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]

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.

NCT02315443 / Completed临床3期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Intravenous NA-1 Initiated by Paramedics in the Field for Acute Cerebral Ischemia Within Three Hours of Symptom Onset

The purpose of this study is to determine whether nerinetide (NA-1) is effective in reducing global disability in patients with acute cerebral ischemia if administered early after symptom onset.

开始日期2015-03-26

申办/合作机构

NoNO, Inc.

[+7]

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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项与 Nerinetide 相关的文献（医药）

2024-01-23·Neurology

Infarct Evolution on MR-DWI After Thrombectomy in Acute Stroke Patients Randomized to Nerinetide or Placebo

Article

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

BACKGROUND AND OBJECTIVES:

The 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.

METHODS:

REPERFUSE-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.

RESULTS:

Sixty-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.

DISCUSSION:

This 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 INFORMATION:

ClinicalTrials.gov NCT02930018.

CLASSIFICATION OF EVIDENCE:

This 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.

2024-01-01·Brain research bulletin

PSD-95 inhibitor Tat-NR2B9c (NA-1) protects the integrity of the blood-brain barrier after transient middle artery occlusion in rats by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase

Article

作者: Xu, Tong ; Xu, Ye ; Zhao, Meiqi ; Xu, Chunfei ; Xia, Lingfan ; Cao, Yungang ; Han, Zhao ; Wu, Yucong ; Xu, Lu

BACKGROUND:

Protection against ischemic stroke may be most effective when multiple components of the neurovascular unit are protected, yet current treatments target mainly neurons. Here we explored whether the PSD-95 inhibitor Tat-NR2B9c (NA-1) can protect not only neurons but also the blood-brain barrier.

METHODS:

Adult male Sprague-Dawley rats were randomly divided into three groups, which were subjected to either sham surgery or transient cerebral ischemia-reperfusion, after which some animals were treated with Tat-NR2B9c. The therapeutic efficacy of Tat-NR2B9c was assessed in terms of the degree of neurological deficit and cerebral infarction, integrity of the blood-brain barrier, cerebral water content, as well as expression of PSD-95, nitric oxide synthase, and matrix metalloprotease-9.

RESULTS:

Tat-NR2B9c (NA-1) ameliorated neurofunctional deficit, reduced cerebral infarction, mitigated blood-brain barrier injury and improved its integrity following ischemia-reperfusion, leading to less cerebral edema. These improvements were associated with upregulation of tight junction proteins in the blood-brain barrier. At the same time, Tat-NR2B9c (NA-1) downregulated neuronal nitric oxide synthase and matrix metalloprotease-9, while reversing the ischemia-induced downregulation of endothelial nitric oxide synthase in brain. We report here the first evidence that PSD-95 is expressed in vascular endothelial cells in the brain.

CONCLUSION:

Our experiments in a rat model of transient occlusion of the middle cerebral artery suggest that Tat-NR2B9c (NA-1) can mitigate ischemic injury to the blood-brain barrier, and that it may do so by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase.

2023-10-10·Neurology

Association of Brain Atrophy With Functional Outcome and Recovery Trajectories After Thrombectomy

Article

作者: Benali, Faysal ; Fladt, Joachim ; Goyal, Mayank ; Hill, Michael D ; Singh, Nishita ; Jaroenngarmsamer, Tanaporn ; Ganesh, Aravind ; Ospel, Johanna Maria ; Tymianski, Michael ; Bala, Fouzi

BACKGROUND AND OBJECTIVES:

Brain frailty may impair the ability of acute stroke patients to cope with the injury, irrespective of their chronologic age, resulting in impaired recovery. We aim to investigate the impact of brain atrophy on functional outcome assessed at different time points after endovascular thrombectomy (EVT).

METHODS:

In this retrospective post hoc analysis of the ESCAPE-NA1 trial, we analyzed CT imaging data for cortical atrophy by using the GCA scale, including region-specific scales, and subcortical atrophy by using the intercaudate distance to inner table width (CC/IT) ratio. The primary outcome was 90-day mRS (ordinal shift analysis), and the secondary outcome was the mRS score over time. Adjustments were made for age, sex, baseline NIHSS, final infarct volume, stroke laterality, total Fazekas score, and nerinetide-alteplase interaction. Sensitivity analyses were additionally performed in only those patients for whom MRI data were available.

RESULTS:

Of 1,102 participants (mean age of 69.5 ± 13.7 years; 554 men), 818 (74%) had GCA = 0, 220 (20%) had GCA = 1, and 64 (6%) had GCA = 2/3. The median CC/IT ratio was 0.12 (IQR0.10-0.15). Cortical atrophy (GCA ≥ 1 vs GCA 0) was associated with worse 90-day mRS (acOR = 1.62 [95% CI 1.22-2.16]; p = 0.001), lower rates of 90-day mRS0-2 (aOR = 0.65 [95% CI 0.45-0.94]; p = 0.022), and higher mortality (aOR = 2.12 [95% CI 1.28-3.5]; p = 0.003), regardless of the region assessed. Subcortical atrophy was associated with worse 90-day mRS (acOR [per 0.01 increase in CC/IT ratio] = 1.07 [95% CI 1.04-1.11]; p < 0.001) and lower rates of 90-day mRS0-2 (aOR = 0.92 [95% CI 0.88-0.97]; p = 0.001). Furthermore, with various degrees of atrophy, we observed heterogeneity in mRS measurements during follow-up: worse mRS scores for higher atrophy grades (p < 0.001). Compared with participants with GCA = 0, the mRS for participants with GCA = 1 was higher at 30 days (adjusted difference = 0.41 [95% CI 0.18-0.65]) and remained worse at 90 days (adjusted difference = 0.72 [95% CI 0.49-0.95]). Similar effects were seen for participants with worse cortical atrophy, regardless of the region assessed, and worse subcortical atrophy. Furthermore, 26/63(41%) and 124/274(45%) patients with severe cortical/subcortical atrophy (GCA 2/3 and highest CC/IT ratio quartile, respectively) achieved good functional outcome (mRS0-2), compared with 539/812(66.4%) with no cortical atrophy and 209/274(76%) in the lowest CC/IT ratio quartile.

DISCUSSION:

In this large RCT-derived population, participants with brain atrophy, as visually assessed on acute noncontrast computed tomography imaging, showed less favorable stroke recovery after EVT and worse 90-day functional outcomes compared with participants without brain atrophy. This may support physicians with recovery expectations when planning post-EVT care with patients and their families.

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.libproxy1.nus.edu.sg/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

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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	美国	NoNO, Inc.	2017-03-01
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	加拿大	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	爱尔兰	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	韩国	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	瑞典	NoNO, Inc.	2017-03-01
急性缺血性卒中	临床3期	英国	NoNO, Inc.	2017-03-01
脑缺血	临床3期	加拿大	NoNO, Inc.	2015-03-26
动脉瘤破裂	临床2期	美国	NoNO, Inc.	2015-11-01

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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	廠願鏇憲繭餘襯遞鹽範(壓觸淵憲構獵艱夢製窪) = 積觸鹹製憲觸願積衊獵夢衊糧艱蓋醖壓壓襯壓 (選艱膚蓋夢膚餘繭製窪, 5.9 ~ 28.1) 更多	-	2022-02-01
				Placebo	廠願鏇憲繭餘襯遞鹽範(壓觸淵憲構獵艱夢製窪) = 夢齋願壓鹽構膚願鑰鏇夢衊糧艱蓋醖壓壓襯壓 (選艱膚蓋夢膚餘繭製窪, 3.1 ~ 27.0) 更多
ESCAPE NA1-Trial (ISC2021)	N/A	脑卒中 \| 闭塞	1,105	Nerinetide	築遞範鏇襯範鹽壓淵膚(鏇鏇網鬱網鹹鹽鹽觸淵) = 選鬱窪夢廠遞廠鏇糧鏇選獵願廠願遞顧鏇衊製 (糧鹽餘範鹽廠積顧餘築 )	-	2021-03-01
				Placebo	築遞範鏇襯範鹽壓淵膚(鏇鏇網鬱網鹹鹽鹽觸淵) = 製選願艱襯窪鏇鹹醖夢選獵願廠願遞顧鏇衊製 (糧鹽餘範鹽廠積顧餘築 )
NCT02930018 (ESCAPE-NA1, Pubmed) 人工标引	临床3期	急性缺血性卒中	1,105	nerinetide	願範憲壓網獵願範願獵(鑰廠糧遞淵鹹網淵繭蓋) = Serious adverse events occurred equally between groups. 艱壓膚觸餘壓鹹積壓鏇 (繭簾網築顧範遞衊網觸 ) 更多	不佳	2020-03-14
				Placebo
NCT00728182 (CTgov)	临床2期	脑卒中 \| 动脉瘤	185	NA-1 (1 NA-1)	獵淵廠艱網衊獵範壓淵(網壓鏇廠觸顧糧範獵簾) = 鹹鬱憲積簾醖蓋壓壓願壓艱餘繭鏇淵膚築夢醖 (鹹範夢餘繭淵鹽廠糧積, 憲築鹹夢鹹鏇繭窪膚觸 ~ 顧夢鹽製衊衊範憲積膚) 更多	-	2013-10-17
				placebo (2 Placebo)	獵淵廠艱網衊獵範壓淵(網壓鏇廠觸顧糧範獵簾) = 製鹽範繭繭齋鬱鬱齋齋壓艱餘繭鏇淵膚築夢醖 (鹹範夢餘繭淵鹽廠糧積, 淵製繭遞壓繭窪觸顧艱 ~ 壓網鏇憲艱鹹鬱醖淵製) 更多