Sound Up: An interview with Dr. Mike Tymianski from “The Stroke Doc”

In the premiere episode of "Sound Up", Stuart Coxe interviews Dr. Mike Tymianski, whose stroke drug trial is followed in Antica's latest film "The Stroke Doc"
Antica Productions    March 15, 2022


 

Transcript

Intro: Welcome to “Sound Up,” an audio blog from Antica Productions. My name is Stuart Coxe. I am the founder and owner of Antica, where we make podcasts and documentaries. We’re based in Toronto, Canada, with outposts in New York, London and Los Angeles. Both Antica and podcasting have been growing tremendously in recent years. So, true to our nature, we created a podcast to discuss podcasting with our podcast partners…as well as collaborators from our documentary side as well! 

Today’s guest is Dr. Mike Tymianski, a leading stroke researcher from Toronto who was featured in the documentary I produced called “The Stroke Doc”, airing on CBC. 

We followed him and his team for almost a decade, yeah you heard that right, a decade, as they conducted what was supposed to be the last phase of human trials for a drug that prevents the worst damage caused by stroke. In layman’s terms, the drug helps the brain ‘hold its breath.’ 

I have been truly inspired by Mike’s work ethic, resilience and humility. So, before The Stroke Doc aired on CBC’s documentary channel, I sat down with him to discuss the film, his love of art and of course, the incredible science we got to watch unfold. 

Stuart: You know, Mike, you are hugely accomplished as we go through the film, you’re a neurosurgeon and you’re a medical researcher, you’re an entrepreneur. A bit intimidating for, I could personally say as a filmmaker, to be chronicling your work .Particularly as someone who didn’t get much beyond grade 13 chemistry. What did we get wrong in the film? 

Mike: Well, actually, you didn’t get anything wrong. You did a terrific job in following the story and presenting it quite honestly and in a balanced way. The one part of the narrative that I think needs a bit of an update is, well, whatever happened with the FRONTIER Ambulance trial? Because that is the trial that started first, before the thrombectomy trial, ESCAPE NA1. And the narrative switches to ESCAPE NA1 and then ESCAPE NEXT. So just as an FYI, FRONTIER continues to be quite successful and it’s continuing to enroll. We’ve expanded from Vancouver to Kelowna as well. We now have three hospitals that the paramedics are bringing patients to. The COVID pandemic slowed down enrollment a bit. So we expect FRONTIER to finish up around the same time that the ESCAPE NEXT trial will finish. But FRONTIER remains a really, really important trial for us because as the documentary shows, the patients that did not respond to our drug in ESCAPE NA1 were those that received TPA ahead of NA1 or Nerinetide. The cool thing about FRONTIER is Nerinetide is always given first because it’s given in the ambulance and then patients can get TPA afterwards, which is, we think, fine. Because by the time they get TPA, NA1 or Nerinetide is already out of the bloodstream. So I just wanted to provide this update that FRONTIER is alive and well and is expected to finish around the same time as our final phase three ESCAPE NEXT. 

Stuart: And just as a small point of clarification, the reason that patients are not given TPA at the ambulance level?

Mike: The reason patients don’t get TPA the ambulance level is that it’s a safety matter, first of all, because TPA has the potential for producing a brain hemorrhage. So it’s really important to get the diagnosis right when you’re enrolling patients into FRONTIER in the ambulance. Only about 70 percent of them have an acute ischemic stroke. The remainder of the patient can have a hemorrhagic stroke or some stroke mimicking condition like a brain tumor. So if you were to give TPA in the ambulance and you happen to give it to a patient with a brain hemorrhage, you make the brain hemorrhage worse. So because of that, TPA can only be given after a patient’s had a CT scan. And until we have CT scanners in the ambulances, that’ll have to wait until the patient gets to the emergency department. 

Stuart: So this is why I’m guessing that you are surmising that TPA had this effect. If you’re not familiar with TPA, it’s a very powerful drug. So the fact that it caused– in one of the studies, the people who got TPA that your drug didn’t show effect, is because TPA is a very powerful drug that has all sorts of other effects on the system. 

Mike: Yeah, TPA actually stands for tissue plasminogen activator. Plasminogen is an enzyme that chews up proteins, and it’s intended to chew up the proteins that make up the blood clots. But our drug is also a small protein. So when plasminogen is activated by a TPA and becomes plasmon, which is the active enzyme, that enzyme chews up our drug as well as blood clots. However, our drug has a half life in the bloodstream of about five to 10 minutes, so within 10 minutes, it’s mostly out of the bloodstream and into the tissues where you don’t have TPA. So if you were to give TPA after our drug, certainly we’ve done those experiments in animals, and the results that we showed was that if you give TPA 10, 20, 30 minutes after our drug, our drug works just great. So if that’s the same situation in humans, FRONTIER is really important because all the patients that got TPA in FRONTIER got it after our drug. 

Stuart: We talked a lot in the end about, after all, the time that we spent filming you as a group about what it takes to be a successful researcher and all the people who worked on the film for the most part, had really no background in medical research. And I’m just kind of curious for you, I mean, what– what’s the psychological profile of a successful scientific researcher? 

Mike: Well, probably the most important characteristic is curiosity. Trying to understand why something is the way it is. So that probably unifies most researchers that they’re curious people. They also have to be strategic, there are a lot of unanswered questions, so most researchers probably think that what they’re working on is important. And in our case, we think that stroke is important and a real challenge. So curiosity, a sense that you’re doing something important. The other really important thing about researchers is that, you know, the documentaries talks about the discovery of insulin, the discovery of penicillin. Nowadays, research is done in teams. So I think that there are very few successful researchers who are loners, who are hermits that work in isolation. To take a question and really carry it through all the translational steps that are needed to get an answer, very often requires a lot of smart people. So being able to work with a team of good researchers have, at least decent, leadership abilities. The other thing that I think unites researchers is that they personally really enjoy the process of asking questions, figuring out how to answer them and going through the steps that are needed to answer them. 

Stuart: Now, a lot of people after the film might have a question about whether they themselves would have been able to keep going in the face of the many obstacles that were thrown your way. And you didn’t mention the kind of words that I would throw your way like grit or resilience. 

Mike: It does take tenacity to do things, and I guess that’s one of my personal characteristics that I kind of stick to it unless there’s a really good reason not to. What it takes is a thick skin. When we started this, everybody thought that the concept of neuroprotection is passé. It’s had its day in science, and science has proven it wrong. One of the first grants that I sent to a national granting agency about this subject was refused, and the reviews said that even though I’m a well-trained scientist, I really should know that neuroprotection is no longer in vogue and that I should be directing my my efforts elsewhere. Of course, them’s fighting words! And fortunately, other granting agencies didn’t have the same perspective, the work was funded and I was able to continue. The other thing is that you have to be able to accept that these things come in small increments. Right? So you have to be the kind of person that’s happy with small incremental wins. You know, when I did neurosurgery, I used to do some really, really complicated operations that took a very long time and people would ask me, Well, how can you do all of these complicated surgeries? And my answer was, well, I just break them up into many, many simple steps. Right? So it’s kind of a way of thinking taking pleasure in the little incremental steps, the days that your experiments work, you think you’re the greatest scientist in the world for days that experiments don’t work. You think you’re just the worst scientist in the world. It’s a way of life being curious and finding ways to satisfy that curiosity. And when you add it all up, I guess it looks like tenacity. 

Stuart: Now, I’m curious, you know, the science from the outside seems like it has a lot of certainty at the edge where you’re talking about, it’s nothing but unanswered questions. Standing on the shoulders of things that you think you know, but may also be called into question by whatever the next researcher brings. And I’m wondering if you could sort of, because this came obviously up a lot during COVID, and it’s in much of our discussion about science. What does science know? And I wonder, sort of, you know, as someone who plies their trade on the edge of what we know and can prove how you characterize that island of knowing that we live on? 

Mike: Well, it’s a really good question. We don’t know what we don’t know. But we do know that there’s a lot of stuff we don’t know. So in that giant sea of uncertainty, you have to have some kind of a firm foundation and that firm foundation is in the case of what we do. Good science. You have to believe in the science. Because science done right, is truth. Every time you get a scientific result, it may have multiple interpretations, but that’s really the setting up of your experiment, right? So that you can pin down what’s going on with the greatest certainty possible. When it comes to an animal experiment with a stroke neuro protectant, it’s fairly straightforward. The stuff either works or it doesn’t. But if it works, it also has to work in the hands of other people. It has to work under conditions that are similar to those that will apply to human beings. Right? You really should only go to human trials when you are convinced that the science is solid. I think that if you do an autopsy on the many, many clinical trials in stroke that have failed, there are a lot of assumptions that turned out not to be true. For example, the brain can’t hold its breath forever. So if you don’t have reperfusion, neuroprotectants may not work nearly as well. Right? So in essence, you have to stick to what you know. While at the same time, not being so dogmatic about it  that your mind is not open to alternative ideas, alternative interpretations of what people think is going on. When you get to the human trials, they are pragmatic, right? It doesn’t really matter anymore how this magic white powder works. The purpose of the trials is to see whether it does. In the case of our clinical trials. What we’re trying to show is whether this drug is clinically beneficial. And the way we’re trying to do it is to do in humans what we have seen work over and over and over and over again in animals. But of course, there are new kinds of uncertainties in human trials. In animals you can control a lot. The animals are often genetically identical. They don’t have other diseases. The timing of the drug, the timing of the stroke, the extent of the stroke, the timing of reperfusion, et cetera, et cetera, can all be controlled with humans. It’s much harder to do that, which is why human trials are much noisier and because of that, they have to be so much bigger than animal studies. And then, despite everything that you think you know, there are the uncertainties of what you don’t know. For example, during COVID are patients treated in the same way? Are the same patients, the ones that are seeking care In a global trial, will patients in one country that has certain ways of treating stroke react differently to another country? So although we’re trying to enroll patients globally, we don’t really have a clear command of the impact of a geographic jurisdiction on stroke care and what it’s going to do with the drug and all that. One day hopefully, we will. But when you are leading, when you’re being the first to do this kind of thing, you don’t have that information yet. So there are always uncertainties when you are exploring uncharted territory, no matter how solid you think your scientific foundations are, how solid your assumptions are. 

Stuart: There’s another quality that you have, which we’ve talked about before that some researchers think really does correlate across people who can discover and then bring things into the world. And that is this combination of expertise and a few different fields. And often the arts and science very, at the very highest level of discovery. You see a connection that people have an interest in the arts and had some accomplishment in their youth. I mean, you had an accomplished gymnast, which is probably one of the most artistic of the athletic series, athletic pursuits. And you pursue the arts with the passion of an amateur, and I mean that in the highest sense of that. As a lover of the arts!

Mike: Yes, I pursue it passionately but without talent. 

Stuart: Yeah. What does that mean? Because I think that, you know, I don’t have all the statistics, but you know, it is fairly common. That’s that at the highest level of scientific discovery, you see this crossover in the individual. 

Mike: It’s because art is an expression of imagination and curiosity. Right? And so is science. Science at the highest level requires tremendous imagination. Thinking tangentially while keeping your feet on the ground. I get as much enjoyment from a great work of art or from seeing something really wonderfully executed that’s artistic as I do from science. It’s just I have no talent to do art, which is why I stick to doing the things that I can. 

Stuart: So for scientists who are listening or reading this, what art would you recommend them to consume to maybe open their imagination? 

Mike: You know, the answer is that there is no answer, because one of my most outstanding lessons about art was when there was a modern art exhibit at U of T and I walked through it with a colleague of mine. We were in medical school at the time and I said to him, what the hell is this? We walked by something and it looked like nothing I could figure out. And I said, how can they call this art? And his answer was. Sometimes the purpose of art is to be thought provoking, and it’s clearly achieved that in you. So,  anything that is thought provoking, anything that resonates with your imagination., anything that encourages you encourages you to do more of it. Is the right art for you. 

Stuart: You know, not to blow too much smoke, but, you know, I was describing the work of you and your team is the work of heroes because not just because what the benefit could be of the research that you bring, but the classic definition of the hero in the archetype is someone who goes away and at some great personal cost to themselves, tries to find new information which may upset and change the status quo when they return, but is essential for the long term survival of the group. And that is the role of the artist as hero and it seems to me the way you described it sounds like the role of the scientist as hero as well. 

Stuart: What’s next over the next year? What can we look forward to from you and your journey? 

Mike: Well, the documentary ends as science continues, and in this instance, it is what we think will be the most important pivotal trial that we’ve done to date. So what’s next now that we have the information from ESCAPE NA1 that the patients that did not get TPA appeared to benefit greatly from our drug, is we want to replicate that and that’s the ESCAPE NEXT trial. So this is a trial that’s being done in 85 hospitals around the world. So Canada, the U.S., several European countries, Singapore, Australia and this is a trial that will be almost identical to ESCAPE NA1. So these are patients who undergo every thrombectomy but without TPA who get our drug or placebo. This was launched just as the COVID pandemic has sort of took a grip on the world. So two years ago. You know, COVID has had a profoundly negative impact on people’s abilities to do clinical trials. But in comparison with the huge challenge of getting through a clinical trial with a treatment for stroke that shows a clinical benefit, in neuroprotection, nobody’s achieved that before. Pulling that off during the COVID pandemic, as challenging as it was, we still felt that we could do it, and I’m happy to report that so far it’s going quite well, enrollment is going well. We think that we’re going to be done in about a year to a year and a half. It depends on some interim results, which will dictate how much longer the trial has to go. But in the middle of this whole insanity of the COVID pandemic, we’ve been able to launch and execute on a scientifically solid trial. And in the end, that is our job to do the trial as well as possible and science will take care of the rest. The other important development is that FRONTIER will also finish and that’s going to tell us whether the drug potentially has even greater effect when it’s given super early and whether it’s effective in patients that got TPA after our drug. And of course, the lab continues as well because when experiments show a problem scientists seek a way to fix it, so we’ve already developed a version of our drug that doesn’t care if the patient got TPA. So it’s resistant to tissue plasminogen activators, and we’ve already started the path of that drug on the clinical development path and expected to reach phase one, hopefully by the time that ESCAPE NEXT is done. So we’re going full tilt, irrespective of the COVID pandemic. And we’re very excited and continue to be very optimistic. 

Stuart: Well, Mike, on behalf of everyone who’s been following you so far and all the people who have benefited from your work, thank you and wish you all the best fates and the gods of science can allow. And look forward to checking in on you in the years to come. 

Mike: Thank you very much. 

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