Another Neuroprotective Agent Fails in Acute Stroke . . . Or Does It?

LOS ANGELES, CA—Nerinetide (NoNO) did not improve functional outcomes in an overall cohort of patients with acute ischemic stroke who underwent endovascular therapy, but the investigational neuroprotectant appeared to have benefits in those who did not receive thrombolytic therapy, results from the ESCAPE-NA1 trial show.

For the primary outcome, favorable functional status (modified Rankin Scale score of 0 to 2) at 90 days, there was no difference between the nerinetide and placebo groups when all patients were included (61.4% vs 59.2%; adjusted risk ratio 1.04; 95% CI 0.96-1.14), Michael Hill, MD, and Mayank Goyal, MD (both Foothills Medical Centre, University of Calgary, Canada), jointly reported at the International Stroke Conference here. There were likewise no differences in any secondary outcomes.

Alteplase (Activase; Genentech) therapy, however, significantly modified the treatment effects (P = 0.033 for interaction). In the roughly 40% of patients who did not receive the thrombolytic, nerinetide was associated with improved functional outcomes, a lower risk of death, and smaller infarcts.

With the study, published simultaneously online in the Lancet, “we think that we have provided perhaps the first clear evidence in humans that neuroprotection is possible,” Hill concluded during his presentation. “We know we’re going to have to do more studies, and we’re looking forward to doing that.”

Experts interviewed by TCTMD agreed that there is enough promising data in this trial to justify further studies.

Perhaps this will renew people’s and industry’s faith in the general idea of doing neuroprotection and achieving a real clinical benefit. Mitchell Elkind

Mitchell Elkind, MD (NewYork-Presbyterian Hospital/ Columbia University Irving Medical Center, New York, NY), said, “I think it’s very exciting to have a trial that shows that there might be some benefit to a neuroprotectant. That’s always been a challenge in stroke: finding a way to interfere with the secondary damage that occurs after stroke.”

But the benefits hinted at in the subset of patients who did not receive thrombolytic therapy are only hypothesis-generating and should lead to additional studies in the future, said Elkind, president-elect of the American Heart Association.

Taking a broader perspective, Elkind said the trial “could lead to some renewed interest in the field of neuroprotection in general. After a number of failed attempts, there’s been a sense that industry has lost interest in stroke because it’s too difficult outside of using devices to open up the clogged vessels. And perhaps this will renew people’s and industry’s faith in the general idea of doing neuroprotection and achieving a real clinical benefit.”

ESCAPE-NA1

Neuroprotection in patients with acute ischemic stroke has proven to be an intractable problem; none of the agents evaluated over the years have been proven to have clinical benefits. Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, a synaptic scaffolding protein, has been shown to have neuroprotective effects in preclinical stroke models of ischemia-reperfusion and in a phase II study of patients who underwent endovascular repair of intracranial aneurysms.

ESCAPE-NA1 tested the novel agent in patients undergoing endovascular therapy for acute ischemic stroke caused by a large-vessel occlusion. The trial, conducted at 48 acute care hospitals in Canada, the United States, Europe, Australia, and South Korea, included 1,105 patients who presented within a 12-hour treatment window, were slated for endovascular treatment, and had brain imaging that confirmed moderate-to-good collateral circulation and a small-to-moderate ischemic core. Alteplase was given when indicated.

The patients were randomized to IV nerinetide given in a 10-minute infusion at a dose of 2.6 mg/kg (maximum 270 mg) or to saline placebo. They were stratified according to receipt of alteplase and to planned endovascular device therapy.

Overall, nerinetide did not improve functional outcomes according to mRS scores at 90 days or a variety of secondary outcomes, including neurological disability, functional independence in activities of daily living, excellent functional outcome, and mortality. Serious adverse events occurred at similar rates in the two groups.

Those findings were similar in the 60% of patients who received alteplase as part of usual care. But in the remaining patients, nerinetide increased the proportion of patients with an mRS score of 0 to 2 (59.3% vs 49.8%; adjusted RR 1.18; 95% CI 1.01-1.38). That works out to a number needed to treat of about 11, Hill noted. Nerinetide also lowered the risk of death (12.8% vs 20.3%; adjusted RR 0.56; 95% CI 0.34-0.95) and reduced infarct volume on 24-hour follow-up imaging in this subgroup.

To explain the interaction, Hill pointed to a pharmacokinetic analysis in a subset of patients showing that nerinetide availability was reduced in the presence of alteplase. “We think that this is clear biological evidence that the reason we saw no effects in the alteplase group was that the alteplase was activating proteases which were chewing up the drug,” he said.

Neuroprotection in the Thrombectomy Era

Larry Goldstein, MD (University of Kentucky, Lexington), said that the signals of benefit seen in the trial were “quite promising” and that the explanation for the interaction with alteplase was reasonable. But he, too, called for additional studies to confirm the subgroup results, noting that researchers investigating potential neuroprotectants have been burned before.

“There’ve been [multiple] studies where there was something very positive in an unplanned subgroup and when tested prospectively, it doesn’t pan out,” Goldstein told TCTMD. “This seems quite plausible, but I think that it needs to be then tested prospectively.”

Clinton Wright, MD, director of the division of clinical research at the National Institute of Neurological Disorders and Stroke, Bethesda, MD, echoed that sentiment. “We have a long history of unfortunate results following subgroups that have benefitted in these exploratory analyses,” he told TCTMD.

But times have changed, both Goldstein and Wright pointed out. The failed neuroprotectant trials were conducted in an era that preceded the deluge of positive clinical trial data showing that thrombectomy with newer-generation devices—primarily stent retrievers—can effectively remove clots and improve outcomes in patients with large-vessel occlusions. It may be that neuroprotective agents will perform better if delivered after the arteries are cleared, allowing the therapies to reach the affected areas of the brain, Wright said.

ESCAPE-NA1 is “ground-breaking in the sense that it’s one of the first big, very-well-designed trials to study a neuroprotective agent in the era of thrombectomy, and that is hopefully an opportunity to revisit not only novel neuroprotectants but also ones that may have been tried previously,” Wright said, adding that “it’s a new era for this type of research.”

Whether many in industry will be ready to take another stab at neuroprotection in stroke is another issue, considering the sting of past failures, Wright said. “I think it’s important to conduct really rigorous research before we go to trials, and I’m sure that industry is going to want to see a lot of evidence before they’re going to jump back in full force.”