nerinetide (NA 1) / NoNO - LARVOL DELTA

Efficacy and Safety of Nerinetide in Acute Ischemic Stroke Patients: A Systematic Review, Meta-Analysis and Meta Regression. (PubMed, Brain Behav) - "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."

Journal • Retrospective data • Review • Atrial Fibrillation • Cardiovascular • CNS Disorders • Epilepsy • Hypotension • Ischemic stroke • Vascular Neurology

Development of a novel cyclotide to target neuronal excitotoxicity (Neuroscience 2025) - "This signalling cascade can be blocked using a therapeutic peptide known as Nerinetide or NR2b9c...Further, administration of c5R-NR2B9c in a mouse model of epilepsy resulted in increased survival and reduced seizure severity after seizure induction. Overall, we show that modifying cyclotides can enhance delivery of therapeutic peptides into neuronal cells, which can be utilized to protect neurons from excitotoxicity."

Alzheimer's Disease • CNS Disorders • Dementia • Epilepsy

ANG2B9C: A NOVEL NEUROPROTECTIVE PSD-95 INHIBITOR WITHOUT HISTAMINE-RELATED SIDE EFFECTS (WSC 2025) - "ConclusionsANG2B9c is a promising neuroprotective candidate that retains the efficacy of nerinetide while eliminating histamine-related adverse effects. Its improved safety profile supports its potential for prehospital stroke treatment and broader clinical use."

Adverse events • Cardiovascular • CNS Disorders • Hypotension • Vascular Neurology • GRIN2B

Targeting Nav1.8 with the nonopioid antagonist suzetrigine in analgesia. Comment on Br J Anaesth 2025; 135: 829-32. (PubMed, Br J Anaesth) - No abstract available

Journal • Neuralgia • Pain • NAV1

Targeting excitotoxicity in acute stroke: hope or hype. (PubMed, Cardiovasc Res) - No abstract available

Journal • Cardiovascular

ENA1, a transporter of nicotianamine that mediates secretion in the root of Arabidopsis. (PubMed, New Phytol) - "Its species-specific regulation and localization suggest an adaptive mechanism for rhizosphere metal management. This discovery advances our understanding of plant metal homeostasis and provides a molecular basis for phytoremediation and biofortification strategies."

Journal

Suzetrigine: A novel selective sodium channel inhibitor for pain. (PubMed, Am J Health Syst Pharm) - "Suzetrigine represents an advancement in pain management as a nonopioid alternative for pain with potentially lower abuse risk and potentially fewer serious adverse effects when compared to opioids. While initial results are promising, further research is needed to establish its long-term safety and efficacy for various painful conditions. Research will continue in the area of analgesics that selectivity inhibit peripheral sodium channels."

Journal • Diabetic Neuropathy • Pain • Peripheral Neuropathic Pain • NAV1

Neuroprotective Agents With Reperfusion Therapies in Ischemic Stroke: Evidence From Recent Randomized Trials. (PubMed, Cureus) - "Interventions included nerinetide, edaravone (and its derivatives), nelonemdaz, cerebrolysin, minocycline, glyceryl trinitrate, and normobaric hyperoxia. Quality assessment using the Cochrane Risk of Bias (RoB) 2.0 tool revealed low to moderate risk of bias across most studies. Although the evidence remains heterogeneous, this review highlights the potential role of neuroprotective agents as adjuncts to reperfusion therapy and identifies promising directions for future clinical trials."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Ischemic stroke

Targeting Nav1.8 with the nonopioid antagonist suzetrigine in analgesia: cause for optimism? (PubMed, Br J Anaesth) - "Recent large trials have shown some efficacy of the new Nav1.8 allosteric inhibitor suzetrigine in acute postoperative pain, and ongoing studies are investigating its potential for painful diabetic neuropathy. If efficacy is confirmed, this type of drug might fill a significant gap in the treatment of acute and chronic pain, offering a safer alternative to opioids and marking the advent of a new class of nonopioid analgesics."

Journal • Diabetic Neuropathy • Neuralgia • Pain • NAV1

Tat-NR2B9c prevent cognitive dysfunction in mice modeling Alzheimer's Disease induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors. (PubMed, IBRO Neurosci Rep) - "Tat-NR2B9c can improve spatial learning and memory ability in AD mice by perturbing PSD-95 interactions with NR2B-subtype but not inhibiting PSD-95 levels. Tat-NR2B9c can prevent cognitive dysfunction in mice modeling AD induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Neuralgia • Pain

Incidence, Associations, and Mechanisms of Unexplained Early Neurologic Deterioration After Thrombectomy in Stroke Patients. (PubMed, Neurology) - "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."

Clinical • Journal • Anesthesia • Cardiovascular • Hematological Disorders • Ischemic stroke

Uncoupling toxic NO signaling: Progress, challenges, and therapeutic promise of disrupting the PSD-95/nNOS protein-protein interaction. (PubMed, Eur J Med Chem) - "Over the past two decades, cell-penetrant peptides such as nerinetide (Tat-NR2B9c) have validated the target from rodent stroke models to phase-III clinical trials, while bivalent constructs achieve low-nanomolar affinity and extended brain exposure. Parallel medicinal-chemistry campaigns have delivered multiple small-molecule scaffolds (IC87201, ZL006, SCR-4026, PCC-0105002) that cross the blood-brain barrier, disrupt the complex at low-micromolar concentrations, and demonstrate efficacy in ischemic stroke, neuropathic pain, and neuropsychiatric paradigms without the liabilities of NMDAR antagonists...Structural elucidation of ligand-bound complexes, covalent and bivalent chemistries, and AI-guided design promise to surmount these hurdles. Collectively, the evidence positions PSD-95/nNOS disruption as a versatile, clinically achievable approach for mitigating excitotoxic and nociceptive pathology and sets the stage for first-in-class therapies that uncouple toxic NO..."

Journal • Review • Cardiovascular • Ischemic stroke • Neuralgia • Pain • Psychiatry

Association between Time and Severe Hypoperfusion with Risk of Hemorrhagic Transformation in Stroke Patients. (PubMed, Int J Stroke) - "Both severe hypoperfusion and time affect the risk of hemorrhagic transformation. However, the interaction between these two variables was not statistically significant, indicating that their effects on hemorrhagic transformation risk are not dependent on each other. Analyzing these variables may help identify patients with a leaky, severely compromised blood-brain barrier in the ischemic core-a "leaky core."."

Journal • Cardiovascular • Hematological Disorders • Ischemic stroke

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