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).

Start Date06 Dec 2020

Sponsor / Collaborator

NoNO, Inc.

[+1]

NCT02930018

/ CompletedPhase 3

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.

Start Date01 Mar 2017

Sponsor / Collaborator

NoNO, Inc.

[+1]

NCT02056574

/ WithdrawnPhase 2

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.

Start Date01 Nov 2015

Sponsor / Collaborator

NoNO, Inc.

100 Clinical Results associated with Nerinetide

100 Translational Medicine associated with Nerinetide

100 Patents (Medical) associated with Nerinetide

Literatures (Medical) associated with Nerinetide

01 Dec 2025·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

Author: Qin, Yujiao ; Wang, Jiacheng ; Zhang, Lu ; Dong, Mingxin ; Guo, Xiya ; 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.

01 Nov 2025·Brain and Behavior

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

Review

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

26 Aug 2025·NEUROLOGY

Incidence, Associations, and Mechanisms of Unexplained Early Neurologic Deterioration After Thrombectomy in Stroke Patients

Article

Author: Sohn, Sung-II ; Mandzia, Jennifer L. ; Kleinig, Timothy J. ; Bang, Oh Young ; Swartz, Richard H. ; Nagel, Simon ; Nogueira, Raul G. ; Frei, Donald F. ; Camden, Marie-Christine ; Zerna, Charlotte ; Demchuk, Andrew ; Starkman, Sidney ; Heck, Donald ; Burns, Paul A. ; Jadhav, Ashutosh ; English, Joey D. ; Hill, Michael D. ; McTaggart, Ryan A. ; Teitelbaum, Jeanne ; Field, Thalia S. ; Lopez, George ; Campbell, Bruce C.V. ; Popper, Alexander Y. ; Shah, Ruchir A. ; Heo, Ji Hoe ; Psychogios, Marios-Nikos ; Puetz, Volker ; Tarpley, Jason W. ; Pensato, Umberto ; Parrella, David Turkel ; Phillips, Stephen J. ; Joshi, Manish ; Almeklhafi, Mohammed ; Holmin, Staffan ; Bharatha, Aditya ; Schindler, Joseph L. ; Murphy, Sean ; Rha, Joung-Ho ; Ospel, Johanna Maria ; Gupta, Rishi ; Thornton, John ; Puri, Ajit S. ; Silver, Frank L. ; Choe, Hana ; Dowlatshahi, Dar ; Budzik, Ronald ; Butcher, Kenneth S. ; Thomalla, Gotz ; Menon, Bijoy ; Chapot, Rene ; Buck, Brain H. ; Coutts, Shelagh B. ; Martin, Coleman O. ; Sahlas, Demetrios J. ; McDougall, Cameron G. ; Sauvageau, Eric ; Goyal, Mayank ; van Adel, Brain ; Kelly, Micheal E.

BACKGROUND AND OBJECTIVES:

Early neurologic deterioration (END) in ischemic stroke after endovascular thrombectomy (EVT) is a frequent complication that remains unexplained in most cases. We aimed to explore the incidence of, and associated variables with, unexplained END (unEND).

METHODS:

This is a post hoc analysis of the ESCAPE-NA1 trial, a double-blind, multicentric, randomized clinical trial evaluating nerinetide vs placebo in adult ischemic stroke patients with anterior circulation large vessel occlusion treated with EVT. END was defined as an increase of ≥4 points in the NIH Stroke Scale score between baseline or 2-6 hours after EVT (whichever was the lowest) and 24-hour assessment. The primary outcome was unEND, defined as END without associated hemorrhagic or thrombotic/thromboembolic events. Backward stepwise multivariable logistic regression was used to identify baseline variables independently associated with unEND. In the CT perfusion (CTP) subgroup, regression analysis adjusted for baseline covariates was used to assess the association between unEND and infarct extension beyond the penumbra (IEBP), defined as a follow-up infarct volume larger by at least 10 mL than the initial critically hypoperfused tissue volume (time-to-maximum >6-second volume).

RESULTS:

Overall, 1063 patients were included in this study; the median age was 70.8 years (interquartile range 60.7-79.7), and 526 (49.5%) were women. Among them, 172 (16.2%) experienced END: 20 (11.6%) had an associated thrombotic/thromboembolic event, 27 (15.7%) had an associated hemorrhagic event, 8 (4.7%) had both associated thrombotic/thromboembolic and hemorrhagic events, and 117 (68.0%) had an unEND (overall incidence of unEND = 11.0%). Variables independently associated with unEND were anesthesia use (adjusted odds ratio [aOR] 7.23, 95% CI 4.63-11.30), age (aOR 1.02, 95% CI 1.01-1.04 per 1-year increase), and onset-to-reperfusion time (aOR 1.02, 95% CI 1.01-1.03 per 10-minute increase). In patients with available baseline CTP (n = 410), unEND was associated with the presence of IEBP (OR 6.81, 95% CI 2.58-18.01) and larger IEBP volume (OR 1.07, 95% CI 1.01-1.13 per 10-mL increase).

DISCUSSION:

UnEND occurred in approximately 10% of large vessel occlusion thrombectomy patients and was associated with older age, longer onset-to-reperfusion time, and anesthesia use. Patients who experienced IEBP, that is, 24-hour infarct volume extension beyond the initial hypoperfused tissue, were 7 times more likely to develop unEND.

News (Medical) associated with Nerinetide

22 Nov 2022

·www.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.

Phase 1Phase 3Phase 2

22 Mar 2022

·www.nonoinc.ca

NoNO Inc. Announces the Start of the Global Phase 3 ESCAPE-NEXT Trial of the Peptide Nerinetide in Acute Ischemic Stroke Excluding Thrombolysis

TORONTO, Dec 6, 2020 – NoNO Inc. is pleased to announce the enrollment of the first patient in the ESCAPE-NEXT trial, NoNO’s second global phase 3 trial of its lead peptide, Nerinetide. ESCAPE-NEXT is 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 (EVT). ESCAPE-NEXT is informed by the ESCAPE-NA1 trial which suggested that treatment with nerinetide may improve functional independence, reduce stroke mortality, and reduce brain damage due to stroke in patients who undergo EVT without the prior administration of thrombolytic (“clot busting”) agents. ESCAPE-NA1 results were presented at the 2020 International Stroke Conference in February. “Our prior trial showed us which stroke patients may benefit from nerinetide. ESCAPE-NEXT is a further pivotal study, focused on those patients, and is intended to confirm the promising findings of clinical benefits suggested by ESCAPE-NA1. ESCAPE-NEXT has a substantially similar design, but focuses on those patients who may experience the greatest benefit from nerinetide” said Dr. Michael Tymianski, President, CEO and founder of NoNO Inc. “We are exploring a novel mechanism of action for a new drug in a very common, but devasting disease. A new drug for acute ischemic stroke has the potential to further transform stroke therapeutics,” said Dr. Michael Hill, MD, Global Principal Investigator and Professor of Neurology at the Cumming School of Medicine, University of Calgary. ESCAPE-NEXT is designed to evaluate the clinical benefits of nerinetide in acute stroke patients who are selected for endovascular revascularization without prior treatment with intravenous thrombolytic therapy. The trial will enroll adult participants in the USA, Canada, Europe and Australia. It has an initial enrollment target of 680 participants, with an option to increase the sample to 1020 following an interim analysis. Pivotal outcomes will be evaluated at 90 days with a further analysis at one year after the stroke.

Phase 3

22 Mar 2022

·www.nonoinc.ca

Press Release - NoNO Inc. | Change Everything

Toronto, Canada, April 7, 2021, 2PM ET – NoNO Inc., an Ontario biotechnology company developing innovative neurotherapeutics for acute stroke and other central nervous system disorders, announced today the publication of prototypes for next generation protease-resistant PSD-95 inhibitors. Published in the journal Science Translational Medicine, the article entitled “Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke” demonstrates the potential of novel next-generation protease-resistant compounds for the treatment of acute ischemic strokes. Such compounds may be practically integrated into current stroke care workflows without the need to modify existing medical practice. These next generation compounds are expected to extend the therapeutic utility of PSD-95 inhibition to all eligible stroke patients, including those that are treated with drugs such as alteplase. The next generation compounds build on nerinetide, NoNO Inc.’s clinical stage lead PSD-95 inhibitor compound. Nerinetide was recently tested in the Phase 3 ESCAPE-NA1 study which provided promising results for the clinical safety and efficacy of nerinetide in acute ischemic stroke, as published in the journal The Lancet. ESCAPE-NA1 showed that nerinetide is promising in stroke patients who do not receive prior treatment with the thrombolytic agent, alteplase, and this is currently being evaluated further in the ongoing global Phase 3 ESCAPE-NEXT study. If ESCAPE-NEXT is successful, both studies will provide support for PSD-95 inhibition as a platform therapy for stroke and related neurological disorders. NoNO Inc. CEO Dr. Michael Tymianski commented that, “Nerinetide and next generation PSD-95 inhibitors continue to grow as a strategy for treating a wide range of neurological disorders that implicate excitotoxicity and neuroplasticity. Neuroprotection for acute ischemic stroke is achievable, and with continued improvements in our PSD-95 inhibitor technology, providing a benefit to patients in additional indications such as stroke recovery, traumatic brain injury and Alzheimer’s disease should be achievable as well.” NoNO Inc. is an Ontario biotechnology company whose focus is on developing therapeutic drugs in areas of unmet medical needs. Its drug pipeline includes therapeutic agents in various stages of development ranging from cellular and molecular discovery to human clinical trials. Its lead projects relate to diseases of the nervous system whose mechanisms involve the protein PSD-95, including stroke, traumatic brain injury and neuropathic pain. NoNO Inc.’s strategy is to inhibit key protein-protein interactions of PSD-95 that are involved selectively in cellular signals that cause cell damage, but without interfering with normal cell functions. For more information, please visit www.nonoinc.ca.

Phase 3Clinical Result

100 Deals associated with Nerinetide

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D11729	-	-	DB12595

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Ischemic Stroke	Phase 3	United States	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	Australia	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	Canada	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	Germany	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	Ireland	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	Sweden	NoNO, Inc.	01 Mar 2017
Acute Ischemic Stroke	Phase 3	United Kingdom	NoNO, Inc.	01 Mar 2017
Brain Ischemia	Phase 3	Canada	NoNO, Inc.	26 Mar 2015
Intracranial Aneurysm	Phase 2	United States	NoNO, Inc.	01 Nov 2015
Intracranial Aneurysm	Phase 2	Canada	NoNO, Inc.	01 Nov 2015

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04462536 (ESCAPE-NEXT, CTgov)	Phase 3	Acute Ischemic Stroke	850	Placebo (Placebo)	ryfrchdwqi = llrailxkbq wznsimhvcb (wuozrdxpnk, xqymitfspn - dovejqoakt) View more	-	22 Jun 2025
				Nerinetide (Nerinetide)	ryfrchdwqi = dlydoqsggk wznsimhvcb (wuozrdxpnk, ejghhxvcfv - krwrjjhrzt) View more
NCT02930018 (ESCAPE-NA1, Pubmed \| Neurology)	Phase 3	Stroke	-	Nerinetide	vhqikvxlcs(grfpxkkxcy) = cbxxknznvp gwnjhkmcyu (drzrbatybq, 1.09 - 21.30) View more	Negative	23 Jan 2024
				Placebo	vhqikvxlcs(grfpxkkxcy) = ovwdfwcbfu gwnjhkmcyu (drzrbatybq, 2.54 - 21.81) View more
NCT00728182 (ENACT, AAN2022)	Phase 2	Brain Infarction	184	Nerinetide treatment	kltdfvfezc(kervijeguu): P-Value = 0.020 View more	Positive	03 May 2022
				Placebo
NCT02930018 (REPERFUSE-NA1, ISC2022)	Phase 3	Infarction	71	NA1	kqrvmhphzv(tbafscrdjg) = yzytqepzda eweghhkatu (lxmlhcuncr, 5.9 - 28.1) View more	-	01 Feb 2022
				Placebo	kqrvmhphzv(tbafscrdjg) = furdtjqcfj eweghhkatu (lxmlhcuncr, 3.1 - 27.0) View more
NCT02930018 (ESCAPE-NA1 \| REPERFUSE-NA1, CTgov)	Phase 3	Acute Ischemic Stroke	1,105	Placebo	ljvxqtzxrh = hxouvdyqrg ypphkakbea (lwpnmrezgk, jsoaneefuy - frfgfstexw) View more	-	14 Dec 2020
NCT02930018 (ESCAPE-NA1, Pubmed \| Nephron Clin Pract) Manual	Phase 3	Acute Ischemic Stroke	1,105	nerinetide	njtvqhhgfy(jlujnkimte) = Serious adverse events occurred equally between groups. fjosyvzrja (btrfqjhiqi ) View more	Negative	14 Mar 2020
				Placebo
NCT00728182 (ENACT, CTgov)	Phase 2	Stroke \| Aneurysm \| Ischemic stroke ... View more	185	NA-1 (1 NA-1)	btluxuzudh(tsefdeswtt) = yhyvxqmqym obprezagos (pkmkzhjgyd, 5598) View more	-	17 Oct 2013
				placebo (2 Placebo)	btluxuzudh(tsefdeswtt) = knfjukvkvx obprezagos (pkmkzhjgyd, 1611) View more

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