In an unprecedented milestone, three studies published simultaneously in The Lancet and Lancet Neurology by Dr. Michael Tymianski, Senior Scientist at UHN’s Krembil Brain Institute, and his team identified a breakthrough in stroke treatment. The findings suggest that nerinetide, a neuroprotective drug, may help safeguard brain tissue and improve outcomes for patients with acute ischemic stroke (AIS).
AIS occurs when a blood clot blocks the supply of oxygen-rich blood to the brain, leading to rapid death of brain cells. The longer the blockage remains, the greater the damage to brain tissue—a process known as infarction. Cell death continues and progressively affects more of tissue surrounding the area initially affected until blood flow is restored in a process called reperfusion. Current treatments focus on restoring blood flow via blood clot-dissolving drugs (called thrombolytic agents) or mechanical clot removal. However, these treatments are time-sensitive, and many patients experience delays before they receive care, leading to permanent disability or death.
For decades, researchers have sought neuroprotectants—drugs that can successfully target and reduce cell death, thereby safeguarding brain cells during the critical period between stroke onset and achieving reperfusion. While previous neuroprotectant trials have failed, nerinetide showed promise in preclinical models. Until now, its effectiveness in humans remained unclear.
Clinical Trials Put Nerinetide to the Test
Dr. Tymianski’s team conducted three large multi-centre, double-blind, randomized controlled trials—ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER—to evaluate nerinetide’s efficacy in AIS patients. While previous pre-clinical studies suggested that nerinetide could reduce stroke-related brain damage, these trials, as designed, initially showed no significant improvement in all the enrolled patients who received the drug compared to placebo.
However, the researchers suspected that trial conditions may have masked nerinetide’s true potential. In re-analyzing the results, they went back to comparing how the trials were conducted with the studies that they had done initially in the laboratory before the clinical trials. They identified key differences between the studies where nerinetide succeeded and the real-world conditions of these trials:
In ESCAPE-NA1, some patients received a thrombolytic agent (blood clot-dissolving drug), which may have interfered with nerinetide’s effects.
In ESCAPE-NEXT, patients were included up to 12 hours after stroke onset, whereas the laboratory studies showed nerinetide worked best within a 3-hour window.
In FRONTIER, paramedics administered nerinetide to all patients in the ambulance before confirming stroke type. This included brain hemorrhages and conditions that mimic strokes, but the drug only acts to benefit patients with acute ischemic stroke.
Meta-Analysis Unlocks Nerinetide’s True Potential
In re-examining the data from the three trials, the Krembil team pooled the data for the patients whose circumstances matched those tested in the laboratory stroke experiments (690 patients out of the original 2,487 patients enrolled in total across all 3 trials). The results were striking: they found that there was a significant improvement in outcomes of AIS patients who received nerinetide compared to the placebo. Not only did more patients in the nerinetide group have better functional outcomes 90 days post-stroke, but there were fewer deaths in this group as well. Additionally, nerinetide slowed the progression of the strokes, resulting in less brain damage on CT and MRI scans. These findings—now published in three separate Lancet articles—strongly suggest that nerinetide can be an effective neuroprotectant if administered under the right conditions.
“Our results are encouraging,” says Dr. Michael Tymianski, Krembil Senior Scientist and lead author of the meta-analysis. "Another trial is ongoing in order to confirm our findings. We are excited by the potential drugs like nerintide have to redefine stroke care and improve outcomes for AIS patients,” he adds.
By providing a buffer against extensive and irreparable brain damage in a critical window before reperfusion, nerinetide could offer hope to stroke patients who face treatment delays. The research team hopes that these findings will serve as a cornerstone for continued research on ways to minimize disability and improve patients’ quality of life after an AIS.
Dr. Michael Hill is the first author of Hill et al., which details the results of the ESCAPE-NEXT trial. He is a Professor at the Cumming School of Medicine at the University of Calgary.
Dr. Jim Christenson is the first author of Christenson et al., details the results of the FRONTIER trial. He is a Professor in the Faculty of Medicine at the University of British Columbia.
Dr. Michael Tymianski is the first and senior author of Tymianski et al., and the senior author of Hill et al. and Christenson et al. He is a Senior Scientist at the Krembil Brain Institute, and a Professor in the Department of Surgery in the Temerty Faculty of Medicine at the University of Toronto.
This work was supported by NoNO Inc., Canadian Institutes of Health, Brain Canada, and UHN Foundation. Dr. Tymianski was a Canada Research Chair (Tier 1) in Translational Stroke Research.
Dr. Michael Hill received personal fees from SunPharma and Brainsgate, owns stock in Circle, has patents for systems and methods for assisting in decision making and triaging for acute stroke patients, and reports previous grants from NoNO Inc., Medtronic, and Boehringer-Ingelheim outside the submitted work. Dr. Jim Christenson received support from Brain Canada, NoNO Inc., and CIHR outside the submitted work. Dr. Michael Tymianski is the Chief Executive Officer for, owns stock in, and is the inventor of patents owned by NoNO Inc.
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Christenson J, Hill MD, Swartz RH, Adams C, Benavente O, Casaubon LK, Cheskes S, Ganesh A, Garman JD, Harris C, Harris DR, Heard K, Jenneson S, Kohli Y, Leroux M, Mayor-Nunez D, Medvedev G, Mehdiratta M, Morrison LJ, Ospel JM, Pennington S, Perez Y, Selchen D, Stebner A, Tallon J, Tkach A, Verbeek PR, Tymianski M. 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. Lancet. 2025 Feb 15; 405(10478p): 571-582. doi: 10.1016/S0140-6736(25)00193-X.
Tymianski M, Hill MD, Goyal M, Christenson J, Menon BK, Adams C, heard K, Kohli Y, for the ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER Investigators. 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. Lancet Neurology. 2025 Feb 13. doi: 10.1016/S1474-4422(24)00515-5.