Novel Stroke Treatment Nerinetide Falls Short in Phase 3


Despite missing the primary end point, data from a subset of patients suggest that the novel peptide may be beneficial in those who have not received alteplase.

Michael Tymianski, MD, PhD, FRCSC

Michael Tymianski, MD, PhD, FRCSC

Findings from the phase 3 ESCAPE-NA1 trial of nerinetide for the treatment of acute ischemic stroke in patients selected to undergo endovascular thrombectomy suggest that the novel peptide does not convey additional benefits in this population compared with placebo; however, treatment with the intravenous drug was associated with improved outcomes in patients without prior administration of alteplase.1

The data were presented at the 2020 International Stroke Conference, February 19-21, 2020 in Los Angeles, California.

“Although patients who had prior administration of alteplase did not appear to benefit, likely due to a reduction of nerinetide plasma levels when alteplase was given first, we are excited by the magnitude and consistency of data in the pre-specified subgroup that were not treated with alteplase as well as the potentially long therapeutic window of nerinetide after stroke onset,” said Michael Tymianski, MD, PhD, FRCSC, president, chief executive officer, and founder of NoNO, the biotechnology company sponsoring the trial. Tymianski is also head of the Division of Neurosurgery at the University Health Network in Toronto and a professor of surgery and physiology at the University of Toronto, as well as the Harold and Esther Halpern Chair in Neurosurgical Stroke Research.2

The double-blind, placebo-controlled, parallel-group ESCAPE-NA1 clinical trial (NCT02930018) was the largest study of endovascular thrombectomy candidates globally, enrolling 1105 patients who were randomly assigned to either a single 2.6 mg/kg dose of intravenous nerinetide (n = 549) or placebo (n = 556) immediately after meeting enrollment criteria, which included enrollment within 12 hours of stroke onset and within 30 minutes of randomization. Per standard of care protocols, alteplase was administered to a subset of patients in each treatment arm (n = 330 in nerinetide group; n = 329 in placebo group).

Overall, 61.4% and 59.2% of patients in the nerinetide and placebo groups, respectively, achieved the primary outcome of 0-2 on the Modified Rankin Scale at 90 days (RR 1.04; 95% CI, 0.96-1.14; P = .350). The treatment was also found to be generally safe and well tolerated, with a similar rate of serious adverse events observed between both groups.

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When further analyzing the subsets of patients who did or did not receive alteplase, the investigators noted a treatment effect modification with use of alteplase. Among the patients who did not receive alteplase, 59.3% achieved the primary outcome compared with 49.8% of those who were randomized to placebo (RR 1.18; 95% CI, 1.01-1.38). A 7.5% reduction in risk of mortality at 90 days was observed in the group who did not receive alteplase, resulting in an approximate 50% reduction in the hazard of death (HR 0.56; 95% CI, 0.35-0.95).

“The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum,” the investigators wrote.1

This trend continued to be relevant across other outcomes. While there was no observed difference in infarct volume among patients who received alteplase plus nerinetide or placebo, those who did not receive alteplase demonstrated reduced median infarct volumes compared with placebo.

“This finding raises the possibility of a drug—drug interaction between alteplase and nerinetide that might have nullified the treatment effect of nerinetide in the alteplase stratum and to a 9% absolute benefit (number needed to treat of 10–11 patients) in the no alteplase stratum,” the investigators proposed.1 “The absence of benefit of nerinetide in the alteplase stratum is likely to be due to enzymatic cleavage of nerinetide by plasmin, leading to subtherapeutic concentrations of nerinetide; this hypothesis was supported by the pharmacokinetic data obtained from a subset of trial participants.”

While this surprising finding is promising, the investigators noted that additional confirmation is required to draw a definitive conclusion on treatment effect.

A second phase 3 trial, FRONTIER (NCT02315443), is currently recruiting and will evaluate nerinetide as an emergency drug delivered in the field by paramedics within 3 hours of stroke symptom onset. If positive, the results of that trial may help confirm the findings in ESCAPE-NA1 and the drug’s neuroprotective potential.

For more coverage of ISC 2020, click here.


1. Hill MD, Goyal M, Menon BK, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicenter, double-blind, randomized controlled trial. Lancet. Published online February 20, 2020. doi: 10.1016/S0140-6736(20)30258-0.

2. NoNO Inc. reports groundbreaking results from the phase 3 ESCAPE-NA1 study of the peptide, nerinetide, in acute ischemic stroke [news release]. Toronto, Ontario, Canada: NoNO Inc. February 20, 2020. Accessed February 21, 2020.

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