AAN 2021 | ESCAPE-NA1: nerinetide for the treatment of acute ischemic stroke

Well, the ESCAPE-NA1 trial was a trial that read out last year. At the time, it was the largest global stroke trial that was ongoing, but more importantly, it was the largest in many years for neuroprotection. So this is a trial that tested the drug nerinetide as an adjunct to endovascular thrombectomy, which essentially creates an ischemia-reperfusion type scenario in human stroke. So the idea was that we would test nerinetide versus placebo in patients who have a stroke caused by a large vessel occlusion and who subsequently receive reperfusion.

So ESCAPE-NA1 was carried out in Canada, the United States, Europe, South Korea, and Australia. It was a study that was coordinated out of the University of Calgary by doctors, Michael Hill and Mayank Goyal. I served as the CEO of the sponsor company, NoNO Inc., but I have more at stake here in that I’m actually the inventor of the drug nerinetide that has been taken through all of its paces all the way to a Phase III clinical trial.

So nerinetide is a peptide. It has 20 amino acids, and it binds a protein in neurons called PSD-95, which is very abundant in synapses. And by binding PSD-95, nerinetide prevents the formation of the toxic free radical nitric oxide during excitotoxicity, which occurs in a stroke. And over the last 20 years, we have shown that nerinetide reduced stroke and improved functional outcome in animals, in mice, in rats, in primates. It’s gone through a Phase I and a Phase II trial, and ESCAPE-NA1 was the first of a number of Phase III trials exploring its efficacy and its safety.

One thing about nerinetide, because it is a peptide, it can be cleaved by peptidases or proteases. And one very important and relevant protease in the world of stroke is plasmin, which is generated when stroke patients receive the clot busting medication alteplase. So alteplase transforms circulating plasminogen into plasmin. And we know that plasmin may cleave nerinetide, though we did not at the time of the design of the trial, know the extent to which the effect of nerinetide would be modified. Consequently, the way that ESCAPE-NA1 was designed was that enrollment was stratified according to whether or not patients received alteplase, meaning that there would be some that would receive drug or placebo and alteplase, some drug and placebo and no alteplase. So overall ESCAPE-NA1 enrolled 1,105 patients, and the primary outcome was the 90-day modified Rankin score, which is a measure of functional disability. And a responder, a success, would be considered somebody who had an mRS of zero to two at day 90.

So the trial results on the whole were neutral. There was only a 2% effect in favor of nerinetide in the trial as a whole. However, this 2% was entirely the result of the effect in the no alteplase strata. So there was no effect of nerinetide in patients who also received alteplase. Whereas in the patients who did not receive alteplase, there was a 9.6% improvement in modified Rankin score, a 40% reduction in mortality, and a 22% reduction in infarction volumes. And the secondary outcomes also trended in the same directions.

We did some pharmacokinetic analyses of plasma samples from a subset of patients enrolled and indeed, the patients who received alteplase had about 40% of the blood levels of patients who did not receive alteplase. And in fact, we have shown in a number of instances, including in a paper that is just coming out in Science Translational Medicine on April 7th, the effects of alteplase on nerinetide and how to get around them.

So overall, we consider this trial to be a major success in the road to generating a neuroprotectant for stroke because in a pre-specified subgroup, we got some extremely encouraging results. And those have encouraged us to proceed to the next trial, which is focusing on the patients who do not receive alteplase. So the ESCAPE-NEXT trial has already launched and is enrolling, again around the world. And this trial will be testing the hypothesis that nerinetide is better than placebo in patients selected for endovascular thrombectomy who do not get alteplase. And hopefully that trial will read out in about a year, a year and a half.