Novel Neuroprotectant Reduces Stroke During Aneurysm Repair

Megan Brooks

October 09, 2012

October 9, 2012 — In a phase 2 study, the experimental neuroprotectant NA-1 (NoNO Inc, Etobicoke, Ontario, Canada) reduced the number of iatrogenic embolic strokes in patients undergoing endovascular repair of a ruptured or unruptured intracranial aneurysm and appeared to be safe.

Findings from the Evaluating Neuroprotection in Aneurysm Coiling Therapy (ENACT) trial provide evidence that tissue neuroprotection is "achievable and measurable" in patients with acute ischemic stroke, Michael D. Hill, MD, from the Hotchkiss Brain Institute, University of Calgary, Alberta, Canada, and colleagues say.

"Our findings lend support to strong preclinical evidence in rodents and in old-world primates that indicate that neuroprotection with NA-1 is feasible, and warrants controlled trials in patients with acute ischemic stroke," they conclude.

Their findings were published online October 8 in Lancet Neurology.

A Door Reopens

NA-1, also known as Tat-NR2B9c, is an inhibitor of PSD-95, a postsynaptic scaffolding protein that links N-methyl-D-aspartic acid glutamate receptors to neurotoxic signaling pathways. NA-1 disrupts these links and inhibits stroke damage.

"After two decades of negative human trials in the neuroprotection area, this is the first one with serious promise to show a true effect in human ischemic stroke," Dr. Hill said in an email to Medscape Medical News.

In a linked comment published with the study, Markku Kaste, PhD, from Helsinki University Central Hospital in Finland, writes that "[a]fter so many trials in the search for a neuroprotective agent failed to improve the outcome of patients with ischaemic stroke, nihilism began to spread and the door to finding such a drug seemed to be closing." He concludes, "The door is now reopening for new neuroprotection trials in stroke."

Most patients undergoing endovascular intracranial aneurysm repair show small, embolic, procedurally induced ischemic strokes on magnetic resonance imaging (MRI). The ENACT trial focused on this population of patients.

The trial enrolled patients aged 18 years and older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the United States. A total of 197 patients were randomly allocated to receive an intravenous infusion of NA-1 or saline control at the end of the repair procedure. The primary outcome was safety, and primary clinical outcomes were the number and volume of new ischemic strokes defined by MRI performed 12 to 95 hours after infusion.

Twelve patients didn't receive treatment because they were found to be ineligible after random assignment, leaving a modified intention-to-treat population of 185 patients (92 in the NA-1 group and 93 in the placebo group). All but 1 patient completed postprocedure MRI.

Compared with placebo recipients, NA-1–treated patients had fewer new brain infarctions, as detected by both diffusion-weighted MRI (adjusted incidence rate ratio, 0.53; 95% confidence interval [CI], 0.38 - 0.74) and fluid-attenuated inversion recovery MRI (adjusted incidence rate ratio, 0.59; 95% CI, 0.42 - 0.83). Overall, ischemic lesion volume did not differ between the groups.

In secondary subgroup analyses, patients with ruptured aneurysms who received NA-1 had smaller new infarcts and a more favorable 30-day National Institutes of Health Stroke Scale (NIHSS) score (0 to 1) than did patients with ruptured aneurysms who received placebo. A nonsignificant trend for better 30-day functional outcome (modified Rankin score, 0 to 2) was also seen in the NA-1 group.

No Serious Side Effects

Three patients died: 1 in the NA-1 group on day 3 owing to hemorrhagic shock from a retroperitoneal hematoma associated with the groin puncture and 2 in the placebo group (1 on day 11 and 1 on day 13) owing to neurologic complications from intraprocedural aneurysm rupture.

Two nonserious adverse events judged to be related to NA-1 occurred; both were transient hypotension that resolved within several minutes. No serious adverse events were attributed to NA-1.

The researchers say the ENACT trial findings are limited by the small sample size, the use of a surrogate primary outcome rather than a clinical outcome, and the use of a modified intention-to-treat analysis. They urge caution in generalizing the findings on both safety and efficacy given the selected nature of the population studied. They also note that NA-1 was given at the end of the procedure to determine whether neuroprotection in people could be attained when it is given after stroke onset.

In his comment, Dr. Kaste notes, "Had the study design allowed for the administration of NA-1 before endovascular treatment, it might have been more effective because findings from animal studies have shown treatment with a potential neuroprotective drug to be more effective when given before a stroke than when given after one. The idea behind the study design of ENACT was that, if the results were encouraging, the treatment should be studied in patients with ischaemic stroke after the onset of symptoms."

Indeed, said Dr. Hill, "the next step is a study among patients with community onset stroke (rather than stroke induced during an aneurysm coiling procedure). We are designing that study now."

The Holy Grail?

Dr. Kaste thinks the ENACT trial results will probably encourage trials of NA-1 carotid surgery, open heart surgery, and other invasive treatments with a high risk for brain injury. In these trials, treatment with NA-1 could be given before surgical or other invasive interventions.

The "good news" from the ENACT trial, Dr. Kaste says, is that the reduction of ischemic damage in patients with brain infarcts is "seemingly possible."

He notes that the NA-1 trial results support those of trials of 2 other potential neuroprotectant agents: edaravone, a free radical scavenger, and ginsenoside-Rd, a receptor-operated calcium-channel antagonist.

Both agents were shown to be effective in small placebo-controlled trials when given within 72 hours of ischemic stroke onset (Cerebrovasc Dis 2003;15:222-229; Eur J Neurol 2012;19:855-863).

All 3 drugs share the feature of being so-called dirty drugs, Dr. Kaste notes, "working through the pathways of ischemic cell death and repair on many levels." However, only after large, well-designed, and well-executed randomized controlled trials "will we know whether NA-1, ginsenoside-Rd, edaravone, or some other drug is the long-awaited holy grail for the treatment of patients with ischemic stroke," he concludes.

The ENACT trial was funded by NoNO Inc; Etobicoke, Ontario, Canada; and Arbor Vita Corp. Several of the authors are employees or have financial relationships with NoNO Inc. Dr. Kaste was principal investigator in the MCI-186-E04 trial of edaravone and a member of the Steering Committee of the CEPO Multiple Dose study of carbamylated erythropoietin. He has served as a consultant for Mitsubishi Tanabe Pharma Corporation and Lundbeck AG.

Lancet Neurol. Published online October 8, 2012. Abstract Commentary