nerinetide (NA 1) / NoNO - LARVOL DELTA

INCIDENCE, ASSOCIATED VARIABLES, AND UNDERLYING MECHANISMS OF UNEXPLAINED EARLY NEUROLOGICAL DETERIORATION IN THROMBECTOMY STROKE PATIENTS (ESOC 2025) - " Data are from the ESCAPE-NA1 trial, a randomized trial evaluating nerinetide in thrombectomy stroke patients... Unexplained END occurred in 10% of stroke thrombectomy patients and was associated with older age, longer onset-to-reperfusion time, and anesthesia use. unEND may be driven by the transformation of benign oligemia (asymptomatic tissue) to ischemic penumbra/infarction."

Clinical • Cardiovascular • Ischemic stroke

NEUROFILAMENT LIGHT AS A MARKER OF NEUROAXONAL INJURY IN THE ESCAPE-NEXT TRIAL (ESOC 2025) - " We conducted a biomarker sub-study of the ESCAPE-NEXT trial and included 193 participants (109 treated with Nerinetide) at 19 sites... Plasma NfL levels correlated with infarct volume, outperformed infarct volume in predicting functional outcomes, and captured treatment effects. These findings support the inclusion of blood NfL as an exploratory endpoint in acute stroke trials."

Cardiovascular • GFAP • Plasma NfL

COMPARISON OF NEUROPROTECTIVE ADJUVANT TREATMENTS IN PATIENTS WITH ACUTE ISCHEMIC STROKE AFTER REPERFUSION THERAPY: A SYSTEMIC REVIEW AND NETWORK META-ANALYSIS (ESOC 2025) - "The efficacy of these treatments, ranked in order of mean RD, was as follows: RH, transcranial direct current stimulation, NBO, imatinib, uric acid, nelonemdaz, butylphthalide, cerebrolysin, ApTOLL, nerinetide, theophylline, remote ischemic conditioning, otaplimastat, simvastatin and albumin. RH and NBO were associated with better functional outcome. Cerebrolysin was linked to reduced risk of sICH, and NBO was associated with lower risk of mortality."

Retrospective data • Review • Cardiovascular • Ischemic stroke

EFFICACY AND SAFETY OF NERINETIDE IN ACUTE ISCHEMIC STROKE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PRE-CLINICAL AND CLINICAL STUDIES (ESOC 2025) - "Nerinetide demonstrates significant neuroprotective post-stroke. The reduced infarct size improved neurological function, and decreased mortality in animal studies are promising. Clinical trials showed modest functional improvements with a safety profile comparable to controls."

Preclinical • Retrospective data • Review • Cardiovascular • Ischemic stroke

Impact of Brain Frailty on Clinical Presentation and Neurologic Recovery in Acute Ischemic Stroke Patients Undergoing Thrombectomy. (PubMed, Neurology) - "This study highlights the association of brain frailty with the clinical presentation and recovery trajectory of patients with AIS undergoing EVT. Specifically, cortical atrophy was independently associated with baseline stroke severity, and the total burden of brain frailty was independently associated with NIHSS recovery trajectories. The results emphasize the importance of considering brain frailty in acute stroke management and prognostication."

Journal • Cardiovascular • Ischemic stroke

Comparing Early National Institutes of Health Stroke Scale Versus 90-Day Modified Rankin Scale Outcomes in Acute Ischemic Stroke Trials: A Systematic Review and Analysis. (PubMed, J Am Heart Assoc) - "The 24-hour NIHSS scores aligned with 90-day mRS scores in 84% of RCT results, indicating intermediate-to-good agreement. However, individual patient data showed that early NIHSS risks misclassifying around 1/4 patients. These data contribute to a better understanding of the nuances of early NIHSS score as an outcome in acute ischemic stroke RCTs."

Clinical • Journal • Cardiovascular • Ischemic stroke

The PSD-95 inhibitor NA-1 is delivered to the brain upon nasal administration with uptake into the olfactory bulb improved by co-administration with the cell-penetrating peptides lowPro and Tat. (PubMed, Drug Deliv Transl Res) - "Compared to intravenously administered NA-1, nasal delivery resulted in significantly lower off-target tissue distribution. These findings highlight nasal administration as a qualified alternative for NA-1 delivery, with potential to bypass the limitations of intravenous administration and enable concurrent use with alteplase during acute ischemic stroke."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Ischemic stroke

Improvements in endovascular stroke treatment workflow over 5 years: ESCAPE to ESCAPE-NA1. (PubMed, Interv Neuroradiol) - "Onset-to-randomization times did not differ significantly between the two trials (ESCAPE-NA1: median 188 [122-319] vs. ESCAPE: 174 [119-285], P = .152). There was no effect of procedural sedation use, age, sex, stroke severity or evidence of a learning effect over the duration of each trial.ConclusionWorkflow interval times in endovascular stroke treatment have significantly improved over time, particularly in patients directly presenting to an EVT-capable hospital."

Journal • Anesthesia • Cardiovascular • Ischemic stroke

Neuroprotective strategies in acute ischemic stroke: A narrative review of recent advances and clinical outcomes. (PubMed, Brain Circ) - "Recent advancements in neuroprotective approaches, including pharmacologic agents such as nerinetide edaravone, and uric acid, as well as nonpharmacological interventions, such as remote ischemic conditioning and normobaric hyperoxia, offer promising potentials in stroke care. This review provides an overview of the current neuroprotective therapies, examines recent clinical evidence, and discusses the strengths and weaknesses of certain clinical trials aimed at cerebral protection."

Clinical data • Journal • Review • Cardiovascular • Ischemic stroke

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. (PubMed, Lancet Neurol) - "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."

Journal • Retrospective data • Cardiovascular • Ischemic stroke

Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis (ESCAPE-NEXT): a multicentre, double-blind, randomised controlled trial. (PubMed, Lancet) - P3 | "While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies."

Clinical • Journal • Cardiovascular • CNS Disorders • Ischemic stroke

Efficacy and safety of intravenous nerinetide initiated by paramedics in the field for acute cerebral ischaemia within 3 h of symptom onset (FRONTIER): a phase 2, multicentre, randomised, double-blind, placebo-controlled study. (PubMed, Lancet) - P3 | "Prehospital nerinetide did not improve neurological functional outcomes in all patients with suspected ischaemic stroke in the mITT population. Nerinetide might benefit patients with acute ischaemic stroke who are selected for reperfusion therapies within 3 h of symptom onset. This finding should be confirmed in a future trial."

Clinical • Journal • P2 data • Cardiovascular • Cerebral Hemorrhage • Ischemic stroke • Solid Tumor

Comparison of Noncontrast Computed Tomography, Multiphase Computed Tomography Angiography, and Computed Tomography Perfusion to Assess Infarct Growth Rate in Acute Stroke. (PubMed, Stroke) - "Secondary analysis of the international ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) which evaluated the effect of nerinetide in patients with large vessel occlusion undergoing thrombectomy...No significant association between progressor phenotypes and 90-day modified Rankin Scale was seen when the noncontrast CT and the mCTA approaches were used. Stroke progressor phenotypes based on CT perfusion criteria (using the hypoperfusion intensity ratio approach) were associated with clinical outcomes, while stroke progressor phenotypes based on noncontrast CT (ASPECTS decay) and mCTA (collateral status) criteria were not."

Journal • Cardiovascular • Ischemic stroke

Clinical Benefit of Nerinetide at One Year in Early Window Participants Enrolled in ESCAPE-NEXT (ISC 2025) - "Late window participants may represent slow progressors who are least likely to benefit from treatments intended to slow stroke progression. For early window ESCAPE-NEXT participants, the benefit of nerinetide was more apparent at 1Y than D90. Early window patients may represent a population that could benefit from treatment with nerinetide."

Clinical • Late-breaking abstract • Cardiovascular • Ischemic stroke

Association between Time and Severe Hypoperfusion with Risk of Hemorrhagic Transformation in Thrombectomy Stroke Patients (ISC 2025) - "We aim to investigate the association of time and severe hypoperfusion with parenchymal hematoma (PH) in ischemic stroke and explore whether there is a combined effect of the two variables on PH. Data are from the ESCAPE-NA1 trial, which evaluated the effect of nerinetide in large vessel occlusion patients treated with thrombectomy... Both severe hypoperfusion and time affect the risk of hemorrhagic transformation in ischemic cerebral tissue. Analyzing these variables may help identify patients with a leaky, severely compromised blood-brain barrier in the ischemic core—a "leaky core.""

Clinical • Cardiovascular • Hematological Disorders • Ischemic stroke

Sex differences in the association of brain frailty measures with functional outcomes after endovascular treatment: analysis of the ESCAPE-NA1 trial (ISC 2025) - "We aimed to investigate the association between imaging markers of brain frailty and functional outcomes after EVT in women and men. This study is a post hoc analysis of the ESCAPE-NA1 trial that evaluated the efficacy and safety of nerinetide in patients with large vessel occlusion receiving EVT within 12 hours of onset... In this cohort of EVT recipients, significant associations between imaging brain frailty measures and 90-day outcomes were seen only in women and not in men. These findings merit validation in other cohorts as they suggest sex differences in the effects of brain frailty on post-stroke outcomes."

Cardiovascular • CNS Disorders

Factors Influencing Nerinetide Effect on Clinical Outcome in Patients Without Alteplase Treatment in the ESCAPE-NA1 Trial. (PubMed, J Stroke) - "Patients in the nerinetide arm who were not treated with concurrent alteplase showed improved clinical outcomes and the treatment effect was larger among patients with favorable ASPECTS profiles."

Clinical data • Journal • Anesthesia • Atrial Fibrillation • Cardiovascular • Ischemic stroke

Comparative efficacy of neuroprotective agents for improving neurological function and prognosis in acute ischemic stroke: a network meta-analysis. (PubMed, Front Neurosci) - "The interventions assessed included Cerebrolysin, Citicoline, Edaravone, Edaravone Dextranol, Human urinary kallidinogenase, Minocycline, Nerinetide, Butylphthalide, Vinpocetine, and Control. To further validate the efficacy and safety of neuroprotective agents, future studies should involve larger sample sizes and conduct multicenter, large-scale randomized controlled trials. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=601346, identifier CRD42024601346."

Journal • Retrospective data • Review • Cardiovascular • Ischemic stroke

Factors Influencing Nerinetide Effect on Infarct Volume in Patients Without Alteplase in the Randomized ESCAPE-NA1 Trial. (PubMed, Stroke) - P3 | "The reduction in infarct volume was greater among patients with poor prognostic factors. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02930018."

Journal • Anesthesia • Cardiovascular • Hypertension • Ischemic stroke

Prevalence of ipsilateral "vulnerable carotid plaques with <50 % stenosis" on CT angiography in embolic stroke of undetermined source. (PubMed, J Neurol Sci) - "In ESUS patients undergoing thrombectomy for anterior circulation large vessel occlusion, vulnerable carotid plaques are more prevalent ipsilateral to the intracranial occlusion. Irregular plaque surface, and a higher degree of stenosis were the most common vulnerable plaque features."

Journal • Cardiovascular • Ischemic stroke

Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases. (PubMed, RSC Adv) - "The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein-protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry. In this study, we deconstruct the nerinetide sequence and study the relationship between plasma stability, intraneuronal delivery and drug efficacy to provide design guidelines for the development of next generation, peptidic PPI inhibitors to treat neurodegenerative diseases."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Ischemic stroke

INTRACALVARIOSSEOUS INJECTION AS A NOVEL DRUG DELIVERY APPROACH IN THE TREATMENT OF MALIGNANT MIDDLE CEREBRAL ARTERY INFARCTION: FROM PRECLINICAL TO 'PROOF OF CONCEPT' EVALUATION (WSC 2024) - P=N/A | "Methods We examined the efficacy of intracalvariosseous (ICO) injection using two neuroprotective drugs (nerinetide and Y-3) in a rat model of stroke...Conclusions We indicated that intracalvariosseous drug delivery achieved higher drug exposure, reduced dosage and improved outcome based on preclinical experiments. The clinical trial proved feasibility and safety of ICO injection, whereas upcoming trials with larger sample size are needed to investigate efficacy of ICO drug delivery."

Preclinical • Cardiovascular • CNS Disorders

IMPACT OF NA-1 ON PERICYTE-DRIVEN VASOCONSTRICTION AND ITS ROLE IN NO-REFLOW DURING CEREBRAL ISCHEMIA-REPERFUSION (WSC 2024) - "Results Intravenously infused tat-NR2B9c/NA-1 (10 uMole/kg dose) beginning at reperfusion demonstrates an ability in pericyte-mediated vasoconstriction for reperfused vessels,reduced infarct size and improved behavioral deficits...Immunofluorescence is further utilized to confirm the microvascular diameter decrease, together with the diameter of capillaries at both pericytes' soma and in the adjacent parts, reversible with an administration of NA-1.ET-1 is revealed to be significantly reduced. Conclusions PSD95 inhibitor inhibits pericyte constriction after ischemia-reperfusion by reducing ET-1, improves capillary no-reflow after ischemia in mice, increases cerebral perfusion, reduces infarct size, and reduces behavioral defects."

Cardiovascular • Reperfusion Injury • DLG4 • EDN1

ASSESSMENT OF INFARCT PROGRESSION PHENOTYPES ACROSS MULTIPLE CT MODALITIES IN ISCHEMIC STROKE: A POST-HOC ANALYSIS OF THE ESCAPE-NA1 TRIAL (WSC 2024) - "Methods Secondary analysis of ESCAPE-NA1 trial which evaluated the effect of nerinetide in patients with large vessel occlusion undergoing thrombectomy...Intermediate progressors showed worse functional outcomes compared to slow progressors only in CTP strata: adjusted common odds ratio for mRS ordinal shift analysis of 1.69 (95% CI=1.14-2.49) (Figure 2). Conclusions Progressor imaging phenotypes determined by CTP were associated with clinical outcomes, while progressor phenotypes determined by NCCT and mCTA were not."

Retrospective data • Cardiovascular • Ischemic stroke

Effects of reperfusion grade and reperfusion strategy on the clinical outcome: Insights from ESCAPE-NA1 trial. (PubMed, Interv Neuroradiol) - "Better reperfusion degrees significantly improved clinical outcomes and reduced mortality, independent of the number of passes and whether eTICI 2c3 was achieved suddenly or gradually."

Clinical data • Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Ischemic stroke • Subarachnoid Hemorrhage