(Nerinetide) - 药物靶点：PSD95_在研适应症：急性缺血性卒中，脑缺血_专利_临床

概要

基本信息

药物类型

重组多肽

别名

Nerinetide (USAN/INN)

靶点

PSD95

作用机制

PSD95抑制剂(Disks大同系物-4抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构-

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

序列信息

Sequence Code 80946

来源: *****

关联

5

项与 Nerinetide 相关的临床试验

NCT04462536 / Completed临床3期

A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis

The primary purpose of this study is to determine if a single dose of nerinetide can reduce global disability in people who have had a stroke and are selected for endovascular therapy without the use of a tissue plasminogen activator (alteplase, tenecteplase, or equivalent).

开始日期2020-12-06

申办/合作机构

NoNO, Inc.

[+1]

NCT02930018 / Completed临床3期

A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of Intravenous NA-1 in Subjects With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy

The ESCAPE-NA-1 study is designed to determine the safety and efficacy of the neuroprotectant, Nerinetide (NA-1), in reducing global disability in subjects with major acute ischemic stroke (AIS) with a small established infarct core and with good collateral circulation who are selected for endovascular revascularization.

开始日期2017-03-01

申办/合作机构

NoNO, Inc.

[+1]

NCT02056574 / Withdrawn临床2期

Phase 2, Multicenter Randomized, Double-Blind, Placebo-Controlled, Safety and Efficacy Study Evaluating a Single Dose of Intravenous NA-1 in Patients With Subarachnoid Hemorrhage Undergoing Endovascular Repair of Ruptured Intracranial Aneurysms

This is a randomized, double-blind, placebo-controlled, single-dose study investigating the safety and efficacy of NA-1 in patients with subarachnoid hemorrhage (SAH) undergoing endovascular repair of ruptured intracranial aneurysms. Up to 300 male and female patients with SAH undergoing endovascular repair of a ruptured intracranial aneurysm will be dosed with 2.60 mg/kg of NA-1 or placebo as a 10 minute intravenous infusion after completion of the endovascular procedure on Day 1 of the study period. Subjects will undergo interim procedures at Day 2-4, Day 30-45, and end-of-study procedures on Day 90.

开始日期2015-11-01

申办/合作机构

NoNO, Inc.

100 项与 Nerinetide 相关的临床结果

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100 项与 Nerinetide 相关的转化医学

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100 项与 Nerinetide 相关的专利（医药）

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80

项与 Nerinetide 相关的文献（医药）

2024-06-01·Neuropharmacology

Tat-NR2B9c attenuates oxidative stress via inhibition of PSD95-NR2B-nNOS complex after subarachnoid hemorrhage in rats

Article

作者: Fang, Yuanjian ; He, Yezhao ; Zhang, Zeyu ; Wang, Kaikai ; Zhang, Haocheng ; Zhang, Anke ; Liu, Yibo ; Wang, Xiaoyu ; Chen, Sheng ; Yu, Qian ; Xu, Longbiao ; Zhang, Jiahao

Oxidative stress plays important roles in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Tat-NR2B9c has shown efficacy as a neuroprotective agent in several studies. Here, we identified the neuroprotective role of Tat-NR2B9c after SAH and its related mechanisms. The results showed that Tat-NR2B9c treatment attenuated oxidative stress, therefore alleviated neuronal apoptosis and neurological deficits after SAH. Tat-NR2B9c treatment could alleviate mitochondrial vacuolization induced by SAH. Compared to SAH + vehicle group, Tat-NR2B9c resulted in the decrease of Acetylated superoxide dismutase2 (Ac-SOD2), Bcl-2-associated X protein (Bax) and cleaved-caspase3 (CC3) protein expression, and the up-regulation of Sirtunin 3 (Sirt3) and Bcl-2 protein level. Moreover, Tat-NR2B9c attenuated excitotoxicity by inhibiting the interaction of PSD95-NR2B-nNOS. Our results demonstrated that Tat-NR2B9c inhibited oxidative stress via inhibition of PSD95-NR2B-nNOS complex formation after SAH. Tat-NR2B9c may serve as a potential treatment for SAH induced brain injury.

2024-03-01·American Journal of Neuroradiology

Prevalence of “Ghost Infarct Core” after Endovascular Thrombectomy

Article

作者: Kashani, Nima ; Rempel, Jeremy ; Tymianski, Michael ; Sahlas, Demetrios ; Goyal, Mayank ; Ospel, Johanna M ; Rinkel, Leon ; Budzik, Ron ; Kelly, Michael E ; Buck, Brian ; Hill, Michael D ; Rex, Nathaniel

BACKGROUND AND PURPOSEBaseline CTP sometimes overestimates the size of the infarct core ("ghost core" phenomenon). We investigated how often CTP overestimates infarct core compared with 24-hour imaging, and aimed to characterize the patient subgroup in whom a ghost core is most likely to occur.MATERIALS AND METHODSData are from the randomized controlled ESCAPE-NA1 trial, in which patients with acute ischemic stroke undergoing endovascular treatment were randomized to intravenous nerinetide or placebo. Patients with available baseline CTP and 24-hour follow-up imaging were included in the analysis. Ghost infarct core was defined as CTP core volume minus 24-hour infarct volume > 10 mL). Clinical characteristics of patients with versus without ghost core were compared. Associations of ghost core and clinical characteristics were assessed by using multivariable logistic regression.RESULTSA total of 421 of 1105 patients (38.1%) were included in the analysis. Forty-seven (11.2%) had a ghost core > 10 mL, with a median ghost infarct volume of 13.4 mL (interquartile range 7.6-26.8). Young patient age, complete recanalization, short last known well to CT times, and possibly male sex were associated with ghost infarct core.CONCLUSIONSCTP ghost core occurred in ∼1 of 10 patients, indicating that CTP frequently overestimates the infarct core size at baseline, particularly in young patients with complete recanalization and short ischemia duration.

2024-01-23·Neurology

The REPERFUSE-NA1 Study

Article

作者: Tarpley, Jason ; Barber, Philip ; Fladt, Joachim ; d'Esterre, Christopher ; Shah, Ruchir ; Goyal, Mayank ; Chan, Leona L ; Field, Thalia S ; Specht, Jacinta L ; Guo, Jen ; Swartz, Richard H ; Buck, Brian H ; Aviv, Richard ; Tymianski, Michael ; Demchuk, Andrew ; Wang, Meng ; Mctaggart, Ryan ; Hill, Michael D

BACKGROUND AND OBJECTIVESThe neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy (EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide.METHODSREPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney U test and multiple linear regression.RESULTSSixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (p = 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range [IQR], 2.54-21.81) in patients with placebo (p = 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error [SE], 60%) in the white matter (p = 0.03) and by 340% (SE, 140%) in the basal ganglia (p = 0.02) in the nerinetide group compared with placebo after adjusting for confounders.DISCUSSIONThis study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth.TRIAL REGISTRATION INFORMATIONClinicalTrials.gov NCT02930018.CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.

1

项与 Nerinetide 相关的新闻（医药）

2024-03-18

·生物制药小编

停药仍能持续减肥

随着3月9日司美格鲁肽得到FDA批准用于辅助预防重大心血管事件，司美格鲁肽等GLP-1类减肥药物的跨界效果也得到了监管机构的认可。然而，这类减肥药物目前现阶段的数据表明，这些药物虽然有行之有效，但一旦停药反弹幅度也很大，且反弹过程中可能导致心血管方面的益处也可能因为反弹而恢复原样。既然减肥药能够跨界到心血管领域，那么其他领域的药物能不能跨界到肥胖呢？不仅可以，即便停药后，依然可以做到持续减肥。近日（3月1日），来自丹麦哥本哈根大学的诺和诺德基金会基础代谢研究中心在Science子刊Science Advances上发表了一篇论文。研究人员采用了之前只在神经病性疼痛和中风中进行开发的PSD-95和PICK1靶点，并试图用新方法将其运用在肥胖症上。NMDA受体和AMPA受体的崭新开发方式在过去的十年中，全基因组关联研究（GWAS）揭示了许多可能导致肥胖发病的生物学途径。在这些途径中，不少基因直接在大脑内富集/表达，在肥胖的遗传研究中，与α-氨基-3-羟基-5-甲基-4-异唑丙酸(AMPA)和n -甲基-d-天冬氨酸(NMDA)受体相关的谷氨酸能信号传导和突触后可塑性相关的基因尤其丰富，这表明谷氨酸能神经递质系统在调节能量平衡的稳态机制在肥胖症中发挥了重要作用。但问题在于，这两条途径的受体在整个中枢神经系统中普遍表达，强行去开发靶向药物很可能造成神经损伤。上游途径惹不起，那就只能从下游着手。因此，科学家们就试图去探索细胞内受体蛋白复合物的靶向，因为靶向蛋白质复合物就能够实现突触后受体信号的精确干扰。而AMPA和NMDA受体都会直接与细胞内支架蛋白相互作用，这些细胞内支架蛋白能够参与膜上谷氨酸受体的锚定和运输。支架蛋白中的许多又含有PDZ结构域。PDZ结构域（PDZ domain）是一种在多种蛋白质中发现的结构元件，它是蛋白质-蛋白质相互作用的重要模块。PDZ结构域得名于最初发现它的三种蛋白质：Postsynaptic density protein-95 (PSD-95)、Dlg1 ( discs large homolog 1) 和 Zonula occludens-1 (ZO-1)，每个蛋白质的名字首字母组成了“PDZ”。也就是说只要靶向含有PDZ结构域的蛋白质，就能够解决不能直接靶向受体的问题了，而这种含有PDZ结构域的支架蛋白就成为了众多中枢神经系统疾病的理想靶点。而此次该靶点就在肥胖症上得到开发。遗传筛选获得理想蛋白质为了确定肥胖治疗的药物靶点，研究人员寻找了至少由一个PDZ结构域组成的蛋白质，这些蛋白质已知参与谷氨酸能AMPA或NMDA受体的蛋白质相互作用。他们确定了六种符合这些标准的蛋白质:谷氨酸受体相互作用蛋白1（grip 1）、GRIP2、与C激酶1相互作用的蛋白（PICK1）、PSD-95。而下一轮筛选由遗传相关性展开，他们采用了UK Biobank（英国生物银行）的数据，并通过调查转录起始位点周围500 kb区域内的所有常染色体变异与体重指数（身体质量指数）和体脂百分比（BF%）的相关性，最终筛选获得了PSD-95和PICK1这两项与肥胖呈现出正相关的靶点。PSD-95抑制剂可降低小鼠体重其实之前就有PSD-95抑制剂NA-1差点成功上市，但临门一脚却因为主要临床不达终点而功败垂成。当时的适应症是心血管疾病。现在，丹麦的研究人员开发了一种二聚肽抑制剂UCCB 01-147，数据对照来看，与NA-1相比，UCCB 01-147以同等摩尔剂量更显著地降低了体重和食物摄入量，且这一降低并非由脱靶效应驱动。PICK1抑制剂可降低小鼠体重同样，研究人员开发了另外一种PICK1二聚肽抑制剂的脂质化变体mPD5，该抑制剂能够干扰AMPA受体的PICK1依赖性磷酸化。同样做到了以剂量依赖性地降低肥胖小鼠的体重。为了证明mPD5是通过PICK1抑制来实现肥胖降低的，因此研究人员用PICK1敲除小鼠进行对照。在高脂饮食喂养的PICK1敲除小鼠中，研究人员发现在DIO野生型同窝出生小鼠中观察到的mPD5降低体重和食物摄入量的作用在PICK1基因敲除小鼠中完全消失，这表明mPD5抑制食欲和减轻体重的作用确实是通过PICK1介导的。抑制剂的持久性对谷氨酸受体的药物干扰可以通过减少兴奋性神经传递、促进神经回路变化并可能引发持续的疾病缓解益处来诱导持久的神经可塑性效应。为了评估mPD5和UCCB01-147治疗的长期代谢效果，研究人员进行了为期13天的治疗研究，然后进行了为期29天的清除/体重恢复期。在这项研究中，两种化合物在13天的治疗期内都获得了显著的减肥益处。与先前的研究一致，两种化合物的体重减轻仅反映在体脂质量的减少上。值得注意的是，尽管两种PDZ结构域干扰化合物的半衰期在几分钟到几小时的范围内，体重减轻在治疗停止后持续约10天。治疗停止四周后，用mPD5治疗的小鼠仍然没有赶上溶媒对照组的体重，这表明PICK1干扰可能对体重有持久影响。在一项后续研究中，评估了mPD5对GLP-1受体激动剂利拉鲁肽的持续减肥效果。治疗停止后，mPD5治疗的小鼠在3天内体重持续下降，体重下降持续约8天。相反，利拉鲁肽治疗的小鼠在治疗停止后立即开始体重恢复，恢复速度比mPD5治疗的小鼠更快。到第35天，利拉鲁肽治疗的小鼠等于溶媒对照组的体重，而mPD5治疗的小鼠则保持显著低于溶媒对照组的体重。为了解决与利拉鲁肽治疗小鼠和mPD5治疗小鼠之间体重减轻差异相关的潜在混杂因素，研究人员还额外进行了一项研究，他们将mPD5治疗小鼠与一组进行热量限制以实现等效体重减轻的小鼠进行了比较。在停止热量限制和mPD5治疗后，各组的体重恢复立即出现差异。与之前的观察结果一致，mPD5治疗的小鼠在停药后体重恢复缓慢，但在恢复期第16天，两组小鼠已经的体重恢复程度已经达到一致。体重恢复的最初分离反映在热量限制组中强烈的反调节性摄食过度。相比之下，mPD5组恢复了与对照组小鼠相同的卡路里摄入量，没有表现出补偿性行为。这样的试验可能表明，假如一名肥胖症患者得到mPD5治疗后，体重减轻，但是停药后，即便他能够获得充足的饮食，也可能不会表征出补偿性暴饮暴食的情况。总结实际上，近年来，关于PSD-95靶点在如阿尔兹海默症，抑郁症等其他领域也展现出了一定可适用性，这也表明PSD-95抑制剂的潜在跨界应用，而PICK1抑制剂展现出了具有一定持久性治疗效果，考虑到目前是诺和诺德在主要资助这两款靶点的开发，可能引起一部分企业效仿。参考来源：https://www.science.org/doi/10.1126/sciadv.adg2636

100 项与 Nerinetide 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11729	-	-	DB12595

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
急性缺血性卒中	临床3期	澳大利亚	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	德国	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	美国	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	加拿大	NoNO, Inc.	2017-03-01
脑缺血	临床3期	加拿大	NoNO, Inc.	2015-03-26
急性缺血性卒中	临床1期	英国	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床1期	爱尔兰	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床1期	韩国	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床1期	瑞典	NoNO, Inc.	2017-03-01
脑卒中	药物发现	加拿大	NoNO, Inc.	2008-08-01

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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


NCT02930018 (REPERFUSE-NA1, ISC2022)	临床3期	梗塞	71	NA1	鹽齋築範壓淵膚廠夢築(製淵簾積餘夢遞艱齋夢) = 壓願淵鬱醖衊簾蓋膚範糧鏇襯選築鑰網積顧繭 (夢夢醖齋繭鏇襯餘廠鬱, 5.9 ~ 28.1) 更多	-	2022-02-01
				Placebo	鹽齋築範壓淵膚廠夢築(製淵簾積餘夢遞艱齋夢) = 構窪醖醖鹹夢網簾選鹽糧鏇襯選築鑰網積顧繭 (夢夢醖齋繭鏇襯餘廠鬱, 3.1 ~ 27.0) 更多
ISC2019	临床3期	脑卒中	-	PVD + Tat-NR2B9c	(鬱獵夢獵遞壓餘壓鏇觸) = 醖觸願鬱願鑰願鏇製齋選鹽齋範鬱齋窪壓壓鑰 (遞夢憲淵獵構鑰獵窪鏇 )	-	2019-02-01
ESCAPE NA1-Trial (ISC2021)	N/A	脑卒中 \| 闭塞	1,105	Nerinetide	鹹艱膚夢積鹹顧糧鏇鏇(壓網顧觸願觸醖鹽壓衊) = 憲廠襯鬱齋繭鹽衊繭觸遞顧築蓋構憲遞窪獵襯 (鹽膚鹽窪膚鑰積廠鬱鏇 )	-	2021-03-01
				Placebo	鹹艱膚夢積鹹顧糧鏇鏇(壓網顧觸願觸醖鹽壓衊) = 積鏇鏇齋觸醖簾夢夢廠遞顧築蓋構憲遞窪獵襯 (鹽膚鹽窪膚鑰積廠鬱鏇 )
NCT00728182 (CTgov)	临床2期	脑卒中 \| 动脉瘤	185	NA-1 (1 NA-1)	鹹鏇憲壓繭鹽構壓憲顧(蓋鏇築憲衊艱鹹網製窪) = 繭衊壓齋繭製鑰觸構簾壓淵範壓餘醖壓網積襯 (鑰觸窪衊簾壓構遞夢襯, 網顧淵餘糧選鑰觸鹽網 ~ 醖選鑰鏇鹹簾簾繭製製) 更多	-	2013-10-17
				placebo (2 Placebo)	鹹鏇憲壓繭鹽構壓憲顧(蓋鏇築憲衊艱鹹網製窪) = 觸遞網繭夢構製蓋繭廠壓淵範壓餘醖壓網積襯 (鑰觸窪衊簾壓構遞夢襯, 艱糧壓襯製構鏇衊鏇觸 ~ 艱淵網鹹鹹蓋積廠積窪) 更多
Escape-NA1 (ISC2021)	N/A	急性缺血性卒中	1,097	Escape-NA1 (Patients with hemorrhage on follow-up imaging)	範網襯壓願範壓鏇網壓(餘淵鑰積觸廠窪顧鑰廠) = 顧網淵窪憲憲鏇積淵鏇築夢鏇鹹鑰鑰醖獵觸壓 (願夢積網願膚築網構構 )	-	2021-03-01
				Escape-NA1 (Patients without hemorrhage on follow-up imaging)	範網襯壓願範壓鏇網壓(餘淵鑰積觸廠窪顧鑰廠) = 鑰窪衊積繭壓獵餘淵遞築夢鏇鹹鑰鑰醖獵觸壓 (願夢積網願膚築網構構 )
NCT02930018 (ESCAPE-NA1, Pubmed) 人工标引	临床3期	急性缺血性卒中	1,105	nerinetide	(顧範艱鹽醖積鹽憲鹹鹽) = Serious adverse events occurred equally between groups. 糧膚築築鹽醖鏇鹹艱醖 (憲壓憲襯醖蓋製繭憲齋 ) 更多	不佳	2020-03-14
				Placebo
NCT02930018 (ESCAPE-NA1, Pubmed)	临床3期	梗塞	1,092	Intravenous Nerinetide	鹹壓餘鏇遞鹽淵鏇積鹽(糧壓鏇糧膚衊壓獵願餘): adjusted risk ratio = 0.71 (95% CI, 0.57 ~ 0.89) 更多	-	2023-04-21
				No Intravenous Nerinetide
NCT02930018 (CTgov)	临床3期	急性缺血性卒中	1,105	Placebo	獵鑰鑰膚襯簾遞鏇襯構(遞壓窪艱艱積構壓醖淵) = 齋鑰醖糧夢夢鏇觸繭夢膚遞醖鏇遞鑰餘遞夢齋 (築艱選憲夢鏇壓鹹範廠, 壓顧壓膚鬱選繭製鬱觸 ~ 廠築窪繭築繭淵膚觸衊) 更多	-	2020-12-14