medwireNews: The patients with acute ischemic stroke who are likely to benefit from nerinetide are those who receive the postsynaptic density (PSD)-95 inhibitor within 3 hours of stroke onset and are candidates for reperfusion without previous thrombolysis, suggests a post-hoc meta-analysis published in The Lancet Neurology.
The study authors explain that these were “the inclusion criteria of the animal studies that provided the rationale” for three clinical trials of nerinetide versus placebo – ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER. However, “none of the trials faithfully replicated the inclusion criteria,” and none met their prespecified primary efficacy endpoints.
To determine if appropriate replication of these criteria might result in more favorable treatment outcomes, Michael Tymianski (University Health Network, Toronto, Ontario, Canada) and colleagues pooled data from the three trials on a subgroup of 690 participants who met the criteria. The patients had a median age of 76 years, 53% were men, and they had a median baseline score of 17 on the 42-point National Institutes of Health Stroke Scale, where higher scores indicate greater severity of stroke impairment.
In all, 389 of the patients had been randomly assigned to receive intravenous nerinetide at a single dose of 2.6 mg/kg up to a maximum of 270 mg, and 301 to receive placebo. The median time from stroke onset to receiving treatment was 118.5 minutes.
At 90 days, the number of patients who had a favorable outcome and met the primary endpoint for their trial was significantly higher in the nerinetide group than the placebo group, at 216 (56%) versus 144 (48%). This equated to an odds ratio (OR) of 1.48 in favor of nerinetide after adjusting for age, stroke severity, and trial.
When Tymianski and colleagues compared scores on the 6-point modified Rankin Scale (mRS), where higher scores indicate greater stroke disability, 42% of the nerinetide group versus 34% of the placebo group achieved an excellent functional outcome (mRS score of 0–1 point, OR=1.56), and 56% versus 51% achieved a good functional outcome (mRS score of 0–2 points, OR=1.39). In both cases, the differences reached statistical significance.
The rate of stroke worsening at 90 days was also significantly reduced among patients in the nerinetide group (8 vs 14%, OR=0.53), and their infarct volumes were numerically smaller, on average, than those of the placebo group (64.6 vs 72.9 mL). There was no significant difference between the groups in the rate of mortality at 90 days, at 16% with nerinetide and 18% with placebo, and the researchers report that no “safety concerns were identified in either group.”
They highlight that a dwell time of 60 minutes or more – from treatment administration to the initiation of reperfusion – reduced the overall probability of a favorable outcome by 20%. This association was attenuated with nerinetide use and the treatment effect increased with longer dwell time, most notably beyond 60 minutes.
In a related comment, Christopher Price (Newcastle University, UK) says “[t]his finding suggests that nerinetide might work best as an agent for patients who cannot receive thrombolysis or thrombectomy imminently, rather than as an agent that enhances reperfusion when administered near to the time of treatment.”
He points out that “after more than a decade of thrombectomy and two decades of thrombolysis, large groups of patients remain unable to access these treatments rapidly.”
The researchers conclude that their findings also provide “the foundation for the next stage of research on the use of PSD-95 inhibitors as neuroprotective treatment for ischaemic stroke.”
This includes the current ACT-42 trial of a next-generation PSD-95 inhibitor similar to nerinetide that is also administered within 3 hours but, unlike nerinetide, it “is not susceptible to cleavage by tissue plasminogen activators,” and as such is being assessed as an adjunct to reperfusion therapy, the investigators remark.
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