Nerinetide

PSD 95 Inhibitor PeptideRx: InvestigationalCompound: Investigational

Also known as: NA-1, Nerinetide, Neuroprotective peptide NA‑1, PSD-95 inhibitor peptide, Tat-NR2B9c

Educational Only — Not medical advice. Consult a qualified clinician before using any peptide.

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Summary

Nerinetide (also known as NA-1, PSD‑95 inhibitor peptide, Tat‑NR2B9c) is an investigational neuroprotective peptide designed to limit neuronal injury during acute ischaemic stroke. It is administered intravenously as a single dose in conjunction with reperfusion therapies such as mechanical thrombectomy. Clinical trials have evaluated its safety and efficacy, but definitive benefit on functional outcomes has not been demonstrated.

Mechanism of Action

Nerinetide is a short peptide that mimics a segment of the NMDA‑receptor subunit NR2B and carries a cell‑penetrating Tat sequence. By binding to the PDZ domains of post‑synaptic density protein‑95 (PSD‑95), it blocks the assembly of the NMDA‑receptor/PSD‑95/nNOS complex, reducing calcium‑dependent excitotoxic signalling. Preclinical data also suggest modulation of eicosanoid pathways, contributing to reduced inflammation and neuronal death after ischaemia‑reperfusion.

What the Research Shows

Preclinical stroke models showed that nerinetide reduced infarct size and improved neurological scores, supporting its neuroprotective potential. In the multicentre ESCAPE‑NA1 trial (2020), 1,105 patients receiving mechanical thrombectomy were randomised to intravenous nerinetide (2.6 mg/kg) or placebo; the primary outcome (mRS 0‑2 at 90 days) was not significantly different (adjusted RR 1.04, p = 0.35). A subgroup analysis suggested that concurrent alteplase may negate nerinetide’s effect. The subsequent ESCAPE‑NEXT trial (2025) focused on patients without prior thrombolysis, but the abstract provides no efficacy data, only that safety was assessed. A 2021 review highlighted nerinetide as one of the few neuroprotectants tested in randomized stroke trials, noting the need for refined study designs.

Reported Benefits

Animal studies consistently reported reduced neuronal death, smaller infarcts, and better functional recovery after ischaemia‑reperfusion. In humans, nerinetide was well tolerated, with serious adverse events occurring at similar rates to placebo, suggesting a favorable safety profile for acute intravenous use alongside thrombectomy.

Limitations of the Evidence

The primary clinical trial did not demonstrate a statistically significant improvement in functional outcome, and a possible negative interaction with alteplase was observed, limiting its use in patients receiving thrombolysis. The ESCAPE‑NEXT results are not yet published, leaving uncertainty about efficacy in thrombolysis‑free patients. Overall evidence remains limited to a few large trials and preclinical data, with no regulatory approval.

Safety Considerations

Across the ESCAPE‑NA1 trial, the incidence of serious adverse events, including hemorrhagic transformation and mortality, was comparable between nerinetide and placebo groups. No specific drug‑related toxicities were identified, and the peptide was generally well tolerated when given as a single intravenous infusion. Caution may be warranted when combined with alteplase, as interaction effects have been reported.

How It Is Administered

Nerinetide is delivered intravenously as a single bolus dose of 2.6 mg per kilogram of body weight (maximum 270 mg) administered during the acute phase of stroke, typically immediately before or during endovascular thrombectomy. The formulation used in trials is a sterile peptide solution suitable for rapid infusion.

Routes of Administration

Intravenous

Goals & Uses

  • Prevention of delayed neuronal death post-ischemiaNeuroprotectionModerate
  • Reduction of infarct volume after endovascular thrombectomyNeurology / InterventionalModerate
  • Acute ischemic strokeNeuroprotectionModerate
  • Neuroprotection in acute ischemic strokeNeurology / StrokeModerate
  • Traumatic brain injuryNeuroprotectionLow

Contraindications

  • Severe renal impairment (eGFR <30 mL/min)RenalModerate
  • Known hypersensitivity to nerinetide or any componentAllergyHigh

Adverse Effects

  • Overall adverse event profile similar to placeboGeneralCommon
  • HeadacheNeurologicCommonPain in the head or upper neck
  • HypotensionCardiovascularUncommonLow blood pressure
  • NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
  • Infusion-related reactionsHypersensitivityUncommon

Drug Interactions

  • Alteplase (tPA)Low

Population Constraints

  • Severe renal or hepatic impairmentOrgan FunctionRelative
  • PregnancyReproductive SafetyRelative
  • Pediatric patientsAgeRelative
  • Pediatrics (<18 y)AgeAbsolute

Regulatory Status

  • European UnionInvestigationalUnder EMA assessment; not approved.
  • United StatesInvestigationalPhase 3 clinical trial (ESCAPE‑NA1).
  • United KingdomInvestigationalMHRA classifies as clinical trial material.

Not approved in any major jurisdiction; currently in Phase 3 clinical development for acute ischemic stroke (ESCAPE‑NA1) and exploratory trials for TBI.

Evidence & Sources

Frequently Asked Questions

What is nerinetide and how does it work?

Nerinetide is a short peptide that blocks the interaction between NMDA receptors and the scaffold protein PSD‑95. By preventing this complex from forming, it reduces excitotoxic calcium influx and downstream inflammatory signaling, which can limit brain damage after a stroke.

How is nerinetide given to patients?

In clinical studies the peptide is administered as a single intravenous infusion at a dose of 2.6 mg/kg (up to 270 mg). The infusion is given during the acute phase of an ischaemic stroke, usually in conjunction with mechanical thrombectomy.

Did clinical trials show that nerinetide improves stroke outcomes?

The large ESCAPE‑NA1 trial did not find a significant improvement in the proportion of patients achieving a good functional outcome (mRS 0‑2) at 90 days. A subgroup analysis suggested that concomitant alteplase may diminish any benefit. Results from the later ESCAPE‑NEXT trial are not yet available.

Is nerinetide safe to use?

Serious adverse events occurred at similar rates in nerinetide‑treated and placebo groups in the ESCAPE‑NA1 study, indicating a comparable safety profile. No specific toxicity was reported, but caution is advised when the drug is combined with alteplase because of a reported interaction.

What is Nerinetide used for?

Nerinetide is educationally associated with: Prevention of delayed neuronal death post-ischemia, Reduction of infarct volume after endovascular thrombectomy, Acute ischemic stroke, Neuroprotection in acute ischemic stroke, Traumatic brain injury. Educational only — not medical advice.

How is Nerinetide administered?

Recorded routes of administration: Intravenous.

What are the potential side effects of Nerinetide?

Reported adverse effects include: Overall adverse event profile similar to placebo, Headache, Hypotension, Nausea, Infusion-related reactions. This list is not exhaustive — consult a qualified clinician.

Who should avoid Nerinetide?

Recorded contraindications: Severe renal impairment (eGFR <30 mL/min), Known hypersensitivity to nerinetide or any component. Consult a qualified clinician before use.

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