Nerinetide
clinical trialsAlso known as: NA-1, Tat-NR2B9c
**Mechanism of Action** Nerinetide (NA-1, Tat-NR2B9c) is a 20-amino-acid peptide that disrupts the interaction between postsynaptic density protein-95 (PSD-95) and N-methyl-D-aspartate (NMDA) receptors. By competitively binding to the PDZ2 domain of PSD-95, it prevents the assembly of NMDA receptor–PSD-95–neuronal nitric oxide synthase (nNOS) complexes. This uncoupling selectively inhibits downstream excitotoxic signaling (e.g., nitric oxide production) without blocking normal NMDA receptor activity, thereby reducing neuronal death during ischemic stress. **Key Research Findings** Preclinical studies demonstrated robust neuroprotection in rodent and primate models of focal cerebral ischemia, with reduced infarct volumes and improved functional outcomes. The phase III ESCAPE-NA1 trial (NCT02930018) evaluated nerinetide in acute ischemic stroke patients undergoing endovascular thrombectomy. While the overall trial did not meet its primary endpoint (modified Rankin Scale at 90 days), a prespecified subgroup analysis showed significant benefit in patients not receiving concurrent alteplase. A subsequent phase II/III trial (ESCAPE-NEXT) is investigating this interaction further. Additional studies have explored its potential in subarachnoid hemorrhage and traumatic brain injury. **Clinical Relevance** Nerinetide represents a novel therapeutic strategy targeting excitotoxicity downstream of NMDA receptors, avoiding the psychotomimetic side effects of direct NMDA antagonists. Its efficacy appears contingent on avoiding co-administration with alteplase, which may cleave the peptide. Ongoing trials aim to clarify optimal patient selection and dosing, with potential applications in multiple acute neurological conditions where excitotoxicity contributes to injury. For research purposes only — not medical advice.
Key data
C105H188N42O30Research & studies
No significant overall difference in functional independence at Year 1 between nerinetide (48.0%) and placebo (47.9%) groups (aOR 1.12, 95% CI 0.74-1.71, P=0.593).; Treatment effect was modified by enrollment window (P interaction=0.044); early window participants (<3 hours) showed higher functional independence with nerinetide (52.6% vs 45.5%, aOR 2.80, 95% CI 1.18-6.66, P=0.019).; Early window nerinetide group also had improved survival at Year 1 (aOR 2.61, 95% CI 1.17-5.83, P=0.019).; No significant clinical benefit of nerinetide was observed among late window participants (3-12 hours).
Nerinetide did not significantly improve 90-day functional independence (mRS 0-1: RR 1.02, 95% CI 0.71-1.47; mRS 0-2: RR 1.07, 95% CI 0.93-1.22).; No significant difference in 90-day mortality (RR 0.89, 95% CI 0.60-1.34) or symptomatic intracranial hemorrhage (RR 0.80, 95% CI 0.44-1.45).; Despite preclinical evidence of neuroprotection, clinical benefits were not observed in this patient population.
Higher BD-tau at admission associated with more extensive early brain injury on CT and predicted larger final infarct volumes.; BD-tau increases from admission to day 2 related to infarct growth, and concentrations rose until day 7, higher in patients with secondary events like recurrent stroke.; After thrombectomy, BD-tau rise was smaller in patients with complete versus incomplete recanalization.; BD-tau outperformed other blood markers and imaging metrics in predicting 90-day functional outcome across infarct size strata and time points.
UnEND incidence was 11.0% (117/1063 patients), accounting for 68% of all END cases.; Independent predictors of unEND included anesthesia use (aOR 7.23), age (aOR 1.02 per year), and onset-to-reperfusion time (aOR 1.02 per 10 minutes).; In the CTP subgroup, unEND was strongly associated with infarct extension beyond the penumbra (OR 6.81) and larger extension volume (OR 1.07 per 10 mL).
Normobaric hyperoxia showed the most consistent benefit in reducing infarct size and improving functional outcomes.; Nerinetide and edaravone demonstrated mixed results as adjunctive therapies.; Functional outcomes were primarily measured using the modified Rankin Scale (mRS) and infarct volume.; Quality assessment using Cochrane RoB 2.0 revealed low to moderate risk of bias across most studies.
Cortical atrophy was independently associated with higher baseline stroke severity (adjusted difference 1.25 points, p=0.021).; Chronic infarcts were associated with higher baseline NIHSS scores (adjusted difference 1.27 points, p=0.049).; Total brain frailty burden was associated with consistently higher NIHSS scores from 30 to 90 days post-stroke.; Subcortical atrophy, white matter hyperintensities, and lacunes were not associated with baseline stroke severity.
Nerinetide increased the odds of favorable outcome at day 90 (aOR 1.48, 95% CI 1.07-2.06).; No significant difference in mortality between nerinetide (16%) and placebo (18%) groups.; Benefit was observed across multiple outcomes including modified Rankin Scale, stroke worsening, and infarction volumes.; Results suggest neuroprotection with nerinetide may be indicated for patients treated within 3 hours of stroke onset and selected for reperfusion.
Frequently asked questions
What is Nerinetide?
**Mechanism of Action** Nerinetide (NA-1, Tat-NR2B9c) is a 20-amino-acid peptide that disrupts the interaction between postsynaptic density protein-95 (PSD-95) and N-methyl-D-aspartate (NMDA) receptors. By competitively binding to the PDZ2 domain of PSD-95, it prevents the assembly of NMDA receptor–PSD-95–neuronal nitr
How does Nerinetide work?
PSD-95 inhibitor peptide that uncouples NMDA-receptor excitotoxic signaling; studied in acute ischemic stroke (ESCAPE-NA1).
What is the research status of Nerinetide?
Nerinetide is currently classified as clinical trials, with 76 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of Nerinetide?
Nerinetide has a molecular weight of approximately 2518.9 g/mol (formula C105H188N42O30).
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