January 14, 2021
Dr. Hill explains how nerinetide may protect brain cells during a stroke
Dr. Michael Hill is the Director of the Stroke Unit for the Calgary Stroke Program, Alberta Health Services. He is also a Professor at The University of Calgary for the departments of Radiology, Clinical Neurosciences, Community Health Sciences and Medicine.
In recent years, Dr. Hill has been involved in several stroke studies, including the reputable ESCAPE and ESCAPE-NA1 trials.
How did you get to where you are in your career today?
The course of my career, I suppose, has been relatively opportunistic. I’ve had a chance to follow opportunities that I saw or were put in front of me to go forward. For example, I started training in internal medicine and then switched over to neurology, obtaining certification in both.
When I was starting out in neurology, the NINDS tPA trial was published, which was the first thrombolytic trial for stroke that clearly had a positive outcome. It outlined a way forward for stroke treatment when really there hadn’t been a clear path yet in acute therapy for stroke.
Thus, the combination of internal medicine and neurology, and hence specializing in vascular neurology seemed like a good marriage for me. Then the evolution of endovascular therapy began.
We ran the ESCAPE trial from Calgary, and I was involved in a series of trials that showed the effectiveness of EVT for the worst kinds of stroke, large vessel occlusions. So our involvement has really taken off since then.
Congratulations on the recent breakthrough with the ESCAPE-NA1 trial. How does it feel?
That’s an interesting one too because that also evolved in a similarly opportunistic way by following the choices that were available at the time. The collaboration between us at the University of Calgary, and the group at the Toronto Western Hospital & University of Toronto, where the compound nerinetide (NA1) was developed, has been a very fruitful and enjoyable one.
It is a very exciting time. We have shown there is a way forward for cytoprotection in stroke, which is a novel concept in itself. We are going to need more research to really solidify our findings and explore more details, such as which patients would be eligible for this sort of treatment and at which stage it should be administered, but overall I think there will be essentially another arrow in the quiver for treating stroke.
Can you give me an understanding of the potential impact of NA-1?
Well, excitotoxicity is a term that describes a whole series of biochemical reactions which ultimately lead to cell death. In the ESCAPE-NA1 trial, we demonstrated the efficacy of the compound called nerinetide or NA1 in treating a very specific group of stroke patients by manipulating this biochemical process.
Excitotoxicity is particularly relevant in the brain and spinal cord, and there are many other neurological diseases in which excitotoxicity occurs.
If nerinetide (NA1) can be applied to prevent cell death in multiple disorders, this would have a huge impact. But in this recent trial, we targeted a very small subset of stroke patients, so we are not talking about all strokes here, but these things have to start somewhere.
Even if nerinetide (NA1) is only applicable to this type of stroke, this will still be a great breakthrough as it is such a common disease.
What are the tangible results or impacts that could be felt by a patient treated this way?
Well, first of all, to be clear, we found an interaction effect between nerinetide and alteplase, which meant that nerinetide only seemed to work on those that did not receive alteplase as well. Within this group that didn’t receive alteplase, we saw quite a large effect size of 9.5% absolute benefit in independent outcome; so it essentially means there is one extra person in ten walking out of a hospital functionally independent instead of being severely disabled or dead. This is quite a large effect size, approximately half the effect of endovascular therapy.
To give you some perspective, I’ve been involved in stroke for over 20 years, and when I began, only 2 out of 10 patients with an LVO would be functionally independent after their stroke, and maybe 3 or 4 out of 10 would die. With endovascular therapy, this really increased it to 5 out of 10 being able to go home functionally independent, and only 1 would die. Now we are talking about 6 out of 10 being functionally independent with EVT plus nerinetide.
We are making incremental progress which is fantastic, and certainly with endovascular therapy, it was such a large leap after the ESCAPE trial and MR CLEAN alike we really were visibly able to see the way things were happening on the stroke inpatient service.
Fewer people staying for long periods in hospitals and being paralyzed, more people going home on the 3rd day instead of staying for several weeks. It is very gratifying for sure.
Dr. Wouter de Monyé loves teaching how to get the diagnosis right and having an impact on patients’ lives.
It must be incredibly gratifying. Were there any pivotal moments in the ESAPE-NA1 trial?
When you design a trial like this you are definitely standing on the shoulders of giants. We were definitely beneficiaries of failed experiments in the past. I mean you learn something every time right?
I think there were a few key things that were done. Firstly actually doing the experiment on primates initially. Lots of ethical issues come up with this and you have to be very careful but doing this was a really important demonstration that it was possible. Then we worked really hard in the trial to make sure we were duplicating that same model but in humans. And I think we were very successful in doing so just based on the study metrics.
Duplicating the preclinical model was probably the most important scientific thing we’ve done. This was how the evolution of highly effective endovascular therapy happened.
Being involved with both EVT and ESCAPE-NA1 has been terrific, and they followed one from the other.
Where would the administration of NA1 work in the structure of the current workflow?
So that’s important and an example of another feature of trial design. In any trial, you need to integrate whatever you are testing within the current paradigm of care. We gave nerinetide (NA1) at any time after randomization up until closure of the groin, so it was not a linear paradigm. It went in parallel with the treatment.
This means it could have been given at many different stages – just before emergency treatment, in the angio suite, while the thrombus was being extracted, or even just after reperfusion.
In hindsight, we now think that the earlier you give it, the better the result, so as we go forward with future studies looking at this compound, we are really going to try and give it early.
How does nerinetide (NA1) work in terms of protecting or restoring the brain cells?
It’s a rational drug-design peptide: a little protein made up of 20 amino acids. A short segment of amino acids is taken from Tat protein, which is an envelope protein from the HIV virus. Tat protein plays an important role in allowing the entire protein to enter a cell, crossing through the blood-brain barrier so it gets into neurons and across a lipid membrane without any problem. We see that pharmacologically, once it’s been intravenously administered, it is out of the patient’s circulation within 10 minutes and into the tissue.
The remaining amino acids form a peptide that interferes with a protein-protein interaction inside the neuron, between the cytosolic surface of the NMDA receptor and a protein cascade which is part of the negative aspects of excitotoxicity, which would ultimately, normally, result in excess production of nitrous oxide, which is fatal to a cell.
They target the excitotoxic pathway downstream from where it has been targeted before. It’s always been targeted on the extracellular surface of various aspects of the receptor, whereas this was the first time it has been targeted inside the cell. It’s never worked well extracellularly because it’s always interfered with the normal functions of the receptor.
You’ve already touched upon what this could lead to in terms of other neurological areas but what are the next steps of opening the door for new leads in stroke research?
Excitotoxicity is a pathological mechanism important in trauma, MS, Alzheimer’s disease and many other neurological diseases. Could you improve outcomes of concussion or a car accident if you can receive this drug to protect neurons immediately after the event? We just don’t know yet, and we will need more research.
Although I’m not saying this idly, some animal model data says the drug is useful in traumatic injury – for example, when looking at rats – but it hasn’t been studied in humans. This is all speculative, so we will have to research and see what the future holds.
How exciting, you must be incredibly excited yourself, what has been the most significant breakthrough for you to date?
Well, what I’ve focused on the most in the past 10 years is therapeutics. Some trials have been successful, and some have failed, but it’s definitely the most recent two for me that have been the most influential: especially the ESCAPE trial, which has had the most impact. It is now 5 years since that was done and, of course, this was not just my research, there is also the MR CLEAN group, the Australian, British, Swiss, French and Spanish groups that all showed how effective endovascular therapy is.
Now we’ve got to get on with it and really implement EVT globally. This has completely changed the face of acute stroke management and how people are triaged, including how hospitals are organized.
I do think we’ve got a really interesting result with ESCAPE-NA1, so if that also evolved to become a big success in stroke and expands beyond then, that may be even bigger… I don’t know.
Can you recall a time in your career to date when you’ve felt most challenged?
I can think of a couple of different occasions. There are many challenges in research because it is a highly entrepreneurial process. You have to come up with an idea, write a grant, be successful (which only occurs 15-20% of the time), receive the money, hire and organize a team, execute the project and produce results and then there is no guarantee the results are going to be what you hope to see!
If you’re successful the first time, you then have a much greater chance of doing it again because success allows you to follow on from the things you’ve done before, so it’s very much like running a business in terms of getting stuff done.
The biggest challenge I find is making sure you can continue to support all your team. If you are the one in charge, receiving all the money coming in, you must make sure you’ve got funds to conduct the research and support the people involved, especially when they risk their time, effort and employment. It is all that kind of stuff that has stopped me from sleeping at night.
Congratulations to you and your team; as we can imagine, it’s been years of extremely hard work!
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