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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项与 Nerinetide 相关的文献（医药）

2026-01-01·INTERNATIONAL JOURNAL OF PHARMACEUTICS

Modifying the PSD-95 inhibitor NA-1 for brain delivery through proteolytic stabilization and conjugation to the potentially brain homing peptide BR1

Article

作者: Gammelgaard, Bente ; Brodin, Birger ; Andresen, Amalie Kjær ; Øie Solbak, Sara Marie ; Kristensen, Mie ; Kolberg, Hannah Grønbech ; Jensen, Camilla ; Thaysen, Maria

Delivering peptide-based therapeutics to the brain through systemic administration is limited by poor blood-brain barrier permeation, rapid proteolytic degradation, and off-target accumulation. The peptide NA-1, targeting PSD-95 interactions, holds promise for stroke treatment but suffers from these limitations. With this study, we explored whether complete D-amino acid substitution of NA-1 and conjugation to the potentially brain-homing peptide BR1 would improve NA-1 plasma stability and brain delivery, while retaining receptor binding and limiting off-target organ accumulation. Four peptide constructs, L- and D-versions of NA-1 and BR1-NA-1, were synthesized and characterized using circular dichroism spectroscopy, surface plasmon resonance, mouse plasma stability assays, cellular uptake studies, and biodistribution analysis in mice. D-amino acid substitution significantly enhanced peptide stability in plasma but compromised receptor binding and to some extent cellular uptake. L-BR1-NA-1 showed improved accumulation in whole brain lysates as compared to L-NA-1, however parenchymal delivery did not differ between the two peptides, indicating vascular retention of the L-BR1-NA-1 form. The present study demonstrated that substitution of L-amino acids with their D-amino acid counterparts improved the proteolytic stability of the constructs. However, this came at the expense of target affinity. BR1 conjugation to L-NA-1 might increase vascular retention, but did not increase parenchymal delivery, indicating that BR1 does not mediate transendothelial passage of the construct.

2025-12-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Development of cell-permeable and plasma-stable peptidomimetic inhibitors against PSD-95/nNOS interaction as potential anti-ischemic stroke agents

Article

作者: Qin, Yujiao ; Wang, Jiacheng ; Zhang, Lu ; Guo, Xiya ; Dong, Mingxin ; Ju, Han ; Liang, Ruiguo ; Zhou, Jie

The N-methyl-d-aspartate receptor (NMDAR)-neuronal nitric oxide synthase (nNOS)-postsynaptic density-95 (PSD-95) ternary complex represents a promising therapeutic target for acute ischemic stroke treatment. Although the shortest peptide ETAV targeting the PDZ2 domain of PSD-95 shows therapeutic potential, its limit in vivo stability restricts its broad application. Therefore, we herein systematically optimized and developed a series of novel peptidomimetics based on ETAV. We identified the optimal candidate compound 32-2, which displays potent neuroprotective effects in both HT22 cells (cell viability: 58.31 % at 10 μM) and primary cortical neurons (cell viability: 63.50 % at 20 μM). Mechanistically, 32-2 significantly reduced glutamate-induced intracellular ROS levels by 80 % compared to the glutamate-induced group, and modulated apoptotic markers (Bcl-2, Bax, cleaved-caspase 3). Furthermore, 32-2 exhibited potent plasma stability and excellent cellular permeability in vitro model. In the tMCAO model, 32-2 significantly reduced cerebral infarct volume compared to model group, being similar to NA-1. These findings establish 32-2 as the first effective peptidomimetic inhibitor of PSD-95 PDZ2 in vivo, offering a promising lead for developing novel stroke therapeutics.

2025-11-01·Brain and Behavior

Efficacy and Safety of Nerinetide in Acute Ischemic Stroke Patients: A Systematic Review, Meta‐Analysis and Meta Regression

Review

作者: Shams, Faizan ; Noor, Muaz ; Yousuf, Muhammad ; Somdev, FNU ; Samiullah, FNU ; Imran, Muhammad Junaid ; Malik, Waqar ; Chaulagain, Aayush ; Raja, Adarsh ; Khurram, Laiba ; Ubaid, Abdullah ; BS, Abdullah ; Ayalew, Biruk Demisse ; Kumar, Laksh ; Ji, Jodho

ABSTRACT:

Purpose:

Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. Nerinetide, a neuroprotective peptide, may limit ischemic brain injury. This systematic review and meta‐analysis evaluated the efficacy and safety of nerinetide versus placebo in patients with AIS.

Method:

Following the PRISMA and AMSTAR 2 guidelines, PubMed, MEDLINE, Cochrane Library, ScienceDirect, and ClinicalTrials.gov were searched until July 2025 for randomized controlled trials (RCTs) involving adult patients with AIS. The primary outcome was mortality, and secondary outcomes included functional recovery (modified Rankin Scale [mRS] scores of 0–1 and 0–2 and Barthel index scores of ≥95), infarct volume, and adverse events. Pooled risk ratios (RR) or mean differences (MD) were calculated using a random‐effects model, and meta‐regression was used to explore baseline moderators.

Findings:

Three RCTs ( n = 2462) were included in the analysis. Nerinetide showed a borderline significant mortality reduction versus placebo (RR = 0.86; 95% CI 0.75–1.00; p = 0.05) with low heterogeneity ( I2 = 11%). No significant differences were found in functional recovery or overall infarct volume, although subgroup analyses without reperfusion therapy suggested a possible benefit. The rates of adverse events, including serious events, thromboembolism, seizures, and hypotension, were similar between the groups. Meta‐regression indicated that atrial fibrillation ( p = 0.0489) and prior stroke ( p = 0.0519) were associated with a higher mortality risk.

Conclusion:

Nerinetide may modestly reduce mortality in AIS without increasing adverse events but does not significantly improve the functional outcomes. The benefits may be greater in patients who do not receive thrombolysis. Further large‐scale trials are warranted to clarify the optimal use and interactions with reperfusion therapies.

项与 Nerinetide 相关的新闻（医药）

2025-10-23

·三优生物医药

三优十周年｜神经系统疾病治疗进展

作者：金汉卿美工：何国红罗真真排版：马超 01 引言延长预期寿命可谓人类公共卫生领域最伟大的成就之一。然而，寿命的增长也伴随与年龄相关的神经系统疾病 (Neurological disorders) 负担不断攀升。神经系统疾病是指发生于中枢或周围神经系统、以感觉、意识、运动等功能受损为主要表现的一类疾病，整体呈现低病死率、高致残率的特点。就在2025年10月14日，世界卫生组织发布了新的《全球神经病学状况报告》1，报告显示神经系统疾病目前影响着全球40%以上的人口——超过30亿人，造成4.35亿伤残调整生命年 (DALY) ，使其成为全球疾病与残疾的主要原因。37种神经系统疾病共导致1180万人死亡、1.62亿年残疾生活年与2.72亿年寿命损失。本文聚焦若干神经系统疾病的治疗前沿，旨在为行业专业人士提供可操作的靶点开发参考。 ▲ 图1：影响神经系统疾病的全球负担2 02 阿尔兹海默病阿尔茨海默病 (Alzheimer’s disease, AD) 是一种以进行性认知障碍为核心表现的中枢神经系统退行性疾病。其病理特征包括淀粉样β (Aβ) 斑块沉积与Tau蛋白异常磷酸化/神经原纤维缠结，并常伴随神经炎症与突触功能障碍。近年，基于脑脊液/影像的病理分层逐步延伸至血液标志物 (如血浆p tau217) ，为早期识别与入组提供更可及的工具。 ▲ 图2：阿尔茨海默病的病理机制3 目前的治疗以对症药物 (胆碱酯酶抑制剂与NMDA受体拮抗剂) 和在早期人群中使用的疾病修饰疗法为主。抗Aβ单抗方面，lecanemab (Leqembi) 已在2023年获FDA批准，而donanemab (Kisunla) 也于2024年获FDA批准用于早期症状性AD (MCI/轻度痴呆) 并按月静脉给药。临床实践通常需要影像/体液证据确认Aβ阳性，并在治疗过程中进行MRI监测以管理ARIA。 • 药物前沿进展聚焦三条主线：抗Aβ策略升级：已上市抗体在早期人群显示减缓进展的临床获益。为实现更高的皮层暴露，罗氏开发Brainshuttle技术，通过偶联可结合转铁蛋白受体 (TfR) 的模块，显著提高穿透BBB能力与脑内分布。抗Tau与联合方案：多款抗Tau通路药物推进中。尽管单药结果不积极，但与Aβ清除形成序贯/联合方案，有望影响下游神经退行改变。炎症抑制与精准分层：围绕神经炎症的多靶点布局逐步成形。例如选择性中和可溶性TNF的XPro™/XPro1595：II期MINDFuL总体未达主要终点，但在炎症生物标志物富集的早期AD亚组出现认知、行为与生物学端点的获益信号，且安全性良好，提示“炎症表型分层”的精准用药方向。 ▲ 图3：阿尔茨海默病的在研药物靶点汇总 03 帕金森病帕金森病 (Parkinson’s disease, PD) 是一种影响中枢神经系统、以运动系统受累为主的慢性神经退行性疾病，症状通常缓慢进展。静止性震颤、肌强直、运动迟缓与步态异常常见于早期，也可伴随认知与行为改变。病理学上，以黑质多巴胺能神经元丢失及细胞内α‑突触核蛋白聚集为特征；早期退变多局限于腹外侧黑质，随病程推进而扩展。路易体主要由聚集的α‑突触核蛋白组成，病变通常自脑干胆碱能/单胺能神经元与嗅觉系统起始，随后累及边缘系统和新皮质。 ▲ 图4：帕金森病的病理机制4 现行治疗方面，左旋多巴及多巴胺替代治疗仍为金标准。早期可用左旋多巴单药，或联合多巴胺激动剂 (如罗匹尼罗、普拉克索、罗替戈汀) 及MAO‑B抑制剂 (如司来吉兰、雷沙吉兰) 。与早期左旋多巴单药相比，早期启用多巴胺激动剂对长期残疾与生活质量并无显著优势。对出现“开-关”波动者，常通过缩短左旋多巴给药间隔，联合COMT抑制剂 (恩他卡朋、阿匹卡朋) 和/或MAO-B抑制剂 (司来吉兰、雷沙吉兰、沙芬酰胺、唑尼沙胺) ，并调增多巴胺激动剂；若出现异动症，可加用金刚烷胺；部分合适人群可考虑设备辅助治疗以缩短“关”期并改善运动障碍。 • 药物/技术前沿主要包括：靶向α‑突触核蛋白的被动免疫：临床前可改善病理与行为。两项大型早期PD试验 (SPARK/cinpanemab与PASADENA/prasinezumab) 虽未达主要终点，PASADENA显示运动进展减缓趋势。基于2b期PADOVA及其OLE与PASADENA长随，罗氏已推进prasinezumab进入III期。 LRRK2降解/抑制策略：LRRK2为公认关键靶点。2025年10月8日，Arvinas公布ARV‑102 (LRRK2降解剂) I期积极数据，显示良好的脑脊液暴露与显著的靶蛋白下调 (外周>90%，脑脊液>50%) ，并伴随pRab10与尿BMP等下游生物标志物降低。基因治疗：AAV2‑GAD向丘脑底核递送在晚期PD中证实安全并带来治疗侧改善；AAV2‑AADC在壳核过表达可增强左旋多巴转化，6个月UPDRS (用药/停药) 约三成改善且用药剂量下降，但4年随访提示临床收益逐步回归基线，提示需进一步优化递送与联合策略。 ▲ 图5：帕金森病的在研药物靶点汇总 04 中风中风 (Stroke，脑卒中) 包括缺血性与出血性两大类，其中以缺血性为主。其发病机制中，缺血造成的级联反应涉及多种中枢神经系统细胞：在缺血核心，神经元发生形态改变，细胞体与轴突消失；小胶质细胞、星形胶质细胞亦随之发生反应性改变。缺血后BBB通透性增加，多种免疫细胞 (白细胞、单核细胞、巨噬细胞) 浸润病灶区，释放神经毒性或神经营养因子，对受损脑组织产生既可能保护亦可能有害的影响。 ▲ 图6：脑卒中的病理机制5 现行治疗策略强调“急性再灌注+二级预防”两端发力。针对急性期，发病4.5小时内静脉溶栓仍为基础。除阿替普酶外，多项指南与综述支持替奈普酶 (TNK) 0.25 mg/kg在部分场景作为替代选择；对大血管闭塞患者，借助灌注成像选择性入组，机械取栓时间窗可拓至6–24小时。针对二级预防，小卒中/高危TIA人群的短期双联抗血小板 (阿司匹林+氯吡格雷) 获益主要集中在起始后21天内；合并房颤者以口服抗凝 (优选DOACs) 为一线，无法长期抗凝者可考虑左心耳封堵 (LAAO) 作为替代或补充方案。 • 药物/技术前沿主要体现在：靶向药： 1. glenzocimab (抗GPVI) 旨在在降低血栓形成的同时控制出血风险； 2. 3K3A‑APC兼具神经与血管保护，早期研究显示良好安全性与出血相关指标改善信号； 3. nerinetide (PSD‑95抑制肽) 总体结论中性，但在未合用tPA或特定流程亚群显现潜在获益，提示存在人群与流程依赖性。细胞与基因治疗： 1. SB623 (基因改造间充质基质细胞) 用于慢性期功能重建显示上肢运动量表改善且安全性良好； 2. MultiStem (同种异体MAPC) 在18–36小时给药窗内安全可行，关键III期验证持续； 3. AAV递送 (如VEGF/神经营养因子/抗炎因子) 临床前证据积极，但跨BBB的安全与递送效率仍是转化瓶颈。 ▲ 图7：脑卒中的在研药物靶点汇总 05 其他神经系统疾病及治疗前沿除AD、PD与中风外，神经系统疾病还包括多发性硬化 (MS)、视神经脊髓炎谱系疾病 (NMOSD) 、肌萎缩侧索硬化 (ALS)、重症肌无力 (gMG) 、偏头痛等。随着靶向药与技术平台的演进，越来越多的创新疗法为不同疾病带来新的治疗希望： NMOSD：已有三条机制获批——补体C5抑制剂 (依库珠单抗/拉夫珠单抗) 、抗CD19 (伊妥珠单抗/inebilizumab) 、抗IL‑6R (沙妥利珠单抗/satralizumab) 。偏头痛：中枢敏化与CGRP通路为关键机制。美国头痛学会已将CGRP疗法 (艾伦单抗/芙马珠单抗/加拉单抗/艾普替单抗) 纳入一线预防选项。 gMG：FcRn拮抗剂 (efgartigimod、rozanolixizumab) 与补体C5抑制剂 (eculizumab、ravulizumab) 确立了分子靶向治疗范式，显著改善症状、加速缓解。 • 基因疗法亦加速进入临床：亨廷顿病 (HD)：等位基因选择性ASO (WVE‑003) 实现突变HTT下调且安全性可接受；AMT‑130 (AAV‑miHTT) I/II期长随提示疾病进展减缓信号。难治性癫痫：ASO上调SCN1A (zorevunersen/STK‑001) 在早期研究显示发作频率下降与行为/认知改善信号；基因调控疗法ETX101 (AAV9) 在SCN1A+德拉维特综合征进入I/II期；抑制性中间神经元细胞疗法NRTX‑1001在成人MTLE一期呈现发作显著降低与良好耐受性。脊髓性肌萎缩 (SMA)：已建立三大治疗支柱——ASO (nusinersen) 、基因疗法 (AAV9‑SMN1，onasemnogene abeparvovec) 与口服小分子剪接调节剂 (risdiplam) 。 06 神经系统疾病治疗总结神经系统疾病呈“低病死、高致残”特征，已成全球疾病负担首因。治疗正由对症控制走向“疾病修饰+精准分层”。阿尔茨海默病方面，抗Aβ单抗 (lecanemab、donanemab) 在早期人群证实减缓进展，血液标志物与穿越BBB的递送技术 (如Brainshuttle) 加速落地，抗Tau与抗炎 (如选择性中和可溶性TNF) 成为重要补充。帕金森病仍以多巴胺替代为基石，但围绕α-突触核蛋白的免疫、LRRK2抑制/降解与基因治疗正在逼近关键验证。中风治疗两端发力：急性期强调再灌注 (TNK与晚窗机械取栓) ，二级预防重视分型与个体化 (短期DAPT、DOACs、LAAO) 。除AD/PD/中风外，NMOSD、gMG、偏头痛已形成明确分子靶向范式；HD、癫痫、SMA等病种的基因/细胞疗法进展迅速。 • 针对神经系统疾病的未来治疗方向将聚焦于： ① 跨BBB递送与长效化——TfR介导、脑内暴露定量学、皮下长效制剂； ② 基因治疗——AAV/ASO精准调控与免疫规避，提升持续表达与安全窗； ③ AOC药物——抗体-寡核苷酸偶联，实现细胞/区域特异输送与基因沉默、上调或剪接校正，为难治性癫痫、遗传性运动障碍等提供新解。 Sanyou 10th Anniversary: Therapeutic Advances in Neurological Disorders 01 Introduction Extending life expectancy is one of humanity’s greatest public-health achievements. Yet longer lives come with a steadily rising burden of age-related neurological disorders. Neurological disorders—conditions of the central or peripheral nervous system characterized primarily by impairments of sensation, consciousness, and movement—generally have low case-fatality but high disability rates. On October 14, 2025, the World Health Organization released a new Global Status Report on Neurology1, estimating that neurological disorders currently affect over 40% of the world’s population—more than 3 billion people—and account for 435 million disability-adjusted life years (DALYs), making them the leading cause of disease and disability worldwide. Across 37 neurological conditions, there were 11.8 million deaths, 162 million years lived with disability, and 272 million years of life lost. This article highlights therapeutic frontiers across selected neurological diseases to provide actionable target ideas for R&D professionals. ▲ Fig. 1 Global burden of conditions affecting the nervous system2 02 Alzheimer’s Disease Alzheimer’s disease (AD) is a progressive, degenerative disorder of the central nervous system whose core clinical feature is cognitive decline. Pathology includes extracellular amyloid-β (Aβ) plaque deposition and abnormal phosphorylation of tau protein/neurofibrillary tangles, often accompanied by neuroinflammation and synaptic dysfunction. In recent years, pathology-based stratification via CSF/imaging has extended to blood biomarkers (e.g., plasma p-tau217), providing more accessible tools for early identification and trial enrollment. ▲ Fig. 2 Pathology of Alzheimer’s disease3 • Current therapies Management combines symptomatic agents (cholinesterase inhibitors and the NMDA receptor antagonist memantine) with disease-modifying therapy initiated in early-symptomatic populations. Among anti-Aβ monoclonal antibodies, lecanemab (Leqembi) received traditional FDA approval in 2023 with labeling that emphasizes ARIA risk and APOE ε4 stratification; donanemab (Kisunla) was approved in 2024 for early symptomatic AD (MCI/mild dementia) and is administered as monthly IV infusions. In clinical practice, Aβ positivity is typically confirmed by imaging or fluid biomarkers, and MRI monitoring is used during treatment to manage ARIA. • Frontline R&D themes Upgrading anti-Aβ strategies. Marketed antibodies show clinically meaningful slowing in early-stage populations. To achieve higher cortical exposure, Roche is developing Brainshuttle technology by coupling to transferrin receptor (TfR)–binding modules, markedly improving BBB penetration and brain distribution. Anti-tau and combination/sequencing. Multiple programs targeting tau pathways are advancing. Although monotherapy results have been mixed, pairing with Aβ clearance in sequential/combination regimens may modulate downstream neurodegeneration. Inflammation control with precise stratification. A growing multi-target portfolio focuses on neuroinflammation. For example, selective neutralization of soluble TNF with XPro™/XPro1595 missed the primary endpoint in the phase II MINDFuL study overall, but showed signals of benefit across cognitive, behavioral, and biomarker endpoints in an inflammation-enriched early-AD subgroup with good safety—supporting “inflammatory phenotype stratification” for precision use. ▲ Fig. 3 Drug targets under development for Alzheimer’s disease 03 Parkinson’s Disease Parkinson’s disease (PD) is a chronic neurodegenerative disorder primarily affecting the motor system with typically slow progression. Early features include resting tremor, rigidity, bradykinesia, and gait disturbance, often with cognitive/behavioral changes. Pathology features loss of dopaminergic neurons in the substantia nigra and intracellular α-synuclein aggregation; early degeneration is often localized to the ventrolateral substantia nigra and expands with disease. Lewy bodies are mainly composed of aggregated α-synuclein, with lesions commonly starting in brainstem cholinergic/monoaminergic neurons and the olfactory system, then involving limbic structures and neocortex. ▲ Fig. 4 Pathology of Parkinson’s disease4 • Current therapies There is no established disease-modifying therapy. Levodopa and dopamine replacement remain the gold standard. Early treatment can be levodopa monotherapy or combined with dopamine agonists (e.g., ropinirole, pramipexole, rotigotine) and MAO-B inhibitors (e.g., selegiline, rasagiline). Compared with early levodopa monotherapy, starting dopamine agonists early shows no clear advantage for long-term disability or quality of life. For “on–off” fluctuations, clinicians often shorten levodopa dosing intervals, add COMT inhibitors (entacapone, opicapone) and/or MAO-B inhibitors (selegiline, rasagiline, safinamide, zonisamide), and titrate dopamine agonists; amantadine may be added for dyskinesia. Device-aided therapies can be considered in selected patients to reduce “off” time and improve motor complications. • Frontline R&D themes Passive immunotherapy against α-synuclein. Preclinical data show improvements in pathology and behavior. Although two large early-PD trials (SPARK/cinpanemab and PASADENA/prasinezumab) missed primary endpoints, PASADENA showed a trend toward slower motor progression. Based on phase 2b PADOVA and its OLE plus long-term PASADENA follow-up, Roche has advanced prasinezumab into phase III. LRRK2 inhibition/degradation. LRRK2 is a validated target. On October 8, 2025, Arvinas reported positive phase I data for the LRRK2 degrader ARV102, showing good CSF exposure and robust target knock-down (>90% peripherally, >50% in CSF) with reductions in downstream biomarkers (pRab10 and urinary BMP). Gene therapy. AAV2-GAD delivery to the subthalamic nucleus showed safety and improvement on the treated side in advanced PD; AAV2-AADC overexpression in the putamen enhances levodopa conversion, producing ~30% improvement in UPDRS (on/off medication) at 6 months and reduced medication needs, though 4-year follow-up suggests benefits trend back toward baseline—highlighting the need to optimize delivery and combinations. ▲ Fig. 5 Drug targets under development for Parkinson’s disease 04 Stroke Stroke comprises ischemic and hemorrhagic types, with ischemic stroke predominating. The ischemic cascade involves multiple CNS cell types: in the core, neurons undergo morphological changes with loss of soma and axons; microglia and astrocytes also react. Post-ischemia, BBB permeability increases; leukocytes, monocytes, and macrophages infiltrate the lesion, releasing either neurotoxic or neurotrophic factors with potentially protective or harmful effects on injured brain tissue. ▲ Fig. 6 Pathology of stroke5 • Current strategies Management emphasizes both acute reperfusion and secondary prevention. For the acute phase, IV thrombolysis within 4.5 hours remains foundational. Beyond alteplase, guidelines and reviews support tenecteplase (TNK) 0.25 mg/kg as an alternative in selected scenarios. For large-vessel occlusion, perfusion-imaging–guided selection enables mechanical thrombectomy in the 6–24 hour window. For secondary prevention, short-term dual antiplatelet therapy (aspirin + clopidogrel) in minor stroke/high-risk TIA confers most of its benefit within 21 days of initiation. In patients with atrial fibrillation, oral anticoagulation (preferably DOACs) is first-line; when long-term anticoagulation is unsuitable, left atrial appendage occlusion (LAAO) can be considered as an alternative or adjunct. • Frontline R&D themes Targeted agents： 1. glenzocimab (anti-GPVI): aims to curb thrombosis while controlling bleeding risk. 2. 3K3A-APC: offers neuro- and vasculo-protection; early studies suggest good safety and favorable bleeding-related signals. 3. nerinetide (PSD-95 inhibitor peptide): neutral overall, but potential benefit in subgroups not receiving tPA or under specific workflow conditions—suggesting population/process dependence. Cell and gene therapies：1. SB623 (gene-modified mesenchymal stromal cells) for chronic-phase functional recovery improved upper-limb scales with good safety. 2. MultiStem (allogeneic MAPC) appears safe/feasible with dosing at 18–36 hours; pivotal phase III confirmation is ongoing. 3. AAV delivery (e.g., VEGF/neurotrophic/anti-inflammatory factors) shows encouraging preclinical evidence, but safe and efficient BBB crossing remains a translational bottleneck. ▲ Fig. 7 Drug targets under development for stroke 05 Other Neurological Diseases and Therapeutic Frontiers Beyond AD, PD, and stroke, neurological disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), amyotrophic lateral sclerosis (ALS), generalized myasthenia gravis (gMG), migraine, and more. With the evolution of targeted drugs and platform technologies, an expanding array of innovative therapies is delivering new hope:NMOSD: Three approved mechanisms—complement C5 inhibitors (eculizumab/ravulizumab), anti-CD19 (inebilizumab), and anti-IL-6R (satralizumab). Migraine: Central sensitization and the CGRP pathway are key. The American Headache Society now lists CGRP-pathway therapies (erenumab, fremanezumab, galcanezumab, eptinezumab) as first-line options for prevention. gMG: FcRn antagonists (efgartigimod, rozanolixizumab) and complement C5 inhibitors (eculizumab, ravulizumab) have established a molecularly targeted paradigm, improving symptoms and accelerating remission. • Gene and cell therapies accelerating into the clinicHuntington’s disease (HD): Allele-selective ASO WVE-003 lowers mutant HTT with acceptable safety; AMT-130 (AAV-miHTT) phase I/II long-term follow-up suggests signals of slowed disease progression. Refractory epilepsy: ASO zorevunersen/STK-001 upregulates SCN1A with early signals of seizure reduction and behavioral/cognitive improvement; gene-regulation therapy ETX101 (AAV9) has entered phase I/II for SCN1A-positive Dravet syndrome; an inhibitory interneuron cell therapy NRTX1001 in adult MTLE phase I shows marked seizure reduction with good tolerability. Spinal muscular atrophy (SMA): A tri-pillar framework is established—ASO (nusinersen), gene therapy (onasemnogene abeparvovec, AAV9-SMN1), and oral small-molecule splicing modulation (risdiplam). 06 Summary of Therapeutic Directions Neurological disorders feature low mortality but high disability , now the top contributor to global disease burden. Treatment is shifting from symptomatic control to disease modification with precise stratification.AD: Anti-Aβ antibodies (lecanemab, donanemab) slow progression in early populations; blood biomarkers and BBB-shuttling technologies (e.g., Brainshuttle) are moving into practice. Anti-tau and anti-inflammatory approaches (e.g., selective neutralization of soluble TNF) are important complements. PD: Dopamine replacement remains foundational, while α-synuclein immunotherapy, LRRK2 inhibition/degradation, and gene therapy approach key validation milestones. Stroke: Dual-pronged care—acute reperfusion (TNK and extended-window thrombectomy) and individualized secondary prevention (short-term DAPT, DOACs, LAAO). Others: NMOSD, gMG, and migraine already have clear targeted paradigms; gene/cell therapies are rapidly advancing in HD, epilepsy, SMA, and beyond. • Future priorities will focus on1. Cross-BBB delivery and durability—TfR-mediated shuttles, quantitative CNS exposure, and long-acting subcutaneous formulations. 2. Gene therapy—AAV/ASO precision control with immune evasion, enhancing persistence and safety margins. 3. AOC (antibody–oligonucleotide conjugates)—cell/region-specific delivery enabling gene silencing, up-regulation, or splice correction, offering new solutions for refractory epilepsy, inherited movement disorders, and more. ▶ Ref 1. Global status report on neurology 2. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(4):344-381. doi:10.1016/S1474-4422(24)00038-3 3. Kamatham PT, Shukla R, Khatri DK, Vora LK. Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier. Ageing Res Rev. 2024;101:102481. doi:10.1016/j.arr.2024.102481 4. Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson's disease. Lancet. 2024;403(10423):293-304. doi:10.1016/S0140-6736(23)01478-2 5. Qin C, Yang S, Chu YH, et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022;7(1):215. Published 2022 Jul 6. doi:10.1038/s41392-022-01064-1 1 推荐阅读三优十周年｜AI-STAL 智能超万亿分子库发展历程三优十周年｜打造全球顶尖的原创新药创新工场三优十周年｜抗体治疗50年风雨江湖三优十周年｜针对宠物疾病的单克隆抗体药物三优十周年｜CAR-T细胞治疗现状挑战与未来三优十周年｜服务篇-体外药效筛选解决方案三优十周年｜AI-STAL篇-Anticalin靶向蛋白库三优十周年｜靶点篇-自身免疫疾病靶点介绍创新前沿｜三优生物类器官产学研联盟启航中和抗体“硬核出击”，斩断CHIKV病毒感染链三优十周年｜服务篇-靶点至PCC药物研发三优十周年｜靶点篇-六大恶性肿瘤靶点介绍创新前沿｜2025ADC热门靶点与技术创新启示三优十周年｜AI-STAL篇-高等电点单域抗体库 6类分子形式之环状多肽分子产生系统解决方案关于三优生物三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。 11

临床研究临床结果

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

2022-11-22

·nonoinc.ca

NoNO Inc. Announces First Patient Dosed with NoNO-42 in a First in Humans Phase 1 Study

TORONTO, Nov 22, 2022 – NoNO Inc. is pleased to announce the dosing of the first participant in its Phase 1 clinical trial evaluating NoNO-42. NoNO-42 is the next generation drug developed in NoNO’s PSD-95 inhibitor platform. It is intended for the treatment of all people experiencing an acute ischemic stroke. The first in human study with NoNO-42 will evaluate the safety, tolerability and pharmacokinetics of single ascending doses of NoNO-42 in consecutive cohorts of healthy volunteers. NoNO-42 builds on NoNO’s ground-breaking results for its first-generation PSD-95 inhibitor, nerinetide. In the Phase 3 ESCAPE-NA1 trial, participants who were treated with nerinetide but not with thrombolytics (“clot-busters”) exhibited improved functional independence, reduced stroke mortality, and reduced brain damage on medical imaging. ESCAPE-NA1 was conducted in stroke in patients who were selected to undergo endovascular thrombectomy, a treatment in which the blood clots causing the stroke are removed in order to restore blood flow to the brain. The study provided evidence that such patients may benefit from nerinetide if they are not previously treated with thrombolytics. However, in patients who had already received thrombolytic treatment nullified the efficacy of nerinetide. The results in the no-thrombolytic arm are currently under confirmatory testing in the ongoing Phase 3 ESCAPE-NEXT trial. NoNO-42 was developed to be administered with or without thrombolytic agents. It extends the potential benefits of PSD-95 inhibition to those patients who, in ESCAPE-NA1 were previously treated with thrombolytics and therefore could not benefit from nerinetide. “The Phase 1 trial of NoNO-42 is a key milestone in extending the benefits of PSD-95 inhibition all acute ischemic stroke patients. Given NoNO-42’s similarities to nerinetide in all material clinical aspects other than its expected efficacy with or without thrombolytics, success with current pivotal trials with nerinetide will de-risk NoNO-42 development substantially” said Dr. Michael Tymianski, President, CEO and founder of NoNO Inc. “The stroke neurology community is extremely excited about the prospects of both nerinetide and NoNO-42, and the academic community is eager to follow-up ESCAPE-NEXT with clinical trials to investigate the efficacy of NoNO-42 in stroke patients” said Dr. Michael Hill, MD, Global Principal Investigator and Professor of Neurology at the Cumming School of Medicine, University of Calgary. NoNO Inc. is a clinical stage, stroke-focused Ontario biotechnology company dedicated to offering people who experience stroke opportunities for a better life. NoNO’s therapeutic strategy is to inhibit key protein-protein interactions of PSD-95 that are involved selectively in cellular signals that cause stroke damage, but without interfering with normal cell functions. Our PSD-95 inhibitor platform consists of: Nerinetide, NoNO’s lead compound for people experiencing an ischemic stroke, currently completing its second global Phase 3 trail in people not previously treated with a clot dissolving drug. NoNO-42, in Phase 1 for use alongside clot dissolving drugs for all people experiencing ischemic stroke. NoNO-SC, administered subcutaneously to enable the treatment of people experiencing stroke outside of medical setting by anyone – anywhere. For more information, please visit www.nonoinc.ca.

临床1期临床3期临床2期

100 项与 Nerinetide 相关的药物交易

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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	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
颅内动脉瘤	临床2期	美国	NoNO, Inc.	2015-11-01
颅内动脉瘤	临床2期	加拿大	NoNO, Inc.	2015-11-01

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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


NCT04462536 (ESCAPE-NEXT, CTgov)	临床3期	急性缺血性卒中	850	Placebo (Placebo)	網夢醖鬱齋憲餘獵憲繭 = 獵鏇窪蓋鏇齋繭襯壓範鬱糧醖蓋鹽鑰鹽簾願淵 (觸積艱蓋顧鬱製齋憲製, 襯獵糧顧醖淵壓鏇餘齋 ~ 鹽築憲簾壓蓋鬱遞築鹽) 更多	-	2025-06-22
				Nerinetide (Nerinetide)	網夢醖鬱齋憲餘獵憲繭 = 鑰鹹糧夢鹹糧艱繭餘築鬱糧醖蓋鹽鑰鹽簾願淵 (觸積艱蓋顧鬱製齋憲製, 範膚簾醖鹹齋蓋廠夢獵 ~ 鏇憲構淵壓構淵製蓋憲) 更多
NCT02930018 (ESCAPE-NA1, Pubmed \| Neurology)	临床3期	脑卒中	-	Nerinetide	衊鹽顧願鏇窪顧淵鑰鏇(醖憲積襯鬱窪鬱鏇構鹽) = 憲構衊壓鏇範鑰鹽觸鑰遞蓋願壓範壓齋蓋構夢 (膚夢積願鹽糧膚鏇夢艱, 1.09 ~ 21.30) 更多	不佳	2024-01-23
				Placebo	衊鹽顧願鏇窪顧淵鑰鏇(醖憲積襯鬱窪鬱鏇構鹽) = 製鹽築壓廠築遞壓網襯遞蓋願壓範壓齋蓋構夢 (膚夢積願鹽糧膚鏇夢艱, 2.54 ~ 21.81) 更多
NCT00728182 (ENACT, AAN2022)	临床2期	脑梗塞	184	Nerinetide treatment	獵膚獵夢鏇願構鹹淵觸(鹹夢選獵鹹餘簾膚範壓): P-Value = 0.020 更多	积极	2022-05-03
				Placebo
NCT02930018 (REPERFUSE-NA1, ISC2022)	临床3期	梗塞	71	NA1	網鹽壓齋淵鏇膚衊簾襯(艱鑰蓋憲憲壓鹽憲衊繭) = 壓觸範鏇壓壓製襯網顧鬱齋窪夢蓋夢蓋淵衊壓 (範製憲鹽窪糧憲獵繭襯, 5.9 ~ 28.1) 更多	-	2022-02-01
				Placebo	網鹽壓齋淵鏇膚衊簾襯(艱鑰蓋憲憲壓鹽憲衊繭) = 壓遞憲鬱簾壓憲網壓遞鬱齋窪夢蓋夢蓋淵衊壓 (範製憲鹽窪糧憲獵繭襯, 3.1 ~ 27.0) 更多
NCT02930018 (ESCAPE-NA1 \| REPERFUSE-NA1, CTgov)	临床3期	急性缺血性卒中	1,105	Placebo	願願鹽鑰壓膚廠鬱鏇顧 = 願選網獵積願範繭壓淵膚淵鬱構淵壓製膚願觸 (積築獵艱築齋糧膚鹽選, 淵齋廠積顧糧鹽構衊繭 ~ 鏇構製簾網糧糧廠夢膚) 更多	-	2020-12-14
NCT02930018 (ESCAPE-NA1, Pubmed \| Lancet) 人工标引	临床3期	急性缺血性卒中	1,105	nerinetide	鹹範鑰齋醖願築餘糧遞(廠艱獵願積窪築醖網糧) = Serious adverse events occurred equally between groups. 獵齋構製鹹鬱鏇築積鏇 (願憲廠鹹齋壓壓繭淵簾 ) 更多	不佳	2020-03-14
				Placebo
NCT00728182 (ENACT, CTgov)	临床2期	脑卒中 \| 动脉瘤 \| 缺血性卒中 ... 更多	185	NA-1 (1 NA-1)	餘觸鹽鏇鏇膚齋築憲簾(齋製餘壓築膚鬱積蓋壓) = 衊簾願網廠餘願膚顧廠鑰夢衊獵獵簾夢鑰鏇鬱 (鬱鬱築襯鏇糧淵襯觸壓, 5598) 更多	-	2013-10-17
				placebo (2 Placebo)	餘觸鹽鏇鏇膚齋築憲簾(齋製餘壓築膚鬱積蓋壓) = 夢選齋壓膚願壓遞顧築鑰夢衊獵獵簾夢鑰鏇鬱 (鬱鬱築襯鏇糧淵襯觸壓, 1611) 更多