Article

Nerinetide (NA-1): the PSD-95 inhibitor peptide and its stroke trial record

Published 30 October 2026 · CognitivePepti Research Desk

Prepared by: Research Desk. Sources are linked for verification.

Published 30 October 2026

At a glance

What it is: nerinetide (NA-1, also Tat-NR2B9c) is a 20-amino-acid peptide designed to disrupt the link between NMDA receptors and the scaffolding protein PSD-95
Animal work: rat studies in 2002 and a non-human primate study in 2012 reported smaller infarcts after experimental stroke
Human trials: three large randomised trials, ESCAPE-NA1, ESCAPE-NEXT and FRONTIER, each missed its primary end point
Post-hoc signal: a pooled 2025 analysis of a subgroup that matched the animal studies reported a difference, but it was not a prespecified test
Status: investigational; not approved by the FDA or EMA as far as we could find

How the peptide was designed

During ischaemia, excess glutamate over-activates NMDA receptors. The receptor's GluN2B subunit binds PSD-95, a scaffolding protein that couples the receptor to neuronal nitric oxide synthase and to nitric oxide production. Blocking the NMDA receptor itself disrupts normal signalling, so the Toronto group of Michael Tymianski took a different route: a peptide made of the last nine residues of GluN2B (the NR2B9c part) fused to the cell-penetrating Tat sequence from HIV, so that it can enter neurons and compete for the PSD-95 binding site.

The preclinical record

Rats, 2002: in Science, Aarts and colleagues reported that the Tat-NR2B9c peptide reduced damage in rat models of focal cerebral ischaemia when given before or after the insult (Aarts et al., 2002, PubMed).
Primates, 2012: in Nature, Cook, Teves and Tymianski reported that a PSD-95 inhibitor given after experimental stroke in cynomolgus macaques reduced infarct volume on MRI and histology and preserved function in behavioural tests (Cook et al., 2012, PubMed).

Both studies came from the developer's group. Tymianski founded NoNO Inc., the company that sponsored the clinical programme.

ESCAPE-NA1

ESCAPE-NA1 enrolled 1,105 participants with large-vessel ischaemic stroke at 48 hospitals in eight countries, all undergoing endovascular thrombectomy within 12 hours (Hill et al., 2020, PubMed). A good functional outcome (modified Rankin Scale 0–2 at 90 days) was reached by 61.4% with nerinetide and 59.2% with placebo, an adjusted risk ratio of 1.04 (95% CI 0.96–1.14; p=0.35). The authors reported an interaction with alteplase, the clot-dissolving drug: the apparent effect was absent in participants who had also received it. Their explanation was that plasmin generated by alteplase can cleave the peptide.

ESCAPE-NEXT

ESCAPE-NEXT was designed to confirm the result in people who had not received a thrombolytic drug. It randomised 850 participants at 77 centres in nine countries (Hill et al., 2025, PubMed). A good outcome was reached by 45% with nerinetide and 46% with placebo (odds ratio 0.97, 95% CI 0.72–1.30; p=0.82). Serious adverse events were similar between groups.

FRONTIER

FRONTIER tested whether paramedics could give the peptide before hospital arrival, within three hours of suspected stroke, in Ontario and British Columbia (Christenson et al., 2025, PubMed). Of 532 participants, the main analysis population of suspected stroke included people later found to have haemorrhage (18%), transient attacks (9%) or stroke mimics (10%). Median time to the study drug was 64 minutes. A favourable outcome was reached by 57% with nerinetide and 58% with placebo (adjusted odds ratio 1.05). In the subgroup that went on to reperfusion, the adjusted odds ratio was 1.84 (95% CI 1.03–3.28), a secondary finding.

The pooled post-hoc analysis

A 2025 individual-participant meta-analysis pooled 690 of the 2,487 participants from the three trials who matched the animal-study conditions: enrolment within three hours and reperfusion without prior thrombolysis (Tymianski et al., 2025, PubMed). Responders were 56% with nerinetide and 48% with placebo (adjusted odds ratio 1.48, 95% CI 1.07–2.06). Because the subgroup was chosen after the trials ended, this is a hypothesis for a new trial rather than confirmation.

Why it matters for neuroscience research

Nerinetide is one of the most extensively tested neuroprotective peptides in humans. The gap between consistent animal results and neutral primary end points in large trials is a recurring theme in stroke research, and the alteplase interaction shows how co-administered drugs can affect a peptide's stability.

Limitations

Primary end points: all three trials were neutral on their prespecified primary outcome.
Subgroups: the positive signals come from subgroup and post-hoc analyses, which carry a high risk of chance findings.
Sponsor: the preclinical and clinical work was led by the developer's group and funded by NoNO Inc.
Translation: the animal models used reperfusion conditions that the trials did not fully reproduce.

Key terms

PSD-95: postsynaptic density protein 95, a scaffolding protein that organises signalling at excitatory synapses
NMDA receptor: a glutamate receptor whose over-activation is linked to neuronal death during ischaemia
Cell-penetrating peptide: a short sequence, such as Tat, that carries attached cargo across cell membranes
Modified Rankin Scale (mRS): a 0–6 scale of disability after stroke; 0–2 is usually counted as functional independence
Post-hoc analysis: an analysis chosen after the data were collected

Supplier

Purita is a store that sells peptides for laboratory research use only. The link below goes to its neurological research category; check the product page and certificate of analysis for what is actually listed.

Purita neurological category

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