麻豆传媒

LOS ANGELES -- A putative neuroprotective agent failed to improve stroke patients' outcomes when given in conjunction with endovascular thrombectomy in the although those not given a thrombolytic did appear to benefit.

Nerinetide led to "good functional outcome," defined as a modified Rankin Scale (mRS) score of 0 to 2 at 90 days, in 64.1% of patients compared to 59.2% of patients getting placebo infusion (adjusted RR 1.04, 95% CI 0.96-1.14, P=0.35).

Nor were there benefits for mortality (12.2% vs 14.4%, adjusted RR 0.84, 0.63–1.13) or any other secondary outcomes or safety outcomes, Michael Hill, MD, of the University of Calgary, Alberta, reported here at the and .

"Once again, the favourable effects of a neuroprotective drug reported consistently in preclinical models of brain ischaemia did not translate to clinical efficacy in humans with brain ischaemia," Graeme Hankey, MD, of the University of Western Australia in Perth, wrote in an accompanying editorial.

Nerinetide is a peptide drug believed to interrupt a pathway tied to excitotoxic neuron death in stroke. The agent had shown strongly positive effects in animal models including macaques with middle cerebral artery occlusion.

In exploratory analyses, however, the 40% of patients in ESCAPE-NA1 who did not receive alteplase (Activase, likely because of presenting outside the treatment window) saw a "large" treatment effect.

Rates of functional independence with an mRS of 0-2 were 10 percentage points higher with nerinetide (59.3% vs 49.8%, adjusted RR 1.18, 95% CI 1.01-1.38, number needed to treat 11), and 90-day mortality was nearly halved in this group (adjusted HR 0.56, 95% CI 0.35-0.95).

"We think that we have provided perhaps the first clear evidence in humans that neuroprotection is possible," Hill said at the late-breaking clinical trial session. "We know we're going to have to do more studies, and we're looking forward to doing that."

The trial has been closely watched for its potential implication to neuroprotection more broadly, commented American Heart Association chief medical officer Mariell Jessup, MD. "The studies of neuroprotectors in the past -- because they couldn't get to the damaged tissue because there was a clot -- there were failures. The theory was you can now open up the thrombus and deliver the neuroprotectant."

If the concept panned out, many other agents would be on the table to try and in other settings, such as aortic surgery or even transcatheter procedures, she said in an interview with 麻豆传媒. "In theory, you would deliver a neuroprotectant in anything that delivers the possibility of debris that goes to the brain."

The trial design wasn't to blame for the overall failure, wrote Hankey.

"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 eicosa peptide nerinetide," Hankey noted.

The researchers noted this surprise finding was not noted in the animal models. Confounding by indication couldn't be excluded, they added.

The trial included 1,105 patients with acute ischemic stroke due to large vessel occlusion treated with endovascular thrombectomy within 12 hours of onset. They were randomized double-blind to a single dose of IV nerinetide at 2.6 mg/kg as quickly as possible during treatment, up to a maximum dose of 270 mg, or saline placebo over a 10-minute period, finished before arterial access closure.

Moderate to good collaterals were required, with the idea it might have been required to deliver the drug. Treatment groups were stratified prospectively by receipt of alteplase, given according to guidelines, and physician's declared choice of endovascular device.

An , is testing nerinetide administered by paramedics prior to hospital arrival and before alteplase would be administered.