、蛋白质稳态受损、兴奋性氨基酸毒性、线粒体功能障碍、氧化应激、神经炎症、少突胶质细胞功能障碍等[7]，其中神经炎症在ALS病理中起着重要作用。ALS中的神经炎症主要以小胶质细胞和星形胶质细胞激活为主要特点，同时伴随外周免疫细胞的浸润以及炎症因子表达升高。过度的炎症反应可能导致神经元和少突胶质细胞的凋亡[8]。此外，研究还发现TANK结合激酶1基因（TANK-binding kinase 1 gene，TBK1）、视神经蛋白基因（optineurin gene，OPTN）、圆柱瘤病基因（cylindromatosis gene，CYLD）等ALS致病基因也可直接参与免疫调节[9]。ALS的病理机制研究主要依赖于啮齿类转基因动物模型，SOD1G93A转基因小鼠是目前研究中应用最广泛的品系。该品系小鼠过表达突变型人源SOD1蛋白（第93位甘氨酸突变为丙氨酸）[10]。随后，研究人员还建立了其他SOD1相关转基因模型，包括人G37R突变、人G85R突变和小鼠G86R突变等。这些突变SOD1（mSOD1）小鼠能较好地再现ALS患者的大部分病理表现，包括MNs的进行性丢失导致的运动功能缺陷、呼吸和吞咽功能的下降、胶质细胞增生和神经炎症，以及细胞质中突变蛋白聚集体堆积等[11]。近年来，随着研究人员对ALS遗传学认识的加深，一些新的ALS模型也得到了发展，如TDP-43，FUS和含缬酪肽蛋白（valosin-containing protein，VCP）等啮齿类动物模型，它们成为了解ALS病理生理和机制研究的重要工具[12]。目前，ALS患者的治疗方案主要基于药物治疗、物理疗法和呼吸支持。批准上市的治疗药物仅有利鲁唑（riluzole）、依达拉奉（edaravone）和tofersen，但这些药物只能延长患者2~3个月的生存期或改善部分症状[13]。因此，寻找有效的ALS治疗方法迫在眉睫。1ALS中的神经炎症神经炎症通常指在感染、损伤或退行性病变情况下，中枢神经系统中被激活的胶质细胞（小胶质细胞、星形胶质细胞）和浸润的外周免疫细胞（单核细胞、中性粒细胞、淋巴细胞等）所发生的免疫应答。研究发现，持续过度的神经炎症参与了阿尔茨海默病、帕金森病、亨廷顿病和ALS等中枢神经退行性疾病的病理过程。尽管ALS的发病机制尚未完全明确，但越来越多的证据表明，ALS中也存在免疫系统异常，中枢和外周神经系统中的慢性促炎微环境可能会加速MNs的损伤以及疾病的进展。对ALS模型小鼠的研究发现，在小鼠发病前，就能够检测到激活的小胶质细胞和星形胶质细胞，并且白介素（interleukin，IL）-（1β，6）、肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）的mRNA和蛋白水平均显著上调[14]。临床研究也表明，在sALS和C9orf72突变ALS患者的尸检中，同样检测到大脑和脊髓中IL-1β，IL-6，TNF-α等炎症因子表达升高，同时外周免疫细胞，如T细胞、肥大细胞、单核细胞来源的巨噬细胞和树突状细胞等向中枢神经系统的浸润有所增加[15]。尸检组织仅能反映疾病终末期的炎症变化，而利用正电子发射断层成像（positron emission tomography，PET）能够识别出ALS患者在发病早期，大脑和脊髓中就已存在广泛的激活态小胶质细胞和星形胶质细胞[16]。临床研究发现，sALS患者血液和脑脊液中IL-1，IL-2，IL-6，IL-8和TNF-α等炎性因子水平显著升高，且IL-2和IL-6可用作疾病严重程度的炎症相关生物标志物[17]。虽然目前的研究还难以确定神经炎症究竟是ALS的发病原因，还是发病后伴随神经元损伤而产生的病理过程，但鉴于它存在于ALS疾病进程的多个时期，因此靶向神经炎症或许是治疗或延缓ALS病理进程的有效策略。2ALS中参与神经炎症的细胞2.1小胶质细胞小胶质细胞约占中枢神经系统细胞的5%~12%，是中枢神经系统中唯一驻留的免疫细胞。它起源于卵黄囊造血前体细胞，在胚胎发育过程中进入中枢神经系统，并成为一类自我更新的细胞群体[18]。在某些病理条件下，小胶质细胞的形态、转录谱和吞噬活性发生快速改变，它们可获得抗炎表型以发挥神经保护作用，或者获得促炎表型以发挥神经毒性作用[19]。在ALS患者死后样本和ALS啮齿动物模型的研究中，已发现大量小胶质细胞促进并维持炎症的证据。在ALS小鼠脊髓中，小胶质细胞活化标志物CD14，CD18，CD68和A类清道夫受体（scavenger receptor A，SR-A）的表达增加，在MNs附近也检测到大量CD68+小胶质细胞[20]。此外，使用PET在ALS患者的大脑中同样检测到小胶质细胞的激活[21]。研究发现，小胶质细胞表型随疾病进展而发生改变。从ALS小鼠疾病早期分离的小胶质细胞表现出保护性/抗炎表型，而从疾病终末期中分离的小胶质细胞则表现出毒性/促炎表型[22]。Frakes等[23]的研究发现，ALS小鼠的小胶质细胞内核因子κB（nuclear factorκB，NF-κB）信号通路激活，大量分泌活性氧和促炎因子IL-1β，IL-6，TNF-α等，从而促进MNs的凋亡；特异性敲除小胶质细胞中NF-κB则可以延长mSOD1小鼠的寿命。此外，激活的小胶质细胞可以通过分泌IL-1α，TNF-α和补体第1成分q（complement component 1q，C1q）诱导反应性星形胶质细胞，进一步促进神经元凋亡[24]。使用Cre-lox系统从小胶质细胞中去除mSOD1虽然可以延长ALS小鼠的寿命，但并不影响疾病的发生。而在mSOD1小鼠脊髓的空间转录组中，发现从疾病早期分离的小胶质细胞就出现了基因改变[25]。这些研究表明，小胶质细胞在ALS的发生和发展过程中均发挥着重要作用。2.2星形胶质细胞星形胶质细胞是中枢神经系统中数量最多的胶质细胞，具有调节神经递质、提供代谢物和能量、分泌神经营养因子以及参与血脑屏障形成等功能。在不同刺激信号的作用下，星形胶质细胞的表型也会发生改变。例如，在神经炎症刺激（如脂多糖）下，产生的A1型星形胶质细胞会上调补体级联和炎症相关基因，发挥神经毒性作用；相反，缺血诱导产生的A2型星形胶质细胞则会上调神经营养因子，促进神经保护和神经修复[26]。研究发现，ALS患者和小鼠的星形胶质细胞与A1型星形胶质细胞具有高度相似性。基因本体论（gene ontology，GO）分析显示，它们共同上调参与免疫应答的基因，包括细胞因子、TNF和干扰素（interferon，IFN）信号等相关基因，同时共同下调突触形成和神经元发生相关基因[27]。在ALS患者和SOD1G93A小鼠的脊髓中，也发现A1型星形胶质细胞标志物C3的表达增加[28]。尽管星形胶质细胞参与ALS的病理机制尚不明确，但大量研究表明，反应性星形胶质细胞对MNs具有毒性作用。将ALS患者死后分离出的星形胶质细胞与野生型MNs共培养，能够促进MNs大量凋亡，这可能是由星形胶质细分泌的含有SOD1，p-TDP 43(phospho-TDP-43)或FUS等突变蛋白的细胞外囊泡所介导的神经毒性作用导致的；此外，SOD1G37R星形胶质细胞条件性培养基同样可促进MNs凋亡，这表明星形胶质细胞也可能通过分泌可溶性分子发挥神经毒性作用[29]。Kia等[30]的研究证实，携带FUS突变的星形胶质细胞通过分泌TNF-α促进神经元凋亡。核苷酸结合寡聚化结构域样受体蛋白3（nucleo-tide-binding oligomerization domain-like receptor protein 3，NLRP3）炎症小体活化介导的神经炎症与ALS病理机制也密不可分。Johann等[31]在mSOD1小鼠脊髓和ALS患者死后组织中均检测到NLRP3，IL-18和活性Caspase 1的高表达，并且发现ALS中NLRP3炎症小体及其相关成分主要来源于脊髓中的星形胶质细胞。通过敲除SOD1G93A小鼠中IL-1α，TNF-α和C1q以减少反应性星形胶质细胞的生成，可显著延长患病小鼠的生存期[32]。这些研究均表明，星形胶质细胞激活后可能通过增强炎症反应，加速ALS的疾病进展。2.3外周免疫细胞在ALS中，炎症反应除了有中枢神经系统胶质细胞的参与，外周免疫细胞在其中所发挥的作用也受到越来越多的关注。在ALS疾病进程中，多种外周免疫细胞的数量和功能会发生改变，进而参与到ALS的病理进程中。2.3.1先天性免疫细胞研究表明，先天性免疫细胞亚群，包括单核细胞/巨噬细胞、自然杀伤细胞（natural killer cell，NK cell）、肥大细胞（mast cell，MC）、树突状细胞（dendritic cell，DC）和中性粒细胞等，都与ALS的发病机制相关。在ALS患者和小鼠模型中，这些细胞的数量发生改变，并向中枢神经系统浸润。目前，单核细胞/巨噬细胞和NK细胞在ALS病理机制中的作用受到了更广泛的关注。单核细胞来源于骨髓中的骨髓前体细胞。在炎症条件下，未成熟的单核细胞会被C-C基序趋化因子配体2（C-C motif chemokine ligand 2，CCL2）或C-X3-C基序趋化因子配体1（C-X3-C motif chemokine ligand 1，CX3CL1）募集到炎症部位，随后分化为效应细胞（包括巨噬细胞），以发挥多种作用。在对SOD1G93A小鼠的研究中发现，神经肌肉接头（neuromuscular junction，NMJ）的去神经支配发生在脊髓MNs丢失之前，而NMJ和MNs远端轴突位于血脊髓屏障外，能够与外周循环系统中的单核/巨噬细胞直接接触[33]。随后的研究表明，ALS外周单核细胞倾向于促炎状态，来自ALS患者的外周单核细胞更容易被激活并分化为炎症表型，产生更多的IL-6和TNF-α。在ALS小鼠中，巨噬细胞的IL-6和TNF-α蛋白水平与疾病进展速率呈正相关[34]。腹腔注射Ly6C抗体，靶向炎症表型单核细胞，使其偏向抗炎表型，可延迟ALS小鼠发病、延长生存期并减少神经元丢失[35]。与外周的有害作用相反，在SOD1G93A转基因小鼠的疾病早期，脊髓中MNs数量与浸润单核细胞数之间的相关性研究表明，单核细胞可能具有神经保护作用。使用人免疫球蛋白G（human immunoglobulin G，hIgG）或CD95-Fc融合蛋白促进单核细胞向中枢神经系统的浸润，能够增加MNs的存活并延迟疾病发作[36]。这些相互矛盾的研究结果，与SOD1模型中小胶质细胞在疾病早期发挥神经保护而晚期出现神经毒性的情况相似。此外，研究发现C9orf72蛋白功能丧失会促进外周单核/巨噬细胞的促炎状态，这也是导致干扰素基因刺激因子（stimulator of interferon gene，STING）介导的IFN信号过度激活的原因之一[37]。在TDP-43突变的小鼠模型和ALS患者的脑血管内和血管周围，同样观察到单核/巨噬细胞的大量浸润，但目前关于单核/巨噬细胞在TDP-43模型中的研究还极为有限[37]。总之，在ALS中，外周单核/巨噬细胞被激活，且能够浸润到中枢神经系统从而影响疾病的进展，但它们对ALS疾病进展的影响究竟是有益还是有害，仍存在较大争议，需要进一步探究。NK细胞在ALS病理机制中的作用近年来才受到关注。在ALS患者的外周血液和中枢神经系统中，均发现NK细胞数量增加，SOD1G93A小鼠脊髓中也存在大量NK细胞浸润[38]。在SOD1G93A小鼠中，抑制NK细胞活性可减少MNs丢失和星形胶质细胞增生；通过anti-NK1.1抗体减少TDP-43A315T小鼠脊髓中NK细胞浸润，同样能够延缓MNs损伤和凋亡[39]。研究认为，NK细胞的毒性作用可能依赖于毒性因子的释放（如穿孔素）或与MNs上NKG2D配体的直接接触。NK细胞来源的IFN-γ可以诱导小胶质细胞向炎症表型转化，调节趋化因子CCL2的表达，进而抑制免疫抑制性调节T细胞向中枢神经系统浸润[38]。但这些仅是对NK细胞的初步研究，未来还需要在不同模型中进一步探究其在ALS中的可能作用。2.3.2适应性免疫细胞适应性免疫细胞主要包括T细胞和B细胞。研究发现，T细胞亚型是ALS疾病进程中炎症反应的重要参与者，然而，关于B细胞与ALS疾病相关性的研究相对较少。T细胞来源于骨髓中的淋巴干细胞，在胸腺中分化、成熟，随后经血液抵达外周免疫器官，发挥多种功能。根据细胞表面表达的CD分子，T细胞可分为CD4+T细胞和CD8+T细胞。在SOD1G93A小鼠疾病早期，CD4+T细胞浸润至脊髓腹角和皮质脊髓束附近，并参与疾病的不同阶段[40]。此前研究认为，ALS疾病后期才会出现CD8+T细胞的浸润，但是最新研究检测到，在疾病早期脊髓中就已存在CD8+T细胞[41]。CD4+T细胞是参与ALS病理机制的主要T细胞群。研究发现，CD4+T细胞在ALS小鼠模型中具备神经保护作用。将mSOD1转基因小鼠与RAG2-/-小鼠（缺乏成熟T细胞和B细胞）或CD4-/-小鼠（缺乏CD4+T细胞）杂交，会加速MNs的死亡；与此同时，脊髓中神经营养因子、胶质细胞谷氨酸转运体和胰岛素样生长因子水平降低；此外，促炎细胞因子和还原型烟酰胺腺嘌呤二核苷酸磷酸（reduced nicotinamide adenine dinucleotide phosphate，NADPH）氧化酶2水平升高[35]。进一步分析发现，调节性T细胞（regulatory T cell，Treg cell）能够抑制效应T细胞以及髓系细胞所介导的促炎反应。在ALS小鼠疾病早期阶段，Treg细胞数量及其特异性转录因子叉头框蛋白P3（forkhead box protein P3，FOXP3）的表达水平有所上升，Treg细胞释放IL-4并抑制辅助性T细胞1（helper T cell 1，Th1），诱导M2型小胶质细胞；但在疾病后期的快速进展阶段，Treg细胞数量减少且功能失调，Th1细胞和M1型小胶质细胞则占据主导地位并发挥促炎作用[42]。ALS患者的Treg细胞同样存在功能失调的情况。来自ALS患者的Treg细胞抑制效应T细胞增殖的能力低于来自健康受试者的Treg细胞；同时，低水平的Treg细胞数和FOXP3表达量与患者死亡率增加相关[43]。将疾病早期ALS小鼠的内源性Treg细胞在体外扩增后，重新转入缺乏功能性T淋巴细胞的ALS小鼠中，结果显示，小鼠的生存时间得以延长[44]。Sheean等[43]的研究显示，通过IL-2c结合雷帕霉素治疗SOD1G93A小鼠，能够增加小鼠体内Treg细胞的百分比，延长小鼠生存期；与此同时，中枢神经系统中胶质细胞增生减少，脊髓和坐骨神经中FOXP3和M2型小胶质细胞转录因子mRNA的表达水平升高。CD4+T细胞亚型也会随疾病进展而发生改变，具有保护性的Treg/Th2细胞比率降低，而促炎性Th17/Th1细胞比率升高。研究发现，Th17细胞及其相关细胞因子（如IL-17A）在ALS患者的脑脊液、外周血中均有所增加，且与疾病严重程度相关。细胞因子IL-17A以剂量依赖的方式下调MNs存活率和神经突起长度，中和IL-17A或抗IL-17A受体治疗后则能够减弱这种有害作用[45]。因此，Th17细胞可能也参与了ALS的病理机制，靶向Th17细胞及其细胞因子或许是ALS的一种有效治疗策略。CD8+T细胞，又称细胞毒性T淋巴细胞，它既能通过释放细胞毒性蛋白或触发程序性细胞死亡来发挥细胞毒性作用，也能通过释放IFN-γ和TNF-α等细胞因子参与免疫反应的调节[37]。CD8+T细胞仅占T细胞总数的一小部分，故而其在ALS疾病中的作用常被忽视。然而，最新研究表明，CD8+T细胞在ALS病理机制中发挥着双重作用。在ALS小鼠中，受损的外周MNs轴突和NMJ的主要组织相容性复合体Ⅰ（major histocompatibility complex I，MHCI）表达升高。MHCI能够激活CD8+T细胞，加速轴突碎片的清除，进而促进髓鞘沿运动轴突和NMJ再生，延缓肌肉去神经支配并延长存活时间。因此，不应简单地将CD8+T细胞定性为仅具有神经毒性作用[46]。CD8+T细胞也能够浸润到ALS患者和mSOD1小鼠的中枢神经系统，不过，浸润的CD8+T细胞通常对MNs发挥毒性作用。在β2-微球蛋白缺陷的SOD1G93A小鼠中，因缺乏MHCI的表达以及成熟CD8+T细胞，MNs得到保护，前肢瘫痪得以延缓，小鼠寿命也有所延长。但CD8+T细胞发挥毒性作用的机制尚不明确，仅有体外研究显示，表达mSOD1的CD8+T细胞产生IFN-γ，诱导MNs中MHCI的295表达，并通过Fas和颗粒酶途径介导MNs凋亡[47]。未来，还需在体内进一步探究CD8+T细胞在ALS中的具体作用机制。图1展示了ALS中由中枢和外周免疫细胞介导的神经炎症。3ALS药物治疗现状及靶向神经炎症的药物研究3.1 ALS药物治疗现状由于ALS的发病机制复杂、患者临床异质性等特点，针对ALS治疗药物的开发仍处于初步阶段。截至目前，美国食品药品监督管理局（Food and Drug Administration，FDA）批准用于治疗ALS的药物仅有3种：利鲁唑、依达拉奉和tofersen。利鲁唑是一种钠通道/谷氨酸受体阻滞剂，它通过减少谷氨酸释放、增加谷氨酸再摄取以及阻断钠通道等方式降低神经元兴奋性，还能刺激脑源性神经营养因子释放，并调节谷氨酸以影响神经可塑性[48]。依达拉奉是一种活性氧清除剂，可捕获羟基自由基和过氧亚硝酸盐阴离子，减少过氧化物的积累[48]。Tofersen是一种SOD1反义寡核苷酸，通过降解SOD1 mRNA来减少SOD1蛋白的合成。Ⅲ期临床试验（临床试验编号：NCT02623699，NCT03070119）结果显示，tofersen治疗降低了患者脑脊液中SOD1蛋白以及血浆中轴突损伤标志物神经纤维丝轻链（neurofilament light chain，NFL）的水平，但肺活量（vital capacity，VC）和手持测力仪测量结果与安慰剂组相比并无差异[49]。3.2靶向ALS神经炎症的临床研发药物目前，ALS药物研发方向也开始靶向神经炎症。下文总结了靶向ALS神经炎症且在临床试验中取得较好治疗效果的药物（见表1）。3.2.1 NP001 NP001是炎性巨噬细胞和单核细胞的小型杂环分子调节剂，能够下调NF-κB炎症途径。Ⅰ期临床试验（NCT01091142）结果表明，NP001安全且耐受性良好，能以剂量依赖性方式降低单核细胞炎性标志物CD16的表达[50]。在Ⅱ期临床试验（NCT01281631）中，NP001可减缓具有明显神经炎症的ALS患者的疾病进展[51]。在另一项正在进行的Ⅱ期临床试验（NCT02794857）中，尽管安慰剂组和接受NP001治疗组之间并无显著差异，但事后分析显示，接受NP001治疗的40~65岁ALS患者，其ALS功能评分量表修订版（ALS Functional Rating Scale-Revised，ALSFRS-R）评分和VC下降速度明显慢于安慰剂组[52]。不过，未来还需要进一步研究来验证这些结果。3.2.2 RNS60 RNS60是一种新型水流体治疗剂，内部含有稳定电荷的氧纳米泡沫结构[53]。RNS60在分子水平上的具体机制尚未完全阐明，潜在的作用机制包括激活促生存途径磷脂酰肌醇3-激酶/蛋白激酶B（phosphatidylinositol 3-kinase/protein kinase B，PI3K/Akt）通路、促进线粒体生物发生、促进少突前体细胞分化以及成熟少突胶质细胞存活、减少炎症并增加Treg细胞等[54]。Ⅰ期临床试验（NCT02525471）显示，ALS患者长期使用RNS60安全且耐受性良好。一项多中心的Ⅱ期临床试验（NCT03456882）旨在评估RNS60的疗效，尽管所评估的生物标志物未发生变化，但RNS60治疗组中用力肺活量（forced vital capacity，FVC）平均下降速度较慢。事后分析显示，安慰剂组中延髓起病型ALS患者的NFL的水平随时间的增加而上升，而RNS60治疗组患者中该指标则保持稳定[54]。因此，RNS60对呼吸和延髓起病型ALS的积极作用值得进一步研究。目前，另一项Ⅱ期临床试验（NCT02988297）正在招募ALS患者，以评估雾化RNS60的治疗效果。3.2.3 Ibudilast Ibudilast（MN-166）是一种磷酸二酯酶4（phosphodiesterase type 4，PDE4）和巨噬细胞迁移抑制因子（macrophage migration inhibitory factor，MIF）抑制剂，此前作为抗炎药物用于治疗哮喘。临床前研究表明，ibudilast能够减少中枢神经系统中小胶质细胞的激活以及促炎细胞因子的分泌，从而发挥神经保护作用。体外研究发现，ibudilast通过哺乳动物雷帕霉素靶蛋白复合体1（mammalian target of rapamycin complex 1，mTORC1）/转录因子EB（transcription factor EB，TFEB）信号通路促进NSC-34细胞中TDP-43和SOD1聚集物的清除，这表明其可能具有治疗ALS的潜力[55]。已完成的Ⅰb/Ⅱa期临床试验（NCT02238626）评估了ibudilast联合利鲁唑治疗的一般安全性和耐受性，分析显示，ibudilast能为上肢或延髓发病ALS患者带来更大益处，可以减缓早期ALS患者的疾病进展[56-57]。另一项在35名ALS患者中进行的Ⅰb期临床试验（NCT02714036）显示，高剂量ibudilast（100 mg·d-1）治疗36周却未能减少神经炎症和轴突损伤，且大部分参与者出现了不良反应，这表明该研究药物在高剂量下耐受性不佳[58]。目前正在进行的多中心Ⅱb/Ⅲ期临床试验（NCT04057898）旨在评估ibudilast治疗12个月后对ALS患者功能活动和生存时间的影响[59]，这一更长期的临床试验结果将为ibudilast治疗ALS的安全性和有效性提供进一步证据。3.2.4 Masitinib Masitinib是一种口服的选择性酪氨酸激酶抑制剂，它通过抑制中枢和外周神经系统中的小胶质细胞、巨噬细胞和肥大细胞的活性来减轻神经炎症，进而发挥神经保护作用[60]。在SOD1G93A大鼠中，masitinib能够通过抑制集落刺激因子1受体（colony-stimulating factor 1 receptor，CSF1R），减少小胶质细胞的活化和增殖。在SOD1G93A大鼠瘫痪发作后开始masitinib治疗，结果显示脊髓中小胶质细胞增殖减少，MNs凋亡也有所减少。若在瘫痪发作后7天开始masitinib治疗，大鼠瘫痪后的生存期可延长约40%[61]。一项针对394名成年ALS患者开展的Ⅱ/Ⅲ期临床试验（NCT02588677）表明，masitinib联合利鲁唑治疗能够显著减缓ALSFRS-R评分的下降[62]。进一步的长期总生存期分析显示，患者早期口服masitinib（4.5 mg·kg-1·d-1），生存期延长2年，且死亡率降低44%[63]。目前，一项评估masitinib联合利鲁唑治疗效果的多中心Ⅲ期临床试验（NCT03127267）正在招募患者。3.2.5 Verdiperstat Verdiperstat是一种髓过氧化物酶（myeloperoxidase，MPO）抑制剂，MPO是活化巨噬细胞和小胶质细胞中的一种促氧化酶，是大脑病理性氧化应激和炎症的关键驱动因子。在ALS患者中，羧乙基吡咯（carboxyethylpyrrole，CEP）几乎在所有星形胶质细胞和小胶质细胞中均增加，可作为ALS大脑炎症依赖性氧化损伤的潜在标志物[64]。MPO的高活性可诱导CEP积累，而mSOD1错误折叠蛋白聚集体则能够激活MPO/HOCl，促进神经元的铁死亡和凋亡[65]。有研究表明，verdiperstat通过抑制MPO，可降低多系统萎缩（multiple system atrophy，MSA）小鼠模型中的氧化应激和炎症水平[59]。目前，在美国和欧盟，verdiperstat均被授予治疗MSA的孤儿药资格。一项Ⅱ/Ⅲ期临床试验（NCT04436510）对verdiperstat在ALS患者中的安全性和有效性进行了评估，然而，该试验显示verdiperstat未能改变疾病进展情况。3.2.6 Proleukin Proleukin（aldesleukin）是一种重组IL-2。研究表明，IL-2是Treg细胞生成、激活和存活的关键细胞因子，能够诱导Treg细胞增殖并增强其功能[59]。一项Ⅱa期临床试验（NCT02059759）证实了aldesleukin具有良好的耐受性，同时能够增加Treg细胞的数量；此外Treg细胞上CD25表达增加，可提高Treg细胞对给药和内源性IL-2的敏感性，进而提高疗效[66]。3.2.7雷帕霉素雷帕霉素（rapamycin）是一种大环内酯类化合物，可抑制哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号通路，增强蛋白质降解并发挥免疫调节作用，因而具有治疗ALS的潜力。研究表明，雷帕霉素可以恢复TDP-43核定位，并减少果蝇和小鼠ALS模型中TDP-43聚集物[67]。一项Ⅱ期临床试验（NCT03359538）结果显示，雷帕霉素可诱导Treg细胞数量增加约30%[68]。以上结果提示，提高Treg细胞数量和功能可能对ALS患者有益。虽然上述临床试验药物的具体抗炎机制尚未完全阐明，但它们能够通过调节促炎细胞的激活，或者提高抗炎细胞的比例来发挥较好的疗效，这进一步证明了免疫细胞在ALS病理机制中起着重要作用。基于此，细胞疗法也开始应用于ALS的抗炎治疗。例如，将Treg细胞在体外扩增后重新输注到患者体内，以观察其对ALS疾病进展的影响，目前相关临床研究正在进行中[69]。此外，由于ALS中存在多种免疫细胞异常的情况，联合使用多种抗炎药物，同时靶向多种免疫细胞，或许能够为ALS抗炎治疗带来更大的益处。4结语由于ALS病理机制的复杂性和ALS患者临床异质性，迄今为止尚未找到能够有效治疗ALS的药物。神经炎症已被认为是ALS中MNs凋亡和疾病进展的关键因素。本文对参与调节ALS中神经炎症的免疫细胞进行概述，表明ALS中的炎症反应是系统性的：除中枢神经系统中小胶质细胞和星形胶质细胞的过度激活外，还存在外周免疫细胞数量和功能的异常，中枢和外周神经系统中免疫细胞之间的相互作用可能共同促进ALS的发生发展。目前，对ALS中免疫反应的复杂性尚未完全理解，因此广泛的抗炎治疗在ALS中并未取得良好效果。鉴于免疫系统具有双重作用，未来的研究不应只是简单地抑制炎症反应，同时还要增强保护性免疫。虽然ALS患者中大部分为sALS，但最新研究发现，sALS患者也具有ALS相关基因的罕见位点突变，其病理和临床特征与fALS具有相似性，这提示遗传因素仍是ALS患病的主要原因，且sALS和fALS中可能具有导致MNs凋亡的共同细胞和分子机制。目前对ALS病理机制研究和非临床药效学评价主要依赖于转基因小鼠模型，因为啮齿类动物与人类亲缘性最高，转基因小鼠模型还可以模拟ALS疾病的主要症状和病理表型，具有一定的转化潜力。但毋庸置疑的是，没有任何一个单一模型能够完全概括人类疾病的结构特征。目前，大多数ALS研究仍然使用mSOD1转基因啮齿类动物，这只能反映具有SOD1基因突变的ALS患者中的神经炎症情况。随着不同突变基因模型小鼠的开发，还应在不同基因突变的转基因小鼠模型中开展研究，以期找到引起神经炎症的共同机制。此外，多种免疫细胞在ALS疾病进展中会发生由抗炎表型向促炎表型的转换，找到这些细胞发生表型转变的时间点可以为ALS抗炎治疗提供更精确的治疗时间和药物选择。参考文献：[1] 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Peripheral and central nervous system immune response crosstalk in amyotrophic lateral sclerosis[J/ OL]. Front Neurosci, 2020, 14: 575[2024-03-06]. https://doi:10.3389/ fnins.2020.00575.[47] Coque E, Salsac C, Espinosa-Carrasco G, et al. Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons[J]. Proc Natl Acad Sci USA, 2019, 116(6): 2312-2317. [48] Johnson S A, Fang T, De Marchi F, et al. Pharmacotherapy for amyotrophic lateral sclerosis: a review of approved and upcoming agents[J]. Drugs, 2022, 82(13): 1367-1388. [49] Miller T M, Cudkowicz M E, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS[J]. N Engl J Med, 2022, 387(12): 1099-1110. [50] Miller R G, Zhang R, Block G, et al. NP001 regulation of macrophage activation markers in ALS: a phase I clinical and biomarker study[J]. Amyotroph Lateral Scler Frontotemporal Degener, 2014, 15(7/8): 601-609. [51] Miller R G, Block G, Katz J S, et al. Randomized phase 2 trial of NP001-a novel immune regulator: safety and early efficacy in ALS[J/ OL]. Neurol Neuroimmunol Neuroinflamm, 2015, 2(3): e100[2024 03-06]. https://doi:10.1212/NXI.0000000000000100. [52] Miller R G, Zhang R, Bracci P M, et al. Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: pre specified and post hoc analyses[J]. Muscle Nerve, 2022, 66(1): 39-49. [53] Vallarola A, Sironi F, Tortarolo M, et al. RNS60 exerts therapeutic effects in the SOD1 ALS mouse model through protective glia and peripheral nerve rescue[J/OL]. J Neuroinflammation, 2018, 15(1): 65[2024-03-06]. https://jneuroinflammation.biomedcentral.com/ articles/10.1186/s12974-018-1101-0. DOI: 10.1186/s12974-018 1101-0. [54] Beghi E, Pupillo E, Bianchi E, et al. Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial[J]. Eur J Neurol, 2023, 30(1): 69-86. [55] Chen Y, Wang H, Ying Z, et al. Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: the new molecular mechanism of ibudilast and its implication for neuroprotective therapy[J]. Biochem Biophys Res Commun, 2020, 526(1): 231-238. [56] Angelopoulou E, Pyrgelis E S, Piperi C. Emerging potential of the phosphodiesterase (PDE) inhibitor ibudilast for neurodegenerative diseases: an update on preclinical and clinical evidence[J/OL]. Molecules, 2022, 27(23): 8448[2024-03-06]. https://doi.org/10.3390/molecules27238448.[57] Oskarsson B, Maragakis N, Bedlack R S, et al. MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design[J]. Neurodegener Dis Manag, 2021, 11(6): 431-443. [58] Babu S, Hightower B G, Chan J, et al. Ibudilast (MN-166) in amyotrophic lateral sclerosis-an open label, safety and pharma codynamic trial[J/OL]. Neuroimage Clin, 2021, 30: 102672[2024-03 06]. https://doi:10.1016/j.nicl.2021.102672. 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Neurosci Biobehav Rev, 2021, 127: 958-978[2024-03-06]. https://doi.org/10. 1016/j.neubiorev.2021.06.027.美编排版：何裕爽感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 4 期。《药学进展》杂志由教育部主管、中国药科大学主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟

临床研究

2025-03-14

·求实药社

生存期延长15月！渐冻症新药临床研究结果积极！

来源：药讯随说 3月12日（当地时间），Clene Inc及其子公司Clene Nanomedicine宣布其纳米药物CNM-Au8在肌萎缩侧索硬化（ALS，渐冻症）临床研究（HEALEY ALS平台研究）患者的交叉方案长期生存事后分析结果积极。 HEALEY ALS平台研究（主研究：NCT04297683）为一项评估多种方案在稳定背景治疗（利鲁唑和/或依达拉奉）ALS患者中有效性、安全性、PK和PD的全球多中心、随机、双盲、安慰剂对照的确证性III期临床研究。研究主要终点为生存改善，次要有效性终点为ALS临床恶化事件延迟时间。平台试验包括7个方案，分别为：Zilucoplan（泽勒普肽，方案A：NCT04436497）、Verdiperstat（方案B：NCT04436510）、CNM-Au8（方案C：NCT04414345）、Pridopidine（普利多匹定，方案D：NCT04615923）、Trehalose（海藻糖，方案E：NCT05136885）、ABBV-CLS -7262(方案F：NCT05740813）、DNL343（方案G：NCT05842941）。方案A：患者3：1随机接受24周活性治疗（每天一次皮下注射Zilucoplan，0.3mg/kg）或匹配安慰剂治疗。方案C：患者2：1随机接受108周活性治疗（30mg）或匹配安慰剂治疗. 本次公布结果如下： 1、全分析集（FAS）：中位生存：CNM-Au8 30mg组 (方案C,n=59)和方案A对照组（n=162）中位生存天数分别为951天、753天，增加198天（6.5月）；限制平均生存时间（RMST）：协变量校正RMST增加124天（4.1月）（95%CI：3-245；p=0.045）； 2、中-重度ALS患者增强获益：基线血清NfL（神经丝轻链蛋白）≥33pg/ml和TRICALS风险得分-6.5至-2.5间人群中，方案C（n=51）较方案A（n=120）中位生存时间从589天提高至951天，增加11.9月；死亡风险降低44%（Cox HR=0.556;95%CI:0.367-0.842;p=0.006),RMST增加197天（6.5月，95%CI：65-329；p=0.004）； 3、符合入选标准集【血清NfL（神经丝轻链蛋白）≥33pg/ml，TRICALS风险得分-6.5至-2.5间，基线慢肺活量≥60%，发病时间≤36月】方案C（n=40）较方案A（n=94）中位生存时间从628天提高至1079天，增加14.8月（451天）；死亡风险降低49%（Cox HR=0.514;95%CI:0.319-0.83;p=0.006),RMST提高215天（7.1月，95%CI：70-360；p=0.004） CNM-Au8是一种具有催化活性、表面清洁、浓缩的金元素多面纳米晶体的水悬浮液。通过提供和/或接收电子驱动大脑中关键的细胞能量生成反应，通过增加神经元和胶质细胞对疾病相关应激的耐受性，使神经修复和髓鞘再生成为可能，并减少有害的反应性分子。免责声明：文章内容仅供参考，不构成投资建议。投资者据此操作，风险自担, 关于对文中陈述、观点判断保持中立，不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证。请读者仅作参考，并请自行承担全部。联系我们 SIT 2025 展位火热预定中！扫码立即咨询电话：13816031174 （同微信）赞助形式包括但不仅限于演讲席位、会场展位、会刊彩页、晚宴赞助、会议用品宣传等。点击此处“阅读全文”咨询更多精彩！

临床结果临床3期

2024-09-16

·BioSpace

The HEALEY Platform Trial: Quick Failures and New Hope for ALS

iStock/ higyou Launched in 2020 to more quickly bring to market an effective medicine for amyotrophic lateral sclerosis, the HEALEY Platform Trial has generated disappointing results for many but also continuing programs from Clene and Prilenia. Clinical wins have been few and far between for the HEALEY ALS Platform Trial . A heterogeneous patient population and delays have posed challenges, with several biotechs discontinuing programs based on underwhelming results. But optimism persists among the trial’s leaders and early participants, with two companies, Clene Nanomedicine and Prilenia Therapeutics, moving their investigational amyotrophic lateral sclerosis (ALS) treatments forward. The first seed for an ALS platform trial was planted when Massachusetts General Hospital’s Merit Cudkowicz read an article on master platform trials by former FDA Principal Deputy Commissioner Janet Woodcock. “I read that one and thought it might be appropriate for ALS,” Cudkowicz told BioSpace . Then, along came Sean Healey, a prominent American businessman who had recently been diagnosed with ALS, with an attractive opportunity. He said, “I might not save myself from this illness, but I want to make a difference. Give me a proposal,” Cudkowicz recalled. So she and her team worked around the clock, ultimately pitching the platform trial, and “[Healey] loved it. He just got it right away, that it was efficient and good for patients.” Healey, in partnership with his global asset management firm, Affiliated Managers Group (AMG), donated $40 million to launch the Sean M. Healey & AMG Center for ALS at Mass General, and set in motion a new chapter in ALS research. Cudkowicz serves as the center’s director. Biopharma quickly jumped on board with the platform trial, with dozens of companies—in addition to Clene and Prilenia, UCB, Biohaven Pharmaceutical and Seelos Therapeutics—vying to be a part of it. Fast forward four years and none of these drugs has hit the trial’s primary endpoints. But Clene CEO Rob Etherington said that doesn’t reflect a failure of the study itself. The HEALEY trial was designed to “fast fail” assets that don’t have utility, he explained, “and it worked in that respect, for a few of the regimens.” Indeed, Cudkowicz noted that Biohaven, which ultimately opted against moving forward with the program, also viewed the trial as a success because “they got a quick answer, a clear answer.” Biohaven did not respond to BioSpace ’s request for comment. But perhaps most notably, Clene and Prilenia showed positive data on secondary endpoints that prompted those companies to progress their candidates, Cudkowicz said. “So, I really actually view that as a success.” The First Five To select the initial round of participants in the trial, Cudkowicz and her team decided to host a competition. She noted that many aspiring platform trials seemed to be stuck at the funding stage and believed a call for proposals would speed up the process. The prize: entry into the Healey ALS Platform Trial, where some costs for the first companies would be covered. The team received 30 proposals from all over the world. Cudkowicz and her colleagues assessed each therapy based on clinical potential, mechanism of action, and diversity of approach. “We did want to pick drugs with different targets for the first five,” Cudkowicz said. Finally, they selected five programs. UBC’s zilucoplan inhibits complement component 5, the dysregulation of which is implicated in ALS, while Biohaven’s verdiperstat blocks the enzyme that reduces oxidative stress and neuroinflammation. Clene’s CNM-Au8, by contrast, is an oral, liquid suspension of gold nanocrystals designed to improve the survival, function, and communication of nerve cells. Prilenia’s pridopidine is also a neuroprotective agent, and Implicit Bioscience’s IC14 is an anti-CD14 monoclonal antibody devised to regulate the pathogenic inflammatory responses to infection and injury. Of these, Clene and Prilenia fared the best. Although both companies’ assets missed their primary endpoints, positive biomarker data and benefit to a subgroup of patients in Prilenia’s case supported moving the programs forward. With Prilenia’s candidate, a subgroup of patients with early-stage ALS who were rapidly declining had “substantially less decline” in ALS Functional Rating Scale-Revised (ALSFRS-R) total score compared to placebo. The company has stated plans to launch a Phase III trial. Meanwhile, Clene has a briefing book in front of the FDA based on HEALEY data and additional biomarker results gleaned from the RESCUE-ALS trial and survival data from ongoing compassionate use protocols. While the agency originally said the data were insufficient to support a new drug application, Clene has since submitted more information, including mechanistic and ALS-specific biomarkers and data on a super-responder group, which Etherington said is now under review. Clene also gathered promising survival and biomarker data from its arm of the HEALEY study. Treatment with CNM-Au8 for up to 133 weeks decreased the risk of death by 49% compared to PRO-ACT database–matched placebo, according to Clene, while also reducing levels of neurofilament light chain (NfL), which is gaining ground as a predictor of clinical outcomes in neurodegenerative diseases. “Without the survival secondary endpoint win and the exploratory endpoint win and the neurofilament biomarker win that HEALEY gave Clene, we’d be in a very different position today,” Etherington said. “We certainly wouldn’t have a briefing book under consideration at the FDA without HEALEY.” The other companies have either shut down their programs or are still determining next steps. Implicit never moved forward to the design phase. UCB’s arm of the trial was stopped early after an interim analysis demonstrated futility, according to a Massachusetts General press release . Meanwhile, Biohaven’s verdiperstat failed to statistically differentiate from placebo, and the drug is no longer listed in the company’s pipeline . Seelos joined after Implicit departed and got mixed results. The company stated in a March press release that while its drug trehalose failed to meet statistical significance in the primary and secondary endpoint in the HEALEY study, it showed a “potential signal of efficacy” in a subgroup of patients not taking Amylyx’s Relyvrio, which was given to some trial participants after its approval in September 2022 . And the HEALEY trial marches on. In July 2022, Calico Life Sciences signed on to test ABBV-CLS-7262, and Denali Therapeutics announced its participation with DNL343 in December of the same year. Data from these arms of the trial are expected in early 2025. Another company, Australian outfit PharmAust, recently committed to studying its drug monepantel, and Cudkowicz said talks are ongoing with several more companies. Cudkowicz said that no matter what the result of the various arms, “you can learn a lot about [ALS].” Patient- and Business-Centric Platform trials are a fairly new phenomenon, and Cudkowicz shared that she learned a lot from the DIAN Alzheimer’s trial at Washington University. The model offers myriad benefits, including efficiency. While a clinical trial typically takes more than a year to get off the ground, the HEALEY study is a perpetual trial , meaning a new drug regimen can be added in just 30 days. It’s also patient-centric. The use of a shared placebo between all regimens means that more patients receive a potentially efficacious drug. This also means companies have to recruit fewer patients. The fact that some of their costs were covered was a significant benefit for the smaller companies in the HEALEY trial. Prilenia, for example, had six employees at the time it applied to join the trial. “The good news was they paid for the drug, so we didn’t have to raise money for [that],” Hayden told BioSpace . The infrastructure build and support were also partially funded by several foundations, Cudkowicz said. “I’m grateful. Without HEALEY, we would never have done this trial,” Hayden said. “We didn’t have the money.” The companies involved also have access to elite experience in the ALS space. Cudkowicz is widely considered to be the dean of ALS drug development, and both Etherington and Hayden referenced the gravitas associated with the HEALEY trial, which includes 75 research sites. “The advantage of HEALEY is undeniably the fact that you have an easy network of top expert centers . . . so you’re really able to access the top centers in the United States of America,” Etherington told BioSpace . “That is a tremendous advantage for young startup companies to have access to and to be involved with.” Etherington added that acceptance into the trial gave CNM-Au8 credibility “because it really was a testament of others’ stamp of approval that are well respected in the space.” Growing Pains Still, a complex structure with so many moving parts is bound to take time to perfect. Etherington noted that every drug is unique, and “a platform study does not enable an individual drug and its unique aspects of mechanism or side effects or administration to actually make any changes” to the trial’s protocol. For example, each cohort in the HEALEY trial has run for six months. For CNM-Au8, this was too short of a window to prove efficacy, Etherington said. “To have everybody come in and have to fit the framework with no exceptions, that’s a challenge.” Notably, Cudkowicz shared that the team is currently considering amending the protocol based on learnings from the first five regimens. “This includes possibly longer duration of follow up on the randomized controlled trial period to address the possibility that some medications need more time to achieve biological and clinical effects,” she said. Cudkowicz added that a voice app developed by Aural Analytics and used in the first four regimens is “turning out to be a very good digital biomarker. We also did home spirometry (a measure of lung function), which looks pretty much just as good as in clinic.” Another challenge for a trial with multiple centers across the U.S., Etherington said, was an initial delay in receiving data from every center, though Clene is now in possession of the final datasets from the HEALEY trial. Because every regimen starts at a different time, they all finish at different times, slowing down the rate at which results are available. For a company conducting a single study, “all hands are on deck,” Etherington said. By contrast, in a platform trial, “we have to be more ecumenical. We have to share, as it were, the load and the timeline, and we need to recognize that the company’s individual interests need to be subjugated, to some degree, to the whole of the platform study.” Hayden agreed, saying that the HEALEY team was sometimes “overwhelmed” with running what amounts to eight trials, and that there sometimes is “a little frustration in terms of the speed of response, the ability to get statistical analysis done. All of that can be slower than we would like.” Cudkowicz acknowledged that the trial has faced challenges in this regard. “Since the idea of platform trials is efficiency and speed, we want all parts of it to be efficient,” she said. “Some of the structural, operational things that slow down trials in general are still in play in platform trials [and] how trials are started up at academic institutions is still too slow, in my opinion. We have some new initiatives to improve this dramatically for the next several new regimens,” she said in an email. Cudkowicz added that interest in the trial overwhelmed the capacity of some of the trial sites. “There’s high interest in it from the companies, from the patients, but now we’ve gotta do it even faster.” A heterogeneous patient population was another challenge, Hayden said. “The study included essentially everybody with ALS, and that was maybe . . . both positive and negative. The positive was that this gave hope to everybody.” However, ALS has a “very heterogeneous population.” The HEALEY trial included patients with definite, probable and possible ALS, as well as those more than three years out from diagnosis. “We were concerned about that right in the beginning because we knew that all the trials that had been successful in ALS had a different population” that included patients with only definite and probable ALS, and a shorter disease duration, Hayden said. Prilenia ultimately prespecified that it wanted to also study pridopidine in patients with early-stage ALS, diagnosed less than 18 months before the trial’s start, and HEALEY investigators were able to recruit from such a population for the arm of the trial testing the drug. And while pridopidine failed the primary endpoint in the full analysis set, in patients with early ALS, “what we saw is that we had a very wonderful positive effect,” Hayden said. “We delayed progression for the first time ever seen in an ALS trial at eight weeks.”

临床3期临床结果

100 项与 Verdiperstat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11684	-	-	DB12440

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
多系统萎缩	临床3期	美国	Biohaven Pharmaceuticals, Inc.	2019-07-29
多系统萎缩	临床3期	奥地利	Biohaven Pharmaceuticals, Inc.	2019-07-29
多系统萎缩	临床3期	法国	Biohaven Pharmaceuticals, Inc.	2019-07-29
多系统萎缩	临床3期	德国	Biohaven Pharmaceuticals, Inc.	2019-07-29
多系统萎缩	临床3期	意大利	Biohaven Pharmaceuticals, Inc.	2019-07-29
多系统萎缩	临床3期	英国	Biohaven Pharmaceuticals, Inc.	2019-07-29
肌萎缩侧索硬化	临床3期	美国	Biohaven Pharmaceutical Holding Co. Ltd.	2019-07-20
帕金森病	临床2期	瑞典	AstraZeneca PLC	2012-04-01
原发性进行性失语	临床1期	美国	University of California	2022-12-20
原发性进行性失语	临床1期	美国	Biohaven Pharmaceuticals, Inc.	2022-12-20

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临床结果

适应症

分期

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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


NCT04436510 (HEALEY ALS, CTgov)	临床2/3期	肌萎缩侧索硬化	167	Verdiperstat (Verdiperstat)	夢遞襯繭鹹餘積憲襯繭(願糧廠觸範艱製築蓋餘) = 範糧觸夢顧廠鏇糧繭齋鑰窪廠獵夢醖構鹽襯蓋 (醖糧夢衊繭築繭襯鬱窪, 0.091) 更多	-	2023-06-12
				Matching Placebo (Matching Placebo)	夢遞襯繭鹹餘積憲襯繭(願糧廠觸範艱製築蓋餘) = 膚網鏇鬱醖蓋糧淵糧鹹鑰窪廠獵夢醖構鹽襯蓋 (醖糧夢衊繭築繭襯鬱窪, 0.086) 更多
NCT04436510 (HEALEY ALS, NEWS) 人工标引	临床2/3期	肌萎缩侧索硬化	-	Verdiperstat	鏇醖積範夢觸獵獵淵蓋(鏇網獵築襯顧範鏇鑰醖) = Verdiperstat did not statistically differentiate from placebo 襯夢廠蓋膚襯網淵鹹艱 (壓鏇淵遞廠製餘鏇鹹積 )	不佳	2022-09-29
				Placebo
NCT03952806 (M-STAR, MDS2022)	临床3期	多系统萎缩	-	Verdiperstat 600 mg	顧蓋餘範窪齋製遞選鹹(簾衊夢鏇醖鏇簾齋淵鏇): P-Value = 0.0005 更多	-	2022-09-15
				Placebo
NCT02388295 (CTgov)	临床2期	多系统萎缩	59	Placebo+AZD3241 (Placebo)	鹽鏇襯築齋憲願選壓窪(夢積範構淵製鹹遞鏇艱) = 鑰膚襯顧襯蓋選窪窪獵鏇願艱繭積餘廠觸願衊 (鬱製蓋獵願鹹襯夢鬱築, 0.61) 更多	-	2017-09-25
				AZD3241 (AZD3241 300 mg)	鹽鏇襯築齋憲願選壓窪(夢積範構淵製鹹遞鏇艱) = 網觸顧積膚壓願鑰夢壓鏇願艱繭積餘廠觸願衊 (鬱製蓋獵願鹹襯夢鬱築, 0.83) 更多