Mixed but 'Intriguing' Results for Neuroprotective Agent in Stroke

October 12, 2023

Two new studies of the potential neuroprotective agent nerinetide (NoNO Inc) for patients with acute ischemic stroke have shown conflicting but intriguing results.

While the phase 3 ESCAPE-NEXT trial failed to show a benefit of nerinetide for stroke patients undergoing endovascular therapy, when the drug was given an average of 4 to 5 hours after stroke onset, the smaller FRONTIER study showed apparent impressive effects on functional outcomes with the drug when given in a prehospital setting to patients with suspected stroke with an average treatment time of around 1 hour from symptom onset.

Michael Hill, MD, professor of neurology at the University of Calgary, Canada, lead investigator of the ESCAPE-NEXT trial, acknowledged that the results of this trial were disappointing, but he said the FRONTIER results were very encouraging and suggested this agent needs to be given as early as possible.

"This is extremely interesting and intriguing from a scientific view. We feel we are on the verge of uncovering something that might lead to the holy grail of cytoprotection in stroke," he told t heheart.org | Medscape Cardiology.

"All of the experimental data with nerinetide support the idea that early treatment is important to see a large effect. We believe this drug is allowing cells to survive in the setting of ischemia," he said. "It is buying time until reperfusion is restored, so it makes sense to give it early. In this way, the paradigm of FRONTIER mimics more closely the preclinical models. Perhaps that's why there seems to be a signal there."

The two studies were presented on October 10 at the 15th World Stroke Congress (WSC) 2023, which is being held in Toronto, Canada.

The co-chair of the plenary session at which the studies were reported, Sean Savitz, MD, director, UTHealth Institute for Stroke and Cerebrovascular Diseases, Houston, Texas, told t heheart.org | Medscape Cardiology that he was excited to see benefit in the FRONTIER study.

"Many of us believe that earlier treatment will be better with neuroprotective agents," Savitz said. "This drug is thought to protect brain cells from injury, and stroke patients are losing brain cells rapidly, so it makes sense to get it on board as soon as possible. Giving a neuroprotective agent in the field as they did in the FRONTIER study seems to be the best way to go forward. Yes, this was just an exploratory study, and we have to wait for further trials, but I am encouraged by these results," he added.


Presenting the ESCAPE-NEXT results, Hill explained that the study was designed to replicate the earlier ESCAPE-NA1 trial, which suggested a benefit of nerinetide for patients with acute ischemic stroke undergoing endovascular therapy but not for those who received thrombolysis. It was later discovered that thrombolysis breaks down the nerinetide peptide, inactivating the drug.

The phase 3 ESCAPE-NEXT trial was conducted at 77 sites in Canada, the US, Europe, Australia, and Singapore. The study enrolled 850 patients with acute ischemic stroke with small established infarct core (ASPECTS score >5) and good collateral circulation, identified on imaging. The patients were within 12 hours of when they were last known to be well and were scheduled to receive endovascular therapy. Patients who had received thrombolysis were excluded.

Patients were randomly assigned to receive a single 2.6-mg/kg dose of nerinetide given by a 10-minute IV infusion or placebo (target within 15 minutes from randomization). The study drug was given at approximately 4–5 hours from stroke onset and an average of 43 minutes before reperfusion.

Results showed no difference in the primary endpoint of mRS 0–2 score (functional independence) at 90 days. This was achieved in 45.7% of patients who received placebo, vs 45.4% of those who received nerinetide. There were no differences in secondary outcomes between the two groups.

There was some suggestion that patients who received nerinetide earlier (within 3 hours) rather than later after stroke onset may have benefited.

No safety issues were seen with the drug.


The FRONTIER study was presented by Jim Christenson, MD, head of emergency medicine at the University of British Columbia, Vancouver, Canada. He explained that this was an exploratory study to inform a larger pivotal trial of nerinetide given at the earliest phases of ischemic stroke.

The Canadian study took a pragmatic approach, enrolling the broadest patient population with suspected stroke identified by paramedics in a prehospital setting. The patients were within 3 hours of symptom onset.

A total of 532 patients were randomly assigned to receive either a single vial of nerinetide (2.5 mg IV over 10 minutes, given at the scene or in the ambulance) or placebo. The average time to nerinetide treatment was 60 minutes from symptom onset. Twenty-five patients withdrew from the study before the first functional assessment, leaving a modified intention-to-treat population of 254 patients in the nerinetide group and 253 in the placebo group.

Results in this modified intention-to-treat population showed an improvement in the shift analysis of the modified Rankin Scale at 90 days in favor of the nerinetide group (odds ratio [OR] 1.54; 95% CI, 1.09 – 2.17; P = .015).

For those patients who were subsequently confirmed to be having an ischemic stroke (194 in the nerinetide group and 171 in the placebo group), a greater benefit was seen (OR, 1.72; 95% CI, 1.13 – 2.6; P = .011).

Among those patients who received reperfusion, there was a further improvement (OR, 2.13; 95% CI, 1.3 – 3.48; P = .003).

Thrombolysis was permitted in this study, as there was about an hour's delay between nerinetide administration and start of thrombolysis, which was believed to be enough time for the drug to work. Results suggested a benefit among patients who received thrombolysis (OR, 2.38; 95% CI, 1.41 – 4.00; P = .001).

Christenson concluded that it is feasible to provide neuroprotective treatment very early in stroke progression, in the prehospital setting; primary care paramedics can deliver an investigational drug requiring refrigeration and delivery by weight with a pump; and nerinetide showed an acceptable safety profile in patients suspected of having a stroke.

Making the Most of the Golden Hour

Commenting on differences between the two studies, Hill said: "The dominant argument that explains the two trials is that we were probably giving the drug too late in ESCAPE. In the FRONTIER study, they gave it very early and saw a strong signal of benefit. That's the most logical explanation of what we're seeing here."

He acknowledged that further studies are needed to confirm the FRONTIER results.

"We need to do more studies in that very early time window ― that first golden hour from stroke onset."

He pointed out that if used in the prehospital setting, it will inevitably be given to some patients who turn out not to be having an ischemic stroke. "The FRONTIER results seem to suggest it is safe for these patients, and while this is encouraging, the numbers are too small to make definitive statements," he added.

Hill reported that a similar drug, currently known as NN42, is now in development by NONO. That drug would be more suitable for use in a prehospital setting, as it does not need refrigeration, can be given by subcutaneous injection, and is resistant to being broken down by thrombolysis. Future studies are now being planned with this new drug.

If these future studies do show benefit similar to that suggested by the FRONTIER study with such a product, Hill said it could represent a turning point in stroke treatment. "It would be like having an EpiPen for stroke patients," he suggested.

Also commenting on the studies for theheart.org | Medscape Cardiology, Ashkan Shoamanesh, MD, the other co-chair of the WSC session, said: "The story with nerinetide seems to be coming together, with a suggestion that earlier time to treatment and lack of circulating nerinetide at the time of thrombolysis treatment are key determinants of a favorable treatment response."

He added: "Although not yet ready for clinical practice, there is a story emerging from these trials suggesting that with further refinement of trial design and patient selection, we could finally end up with a definitive trial proving the benefit of a neuroprotective agent in patients with acute ischemic stroke."

The ESCAPE-NEXT trial was funded by grants from NONO Inc and IQVIA Biotech and the Canadian Institute for Health Research. The FRONTIER study was funded by grants from the Brain Canada Foundation and NONO Inc.

15th World Stroke Congress (WSC) 2023: Presented October 10, 2023.

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