First Clinical Evidence of Neuroprotection in Acute Stroke?

February 20, 2020

LOS ANGELES ― A new potential neuroprotectant agent has been found to be beneficial for patients with acute ischemic stroke undergoing endovascular thrombectomy in a large placebo-controlled trial, but only for those patients who did not also receive thrombolysis.

There was no difference between groups on the primary outcome in the main analysis of the trial, lead author Michael Hill, MD, reported.

However, "In our study, we found a dramatic interaction of nerinetide with alteplase. There was a large benefit of nerinetide in patients not given thrombolysis, but in patients who received alteplase, this benefit was completely obliterated," Hill told Medscape Medical News.

"In patients not treated with thrombolysis, we found a large effect size with a 9.5% absolute improvement in patients having an independent outcome (modified Rankin Score [mRS] 0-2) and a number need to treat of 10 to 11," he said. "We also found a mortality benefit and a reduction in the size of strokes, with all other secondary outcomes going in the right direction.

"The drug works really well in patients who do not get thrombolysis, but it doesn't work at all in patients who have had thrombolysis. The thrombolytic appears to break the peptide down so it is inactive," he added.

"This is the first evidence that neuroprotection is possible in human stroke. This has never been shown before," Hill noted. "Many previous clinical trials of potential neuroprotectants have been negative. We think this is a major breakthrough. This is pretty exciting stuff with really tantalizing results."

Hill, who is professor of neurology at the University of Calgary, Alberta, Canada, presented results of the ESCAPE-NA1 trial today at the International Stroke Conference (ISC) 2020. The trial was also simultaneously published online in the Lancet.

Endogenous Nitric Oxide

The new agent ― known as NA1 or nerinetide ― is a 20 amino acid peptide with a novel mechanism of action; it inhibits signaling that leads to neuronal excitotoxicity. "It reduces endogenous nitric oxide generated inside the cell during ischemia, which is one of the main biochemical processes contributing to cell death," Hill explained. In a primate model of ischemia reperfusion that was published in Nature in 2012, it was highly protective, he added.

The drug is given just once at the time of thrombectomy. It is short lived in the blood but detectable in the brain for up to 24 hours, Hill said.

The trial included 1105 patients who had experienced acute ischemic stroke due to large-vessel occlusion within a 12-hour treatment window and for whom imaging results suitable for thrombectomy were available. The patients were randomly assigned to receive either intravenous nerinetide in a single dose of 2.6 mg/kg or saline placebo at the time of thrombectomy.

Patients were stratified by intravenous alteplase treatment and by declared endovascular device choice.

The primary outcome was a favorable functional outcome 90 days after randomization, defined as an mRS score of 0–2. In the main analysis of the whole population, this favorable outcome was achieved for 61.4% of the group that received nerinetide and for 59.2% of the placebo group, a nonsignificant difference. Secondary outcomes were also similar between the two groups.

But an exploratory analysis showed evidence that nerinetide's treatment effect was modified by alteplase treatment.

Among the patients who did not receive alteplase, use of nerinetide was associated with improved outcomes, whereas no benefit was found in the alteplase stratum. The difference in absolute risk slightly but not significantly favored placebo.

In the stratum that did not receive alteplase (40% of the trial population), the favorable mRS outcome was achieved by 59.3% of patients who received nerinetide, compared with 49.8% of those given placebo ― a significant difference (adjusted risk ratio, 1.18; 95% confidence interval, 1.01 – 1.38).

There was also a 7.5% absolute risk reduction in mortality at 90 days post treatment with nerinetide for the patients who did not receive thrombolysis. This resulted in an approximate halving of the hazard of death (adjusted hazard ratio, 0.56).

In addition, infarct size was reduced in those patients who received nerinetide but not thrombolysis.

Among the patients who received alteplase, the proportion of patients who achieved an mRS of 0–2 was similar between groups, as were median infarct volumes.

The observed treatment effect modification by alteplase was supported by reductions in peak plasma nerinetide concentrations in the alteplase stratum, the researchers report.

They say that the combination of the clinical results in the no-thrombolytic stratum and subsequent tests documenting that nerinetide is broken down by plasmin (which is generated by alteplase) "provide evidence that the clinical observation of effect modification is not a chance finding." But they add: "This novel observation will require additional confirmation, and we cannot draw a definitive conclusion on treatment effect in this study."

"Shaking Up the Field"

There is still more work to do, Hill said. "We don't fully understand the pharmacology, and we will certainly have to do another trial, but we believe this agent is going to shake the field up.

"This is a totally new drug, and we have to think carefully about where it could fit in," he said. "The obvious first group is those patients who do not receive thrombolysis. This is a large group, as most patients do not present in time for thrombolysis. Then we can work on the biochemistry and see if we can develop a version of nerinetide that is resistant to breakdown by thrombolysis."

Another possibility would be to withhold thrombolysis and give nerinetide instead. "It may be that thrombolysis is not needed if patients are receiving thrombectomy ― this is being suggested now in initial studies," Hill stated.

They also chose a very select group of patients ― those undergoing thrombectomy, who represent only 10% to 15% of stroke patients. "We have to work out how to expand that population," he said.

Hill noted that there have been many examples in the past of potential neuroprotectant agents that have worked in animal models of ischemia-reperfusion but that failed in humans with acute stroke.

"Until recently, we have not had a reliable ischemia-reperfusion model in humans, but now with endovascular therapy, we have a situation where the blood flow is reliably restored, which is an ideal situation to test new neuroprotectant agents. That may be another factor that has contributed to our positive findings," he said.

In an accompanying comment in the Lancet, Graeme J. Hankey, MD, the University of Western Australia, Perth, notes that although endovascular thrombectomy after use of intravenous alteplase improves reperfusion and clinical outcomes for a fifth of patients with ischemic stroke caused by large-artery occlusion, half of patients do not recover an independent lifestyle. Cytoprotection aims to augment the resilience of neurons, neurovascular units, and white matter during ischemia until perfusion is restored.

Hankey also points out that numerous cytoprotection strategies have been reported to reduce brain infarction in preclinical models of ischemic stroke but have not been found to improve clinical outcomes in clinical trials involving patients with ischemic stroke.

The advent of thrombectomy provides an opportunity to reassess cytoprotection as an adjunctive therapy for patients with types of temporary brain ischemia that align more closely with successful preclinical models of ischemia, cytoprotection, and reperfusion, he adds.

On the results of the current study and the benefit in the no-thrombolysis group, Hankey states: "Although this result might be a chance finding or confounded by the indication for alteplase, complementary pharmacokinetic data in a small number of patients treated with nerinetide showed that alteplase lowered plasma concentrations of nerinetide, probably by converting plasminogen to plasmin, which cleaves peptide bonds not only in fibrin but also in the eicosapeptide nerinetide."

He says the ESCAPE-NA1 trial "informs the study of cytoprotection as an adjunct therapy to reperfusion in acute ischemic stroke" and suggests that researchers who have reported encouraging results of other cytoprotective therapies for ischemic stroke should test their compounds for interactions with concurrent thrombolytic therapies.

The ESCAPE-NA1 trial was sponsored by NoNO, the company developing nerinetide. Hill has received grants from NoNO for the conduct of the study, is named on a US patent for systems and methods for assisting in decision making and triaging for acute stroke patients, and owns stock in Calgary Scientific. Other coauthors are employees of NoNO or have stock options in the company. Hankey has received personal honoraria from the American Heart Association, AC Immune, Bayer, Bristol-Myers Squibb, and Medscape outside the area of work that he commented on.

International Stroke Conference (ISC) 2020: Abstract LB2. Presented February 20, 2020.

Lancet. Published online February 20. Abstract, Comment

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