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 Mar 2025·LANCET NEUROLOGY

Safety and efficacy of nerinetide in patients with acute ischaemic stroke enrolled in the early window: a post-hoc meta-analysis of individual patient data from three randomised trials

Article

BACKGROUND:

In three neuroprotection trials of nerinetide for acute ischaemic stroke, inconclusive results have been reported with respect to the prespecified primary outcome. However, none of the trials faithfully replicated the inclusion criteria of the animal studies that provided the rationale for the clinical trials-ie, treatment within 3 h of stroke onset and selected for reperfusion without previous thrombolysis. We aimed to investigate whether a clinical benefit of nerinetide might be seen in the subgroup of patients enrolled in these three clinical trials who met the criteria used in the animal studies.

METHODS:

In this post-hoc individual patient data meta-analysis, we pooled data from the ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER trials, which were done at 135 stroke centres in 13 countries (Canada, Australia, Germany, Ireland, Italy, the Netherlands, Norway, Singapore, South Korea, Sweden, Switzerland, the UK, and the USA). We included all participants who were enrolled within 3 h of acute ischaemic stroke onset, treated with study drug (nerinetide or placebo; randomised 1:1), and selected for reperfusion with thrombolysis, endovascular thrombectomy, or both. The primary endpoint was the number of responders at day 90, which was defined as people with a favourable outcome as per the primary endpoint prespecified in their respective trial. The primary endpoint was analysed by logistic regression, adjusted for age, stroke severity, and trial.

FINDINGS:

Between March 26, 2015, and Jan 31, 2023, 2487 participants were enrolled in the three trials, of whom 690 met criteria for this pooled analysis (389 participants in the nerinetide group and 301 participants in the placebo group). 364 (53%) of 690 participants were men and 326 (47%) were women. The median age of participants was 76 years (IQR 66-83) and median baseline National Institutes of Health Stroke Scale score was 17 (11-21). 216 (56%) of 389 participants were responders at day 90 in the nerinetide group compared with 144 (48%) of 301 in the placebo group (adjusted odds ratio [aOR] 1·48, 95% CI 1·07-2·06; p=0·017). 62 (16%) of 389 people in the nerinetide group died compared with 55 (18%) of 301 people in the placebo group (aOR 0·81, 95% CI 0·53-1·24; p=0·34). No safety concerns were identified in either group.

INTERPRETATION:

Nerinetide showed a clinically significant benefit over several outcome measures, including the modified Rankin Scale score, the incidence of stroke worsening, and infarction volumes. Neuroprotection with nerinetide might, therefore, be indicated for patients within 3 h of stroke onset and who are selected for reperfusion. These inclusion criteria should be tested in a future trial.

FUNDING:

None.

01 Feb 2025·EBioMedicine

Intracalvariosseous injection: an approach for central nervous system drug delivery through skull bone marrow with a preclinical research in stroke

Article

Author: Wang, Nanxing ; Shi, Kaibin ; Yang, Mo ; Shi, Fu-Dong ; Sun, Zhiwei ; Liu, Xiangrong ; Liu, Wenqian ; Wang, Yilong ; Wang, Chaoyu ; Wang, Yongjun ; Pan, Yuesong ; Zhang, Mingjun

BACKGROUND:

Central nervous system (CNS) accessibility constitutes a major hurdle for drug development to treat neurological diseases. Existing drug delivery methods rely on breaking the blood-brain barrier (BBB) for drugs to penetrate the CNS. Researchers have discovered natural microchannels between the skull bone marrow and the dura mater, providing a pathway for drug delivery through the skull bone marrow. However, there has been no research on the feasibility, safety, and efficacy of this delivery method for drug treatment of stroke.

METHODS:

We used a microporous method for intracalvariosseous (ICO) injection to deliver drugs directly into brain parenchyma through skull bone marrow. Safety of ICO was assessed by monitoring changes in skull and peripheral blood neutrophil counts, and FITC-dextran extravasation across the BBB. Drug delivery pathways were observed through transparent skull-dura mater-brain tissue. In a rodent stroke model, NA-1 or Y-3 neuroprotective agents were administered via ICO to evaluate safety and efficacy by assessing neurological deficits, infarct size, neuroinflammatory factors, neuronal apoptosis, and liver/kidney function. Drug concentration in tissues was measured using fluorescence tracing and high-performance liquid chromatography to gauge ICO delivery efficiency.

FINDINGS:

ICO injection delivers drugs to the brain parenchyma through microchannels between the skull bone marrow and the dura mater, offering higher delivery efficiency than intravenous injection. After ICO injection, there were no changes in neutrophil counts in the skull bone marrow and peripheral blood, and the amount of FITC-dextran passing through the BBB remained unchanged. This confirmed that ICO injection does not cause skull infection or break BBB, which suggested ICO injection is safe and feasible. In the treatment of stroke with neuroprotective agents, although the drug dosage of ICO injection was lower than intravenous injection, drug accumulation in the brain increased after ICO injection, which helped repair nerve damage, reduce neuronal apoptosis, and decrease the expression of inflammatory factors.

INTERPRETATION:

ICO injection is a central nervous system drug delivery method that utilizes natural microchannels between the skull and dura mater for efficient drug delivery. Our results assessed the feasibility and safety of ICO injection at the preclinical level and evaluated its efficacy in animal models of stroke. The findings provided a foundation for the clinical translation of ICO injection.

FUNDING:

This study was supported by The National Natural Science Foundation of China (No. 82425101); Beijing Municipal Science & Technology Commission (No. Z231100004823036); Capital's Funds for Health Improvement and Research (2022-2-2045); National Key Research & Development Program of China (2022YFF1501500, 2022YFF1501501, 2022YFF1501502, 2022YFF1501503, 2022YFF1501504, 2022YFF1501505).

01 Jan 2025·STROKE

Factors Influencing Nerinetide Effect on Infarct Volume in Patients Without Alteplase in the Randomized ESCAPE-NA1 Trial

Article

Author: Poppe, Alexandre Y. ; Menon, Bijoy K. ; van Adel, Brian ; Joshi, Manish ; Kashani, Nima ; McTaggart, Ryan A. ; Field, Thalia S. ; Ospel, Johanna M. ; Zerna, Charlotte ; Shah, Ruchir ; Silver, Frank L. ; Rempel, Jeremy L. ; Campbell, Bruce ; Almekhlafi, Mohammed A. ; Hill, Michael D. ; Swartz, Richard H. ; Nogueira, Raul G. ; Dowlatshahi, Darius ; Demchuk, Andrew M. ; Chapot, René ; Heard, Kathy ; Sauvageau, Eric ; Goyal, Mayank ; Puetz, Volker ; Tymianski, Michael

BACKGROUND::

In the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke), treatment with nerinetide was associated with a smaller infarct volume among patients who did not receive intravenous alteplase. We assessed the effect of nerinetide on the surrogate imaging outcome of final infarct volume in patients who did not receive intravenous alteplase and explored predictors of outcome and modifiers of nerinetide’s effect on infarct volume.

METHODS::

ESCAPE-NA1 was a multicenter, randomized trial in which patients with acute stroke with a baseline Alberta Stroke Program Early CT Score >4, undergoing endovascular thrombectomy, were randomized to receive intravenous nerinetide or placebo. Patients not receiving intravenous alteplase were included in this post hoc secondary analysis of the trial data. Final infarct volume was manually segmented on 24-hour noncontrast computed tomography or diffusion-weighted magnetic resonance imaging. Predictors of final infarct volume were identified using multivariable linear regression with cubic-root-transformed infarct volume as the dependent variable. Evidence of treatment-by-predictor interaction was tested by including interaction terms in the model.

RESULTS::

Four hundred forty-six patients (219 who received nerinetide and 227 who received a placebo) out of a total of 1105 enrolled patients were included in this secondary post hoc analysis of the randomized ESCAPE-NA1 trial. Nerinetide was a strong predictor of smaller infarct volume (adjusted β coefficient, −0.35 [95% CI, −0.67 to −0.02]). Other predictors of smaller infarct volume were history of hypertension, good pial collateral filling on multiphase computed tomography angiography, a middle cerebral artery occlusion compared with an internal carotid artery occlusion, lower baseline National Institutes of Health Stroke Scale score, lower baseline systolic blood pressure, lower baseline serum glucose, shorter onset-to-randomization time, and higher Alberta Stroke Program Early CT Score. There was evidence of a treatment-by-systolic blood pressure and treatment-by-anesthesia interaction: nerinetide attenuated the negative effects of elevated baseline ( Pinteraction =0.02) and postdose ( Pinteraction =0.04) systolic blood pressure and use of general anesthesia ( Pinteraction =0.06) on final infarct volume. We observed a marginally significant interaction with reperfusion status, such that nerinetide may attenuate the harmful effect of poor reperfusion status on infarct volume ( Pinteraction =0.08).

CONCLUSIONS::

Nerinetide treatment was strongly associated with smaller final infarct volumes among patients not cotreated with alteplase. The reduction in infarct volume was greater among patients with poor prognostic factors.

REGISTRATION::

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02930018.

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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R&D Status

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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	South Korea	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
Aneurysm, Ruptured	Phase 2	United States	NoNO, Inc.	01 Nov 2015

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02930018 (REPERFUSE-NA1, ISC2022)	Phase 3	Infarction	71	NA1	stnqhsajqk(ftcinrmmul) = rqcaoezkoo cdwgixiqbl (utpcqioeeb, 5.9 - 28.1) View more	-	01 Feb 2022
				Placebo	stnqhsajqk(ftcinrmmul) = afbyypdpcw cdwgixiqbl (utpcqioeeb, 3.1 - 27.0) View more
NCT02930018 (ESCAPE-NA1 \| REPERFUSE-NA1, CTgov)	Phase 3	Acute Ischemic Stroke	1,105	Placebo	owfgqcgxqo = hxmtbjwnrt ebqxvunavh (wgxlcgfwje, elbkryhfmu - rrbcjsvops) View more	-	14 Dec 2020
NCT02930018 (ESCAPE-NA1, Pubmed \| Lancet) Manual	Phase 3	Acute Ischemic Stroke	1,105	nerinetide	qukipwiltu(tibuknpbuq) = Serious adverse events occurred equally between groups. byhrocwnen (ixnfxhjzwp ) View more	Negative	14 Mar 2020
				Placebo
NCT00728182 (ENACT, CTgov)	Phase 2	Stroke \| Aneurysm	185	NA-1 (1 NA-1)	ofiwqsascg(evlanhrzxl) = xwucjvxjtx emvihxixwn (pcjfbyulxw, 5598) View more	-	17 Oct 2013
				placebo (2 Placebo)	ofiwqsascg(evlanhrzxl) = qmjtpavbyi emvihxixwn (pcjfbyulxw, 1611) View more

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