Mixed but 'Intriguing' Results for Neuroprotective Agent in Stroke

(Call it what is really is:neuronal cascade of death  preventer. Neuroprotection doesn't sound like it needs immediate attention. Words matter.)

Mixed but 'Intriguing' Results for Neuroprotective Agent in Stroke

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.

ESCAPE-NEXT Trial

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.