Nerinetide
A stroke neuroprotectant whose benefit may depend on alteplase
Nerinetide is a 20-amino-acid peptide designed to protect brain cells during a stroke by interfering with post-synaptic density protein 95. It worked in animal models, but three large human trials missed their primary outcomes. The recurring hint is that it may help patients undergoing thrombectomy who have not been given alteplase.
What is it?
Nerinetide was tested in a setting chosen to mirror the animal models in which it worked: patients whose blocked artery is reopened quickly by endovascular thrombectomy, so that the drug can act on ischaemia-reperfusion injury. The ESCAPE-NA1 investigators describe it as an eicosapeptide that interferes with post-synaptic density protein 95 and is effective in preclinical stroke models of ischaemia-reperfusion.
In ESCAPE-NA1, 1,105 patients undergoing thrombectomy were randomised. Good functional outcome at 90 days was 61.4% on nerinetide against 59.2% on placebo, not significant; but the investigators found evidence that the treatment effect was inhibited in patients who had also received alteplase. Imaging sub-studies found less early infarct growth with nerinetide in the no-alteplase group.
ESCAPE-NEXT then tested nerinetide in 850 thrombectomy patients without prior alteplase, and found no benefit (45% against 46% good outcome). FRONTIER gave it in the ambulance within three hours of symptoms to 532 people and also missed its primary outcome, though results in confirmed ischaemic stroke leaned towards nerinetide. Serious adverse events were similar to placebo in all three trials. It is not approved anywhere.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Published Research
The trials of nerinetide, from their PubMed abstracts.
ESCAPE-NA1
In 1,105 thrombectomy patients, 61.4% on nerinetide and 59.2% on placebo had a good outcome (mRS 0-2) at 90 days (risk ratio 1.04, p = 0.35); alteplase appeared to inhibit the treatment effect, and serious adverse events were equal.
ESCAPE-NEXT
In 850 thrombectomy patients without prior thrombolysis, 45% on nerinetide and 46% on placebo achieved mRS 0-2 at 90 days (odds ratio 0.97, p = 0.82); serious adverse events were similar.
FRONTIER: given by paramedics
In 532 people treated in the field a median of 64 minutes after onset, favourable outcome was 57% against 58% (adjusted odds ratio 1.05); in the 302 with ischaemic stroke, results leaned towards nerinetide without reaching significance.
Infarct growth without alteplase
In ESCAPE-NA1 patients with perfusion imaging, alteplase modified nerinetide's effect on infarct growth (P = 0.005); among patients not given alteplase, infarct growth over 24 hours was larger with placebo than with nerinetide.
REPERFUSE MRI sub-study
In 67 patients with adequate MRI after thrombectomy, median infarct volume (12.98 vs 10.80 mL) and early infarct growth (5.92 vs 10.80 mL) did not differ significantly between nerinetide and placebo, and alteplase modified nerinetide's effect on growth in white matter and basal ganglia.
Side Effects & Contraindications
Reported Side Effects
From the trials above.
Contraindications & Cautions
No label; it is investigational.
Legal Status
Nerinetide is investigational.
Frequently Asked Questions
?What is nerinetide?
An investigational 20-amino-acid peptide meant to protect brain cells during stroke by interfering with post-synaptic density protein 95.
?Did nerinetide work in stroke trials?
Not on their main measures. ESCAPE-NA1, ESCAPE-NEXT and FRONTIER all missed their primary outcomes, although some analyses suggested benefit in patients not given alteplase.
?Why might alteplase matter?
ESCAPE-NA1 found the treatment effect appeared to be inhibited in patients who received alteplase, and imaging analyses showed less infarct growth with nerinetide only in those who did not.
?Is it safe?
Serious adverse events occurred at similar rates to placebo in all three large trials.
?Why was it given by paramedics in one trial?
FRONTIER tested whether starting nerinetide in the ambulance, a median of 64 minutes after symptoms began, would protect the brain before hospital treatment; it did not improve the primary outcome, and those given nerinetide happened to have more severe strokes at baseline.
References
- [clinical-trial] Hill MD, et al. "Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial." Lancet, 2020;395(10227):878-887. PMID: 32087818.
- [clinical-trial] Hill MD, et al. "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." Lancet, 2025;405(10478):560-570. PMID: 39955119.
- [clinical-trial] Christenson J, et al. "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;405(10478):571-582. PMID: 39955120.
- [pubmed] Rex NB, et al. "Nerinetide Reduces Early Infarct Growth Among Stroke Patients Undergoing EVT Without Intravenous Alteplase." Stroke Vasc Interv Neurol, 2024;4(2):e001034. PMID: 41583582.
- [pubmed] Fladt J, et al. "Infarct Evolution on MR-DWI After Thrombectomy in Acute Stroke Patients Randomized to Nerinetide or Placebo: The REPERFUSE-NA1 Study." Neurology, 2024;102(2):e207976. PMID: 38165335.
Sources & Citations
Studies were read from their PubMed records, October 3, 2026.
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