Hello, everyone, and welcome to today's panel discussion. My name is Karen Hunady, and I'm the Director of Corporate Communications and Investor Relations at Athersys. I'd like to thank you for joining us today to learn more about the TREASURE data. The TREASURE study was conducted by Healios, our partner in Japan, and it was a randomized, double-blinded, placebo-controlled study evaluating MultiStem administration for the treatment of ischemic stroke. We have put together an expert panel of key opinion leaders in the field of neurology to discuss their own perspectives on the TREASURE data. I wanna thank each one of them for taking the time out of their busy clinical schedules to be here with us today. Dr. Robert Willie Mays, our Vice President of Regenerative Medicine and Head of Neuroscience Programs here at Athersys, will be moderating the event today.
He's gonna be taking questions from all of you on this webinar and directing those questions to the panelists. We will be answering all the questions verbally. If you have a question at any time during the webinar, please type it into the Q&A window, and you'll find the Q&A option at the bottom of your Zoom screen. This presentation is also being recorded, and the webcast will be available on our website at www.Athersys.com shortly after the event. If for any reason we did not get to answer your question, you may also send it to ir@athersys.com after the event concludes. The views and opinions expressed by our panelists today are their own. Dr. Mays and our panelists may be making forward-looking statements, and the safe harbor rules govern our remarks we make today.
These forward-looking statements relate to, among other things, statements regarding anticipated results of clinical trials, including, and the potential benefits of, our MultiStem product candidate. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, including, among others, the possibility of unfavorable results from ongoing and additional clinical trials involving MultiStem and the risk that positive results in a clinical trial may not be replicated in subsequent or confirmatory trials. The company assumes no obligation to update forward-looking statements to reflect actual results, subsequent events or circumstances, or other changes affecting forward-looking information except to the extent required by applicable securities laws. Now with that, it is my pleasure to turn the meeting over to Dr. Robert Willie Mays, the moderator for our event today.
Thank you, Karen. To my esteemed key opinion leaders, you guys can start to turn your videos on now. Thanks, everybody. Really appreciate everyone joining us on the call today, time to participate in the webinar and to hear from and interact with some of the world's leading stroke neurologists, as well as one of the preeminent clinical trial statistical researchers in the United States. Recently, our partner, Healios, announced top-line data results from their phase II/III randomized, double-blind, placebo-controlled clinical trial called TREASURE, which, as Karen said, evaluated the efficacy and safety of the MultiStem cell product compared to placebo in 206 ischemic stroke patients enrolled at 48 clinical sites throughout Japan. In the morning, the trial results were made public, and we had a lot of press releases, both us and Healios.
I received, enthusiastic emails or congratulatory messages from stroke neurologists, investigators from our MASTERS-2 clinical sites, who had reviewed the press release, academic researchers we work with, and the panelists we've engaged today. My hope for this round table discussion is that the experts we've assembled can answer your questions directly, share their perspectives, and convey to the Athersys community the same sense of excitement regarding the data from TREASURE and the potential for MultiStem to change the lives of stroke patients and their families. Just I'll shut up here as quickly as possible. Just a few ground rules for the round table. As Karen said, this is completely unscripted. The panelists' comments and opinions are their own.
We hope to provide to all of you the human side of treating stroke from the perspective of these leading neurologists who see patients and their families every day and better understand what long-term recovery and independent living could mean for those people that are affected by stroke. I will be reading questions and asking for responses from the panel. Otherwise, I'll try to be as unobtrusive as possible. The panelists, if I don't ask you a question directly, feel free to add on to the comments and perspectives others have already shared. If you're joining live and you don't get a chance to get your question asked, you may send it to ir@athersys.com after the webinar, and we will make sure that it gets answered. With that, panelists, I'd like you to begin with some brief introductions.
I'd like you to tell us your name, your affiliation, and any specific stroke interests or research focus you have. I did this alphabetically, so Tom, I'm gonna start with you.
Great. Thanks, Willie. I'm Tom Carmichael. I'm Professor and Chair of Neurology at UCLA. I see stroke patients clinically. I do neuro rehab and stroke recovery clinically. I have a basic research lab that looks at cellular and molecular mechanisms of brain repair after stroke.
Thank you very much, sir. Dr. Chiu.
Hello, Willie. Hello, everybody. I'm David Chiu. I head the Stroke Research Program at Houston Methodist Hospital, and I'm Professor of Neurology at Weill Cornell Medical College. I'm a proud site principal investigator at Houston Methodist Hospital for the MASTERS-2 trial.
Great. Thank you very much, David. We'll go to the other David, Dr. Hess.
Thanks, Willie. I'm David Hess down here in hot Georgia, 100 degrees today, in Augusta, Georgia, Dean of the Medical College of Georgia and a stroke neurologist. I've been working with Athersys, boy, since probably the mid-2000s and worked in some of the preclinical evaluation and then the MASTERS-1 trial, was one of the primary authors. I continue to be active in stroke research, mostly acute stroke, looking for stroke agents that are effective in people. We have a lot of them that work in rodents, but we don't have a lot of them that work in people yet.
Great. Thank you very much, David. To prove to all the attendees today that these really are stroke neurologists, Dr. Savitz would be next, but because he is currently working to care for stroke patients, he'll pop in later when he gets a chance. He's in the clinic right now. We'll go to Dr. Wechsler.
Thanks, Willie. I'm Larry Wechsler. I'm a Professor of Neurology and Chair of Neurology at Pennsylvania Hospital at the University of Pennsylvania, where I've been for the past couple of years. Before that, I was at UPMC for 35 years, and for the last 11 of those years, chairman of the neurology department at UPMC. Before that, the director of the Stroke Institute, which I founded way back in 1995 to help find new and better therapies for stroke. I've been involved in cell therapy for stroke since the late 1990s. Involved in many of the clinical trials that have been going on for the past couple of decades, including MASTERS. I was right after David Hess on the Masters paper. We were all very intimately involved with that study and look forward to this discussion about the TREASURE trial.
Great. Thank you very much, Larry. We're going to close with our esteemed statistician from Harvard. LJ, please introduce yourself.
Yes. Thank you, Dr. Mays. It is a really great pleasure to join this distinguished panel. I am a professor of biostatistics at Harvard, and I've been doing clinical trial methodology research, also practice doing the clinical trials for, I want to say, more than 35 years. Some of my methodology developments actually routinely used in clinical trials. If you remember tPA's clinical trial, sponsored by NIH many years ago, it's very interesting. They use multiple outcomes, actually use a totality of evidence. Today we are going to talk about the totality of evidence from a TREASURE study. Thank you.
Thank you, LJ. Yeah, we're gonna talk about that, NIH clinical trial here in a little bit. But LJ, I'm gonna put the first question to you. After the release of the top line data, we had a lot of people that were either writing articles or commenting directly to us or in the Twitterverse about us cherry-picking results or us manipulating the data. I was wondering if you could just spend one second to talk about what is post-hoc analysis versus defined pre-specified analysis of a clinical set of data.
Thank you, Willie . I think the clinical trial methodology, or in general, just clinical trial, I don't think it is not optimal way to actually assess treatment effect, including the safety. The reason I'm saying that, you picking up a primary endpoint. In this case, we call this excellent outcome, right? Excellent outcome, you know the definition. I believe you do. It's a very, very tough hurdle to pass. Somehow you have to require the patient almost like behave normal after the stroke. You notice in the TREASURE data, 90 days, the number of outcome, excellent outcome is very small. It's no surprise, because very few people can pass this really high hurdle. Well, the TREASURE data, TREASURE study, picking up this primary endpoint. Everybody looking at this primary endpoint as usual.
If the P value less than 0.05, everybody jumping up and down, have a beer. Otherwise, people say you sucked. I think the clinical trial is not really only built upon a single outcome, which we call pre-specified primary endpoint. There are so many secondary, very important key endpoints we should have thinking about it. That's why we're talking about totality of evidence. In fact, I'm dealing with many, many rare disease clinical trials these days. The FDA actually emphasized how to utilize multiple outcomes instead of using a single so-called primary endpoint to evaluate treatment effect. I think that as opposed to post-hoc analysis, the wording sometimes is a little misleading, but unfortunately, we follow the same pathway. We sit in a box doing clinical trials.
That's really unfortunate, but on the other hand, if we look at this global picture from different angles, looking at the treatment effect from a different progression domain, from a disease burden domain, you will see the TREASURE data provide a lot of meaningful how to interpret MultiStem, the treatment benefits. Let me stop here, Willie.
Great. That's a great answer. Thank you very much, LJ. In light of the fact that stroke to this day still has a very significant unmet medical burden, David Hess, could you describe to me what are the therapeutics or the interventions that have met the high bar of getting approval for treatment in the acute timeframe for ischemic stroke?
Thanks, Willie. There's really just really two interventions that have met the high bar. You know, you got tPA, which you know was you know approved back in, what, 1996 and NINDS trial in 1995. That's approved by the FDA. You know, people will argue how far out you can go, you know, at least three, maybe 4.5 hours, and maybe with advanced imaging, longer. As most of you may know, the risk of tPA is bleeding, and the most feared risk is bleeding into the brain, which has always led to that being used less than I think most of us would like. You know, still many emergency medicine doctors are still reluctant to use it.
You know, that kinda led to the rise, as Larry Wechsler now knows, he's done a lot of telemedicine, you know, telestroke to provide neurologists, you know, immediately to emergency rooms throughout the country and the world. The other treatment which took many trials to get there was mechanical thrombectomy, where you're basically mechanically removing the clot. You know, that window is variable, at least depending upon using imaging to define penumbra, you know, may be able in some patients to be used out to 24 hours. But that's it. Both of those are reperfusion therapies, tPA being a liquid reperfusion therapy, if you will, a mechanical thrombectomy, mechanical one.
Many other, t here's been many other attempts at developing neuroprotective, or in this case, I would call it maybe more of a neuro recovery or a really therapy that targets both. Despite many attempts, and many things that look good in rats and mice, it's been very hard to translate anything else to the clinic. You know, that's pretty much all we have in the United States. Now, I realize in some other countries, there are other therapies approved, but that's pretty much what's available in the United States.
Great. Thank you very much for kind of setting the stage there. The next one to Larry, and then after that, I'll be coming to you, Tom. Larry, as a PI in MASTERS-1, and then having seen the top-line data from TREASURE, are there any signals that are consistent between those two trials or any data endpoints that have you excited as a stroke trialist?
There are. I completely agree with LJ's sentiment that, you know, we have to go beyond the top-line results and look at the totality of evidence. When you look at the results from both MASTERS-1 and TREASURE, I see things that are really very encouraging and very promising. What I see is that particularly, first of all, if you look across the various outcome measures that were used in both those trials, you see consistent trends favoring the treatment group. Not all statistically significant, but all trends in the same direction. I think that tells you something important. The second thing you see is that this difference between 90 days and 365 days.
What you see in both studies is that for the most part, in several, if not most of the outcome measures, you don't see much change in the placebo group between 90 days and one year. The groups are fairly stable, and that's kind of what we expect based on the natural history of what we know happens with stroke recovery, that there's a plateau effect, and the most rapid part of recovery is within that first 90 days, and then there's kind of a plateau, and very little further improvement out to one year. However, in the treatment group, we do see further improvements in favorable outcomes across multiple outcome measures between 90 days and one year that we are not seeing the placebo group.
Again, even though the differences don't reach statistical significance, I think for me as a stroke trialist and as a stroke doctor, that's telling me something. That's telling me that there's something to this treatment, that this treatment is doing something because it's widening that gap. There's further improvement that we don't see as part of the natural history in the placebo group. So those are the signals to me that there's something going on positive with MultiStem.
Great. Thanks very much. Tom, considering your expertise and the focus of your lab on recovery, trying to, you know, help stroke patients with neuroplasticity, could you discuss other stroke treatments or drugs that offer the same sort of continual improvement over an extended period of time?
Well, there really isn't anything out there. It's really interesting to note the difference between the acute interventions that Dr. Hess and Dr. Wechsler have described and the progression of recovery. The acute therapies, tPA or mechanical thrombectomy, function on the plumbing, you know, opening the pipe. The benefit is nearly immediate. Then there is the normal process of functional recovery after stroke, which is most dramatic in the first six weeks really, if you look at population studies. It continues to about three months, and then it plateaus, and then at six months it is essentially flat. In fact, population studies indicate that most patients decline after in the chronic phase after six months due to inactivity and other things. They actually lose function.
One of the interesting things about this therapy and this trial, TREASURE and then MASTERS, but the TREASURE data was that, patients continued to recover even after the phase of spontaneous recovery naturally closing. There was still improvement that was significant on the Barthel Index and noticeable in others after three months, when you would expect it to be plateauing and then flat. The interesting thing here too is this wasn't a plumbing solution. We're just opening the clogged pipe, but instead modulating some of the things that you've probably discussed with before with the MultiStem therapy, inflammation and secondary damage. The time window for the therapy is longer. It's easier to administer MultiStem.
The interesting thing about this data is it is distinct from the range of therapies out there and the fact that it promotes recovery over time, when normally spontaneous recovery itself is fairly flat and there is no therapy that has been demonstrated efficacious there.
Great. Thanks very much, Tom. Sean, welcome to the party. Next question's for you, and then Dr. Chiu, you'll be on deck. We got this question a lot, Sean. How is it that you can give a single IV administration of cells within the first 18-36 hours after the onset of a stroke, yet people continue to show benefit between day 90 and day 365? Touching on what Tom just talked about, what's kind of a hypothesis for what we believe the cells may be doing?
I think this data really helps to validate what we've been understanding in the animal literature. From the animal studies that we've been doing, it really to me indicates that, you know, in contrast to the acute stroke treatments of plumbing, where 90 days has been found to be valid endpoint to look for benefit, when we think about this type of therapy, which is entirely different, we're looking at repair and plasticity. In this respect, the brain is actively undergoing changes over a longer period of time. It really makes sense to me that we're seeing TREASURE showing data that is replicating what was being found in the MASTERS trial, where people are showing potential benefit at that time point rather than at 90 days.
Not that we couldn't potentially find a treatment effect at 90 days, but that we're seeing a much more of that signal clearly separating out between the treated patients and the placebo-treated patients at one year because of the mechanisms we think that the cells are promoting. The brain is undergoing changes. It takes longer. As Dr. Carmichael just mentioned, you know, we don't even really have any treatments that can promote recovery in these time periods. To me, I think this is, you know, a wonderful opportunity to be developing a completely different paradigm of treatment that we don't have right now, where the brain can be enhanced in terms of the ability to undergo repair.
We just think about that from the perspective of the multitude of possibilities where, you know, the brain is not static, that it actually has that opportunity to undergo changes that would promote repair.
Great. Thank you very much. Thanks for making it. I know you're in the clinic right now. So Dr. Chiu, building off of Larry and Sean and Tom's comments, can you compare MultiStem's performance based off of the TREASURE data, and what you know about the MASTERS-1 data to other clinical trial outcomes, for example, the tPA trial that LJ had spoken about earlier, in the NINDS trial.
You bet. You know, the results of TREASURE are tremendously exciting. To me, they evoke strong parallels with where we stood with tPA in 1995, and that was just before the NINDS tPA trial results were announced. That year, ECASS came out from Europe. So an interesting parallel, a non-US study. ECASS, the original ECASS trial, the ECASS I study, had 620 patients with acute ischemic stroke who were treated with tPA versus placebo. That study, when it came out, was negative for the intention to treat primary analysis, but there were strong signals of benefit, and it was positive in a subset of patients that was designated the target population.
Later on that year, as people have mentioned, you know, in December of 1995, I think Dr. Hess, you know, remembers that that's when the NINDS tPA trial results broke open. That study revolutionized the field of stroke. That's really not an exaggeration. I remember being a young stroke neurologist at the time, and my boss at the time, Jim Grotta, was in a press conference along with the other NINDS tPA investigators, you know, announcing the results in front of a group of reporters and the conference was broadcast on all the television networks. It's something that I'll never forget, really kind of a seminal moment in the field of stroke.
You know, subsequently, of course, that paper, the NINDS tPA trial, was selected as the most impactful paper published in the New England Journal of Medicine of the decade of the 1990s. You know, I think that is a high bar to be compared to, but I'll tell you why I'm feeling very strong reverberations of where we stood in 1995 with tPA. The treatment effect size that is seen in the TREASURE trial with MultiStem therapy is comparable to the treatment effect size of tPA in the NINDS trial, and ECASS III.
These two trials, the NINDS trial, the ECASS III study, are basically the two major tPA trials in the field of stroke that effectively are the two pillars in our evidence base that really has led to, you know, tPA being recommended in our current stroke treatment guidelines. If you kind of look at this comparison further, obviously tPA was the first proven effective treatment for acute ischemic stroke, the first thrombolytic treatment, the first reperfusion therapy. MultiStem is poised to be potentially the first cell therapy for stroke. As Dr. Hess mentioned, the first neuroprotective neural recovery therapy for stroke, first non-reperfusion therapy for stroke. I would add the first potential treatment for stroke that could be applied beyond the first 24 hours.
You know, delving into this even further, if there is a difference in sort of this kind of, you know, comparison of tPA and MultiStem, there are potential advantages with MultiStem. The lack of the risk of intracranial bleeding or other types of major hemorrhage, and the fact that potentially, you know, more patients could benefit from treatment because we have a much longer window of opportunity of treatment with MultiStem. You know, I've used this analogy before because I think it helps to sort of encapsulate the reasons that I feel so excited. You know, we're talking about game seven of the World Series here. There's really, you know, so much at stake. There's the winning run on third base with no outs. We've obviously got work still to do. The MASTERS-2 trial will obviously be pivotal, a 300-patient trial. You know, no pressure.
Yeah. Great. Thank you very much. That will help me sleep tonight. Here's a question from our friend, Jeff. Hi, Jeff. Thanks for listening. He has a question. I'm gonna throw this open to all of the neurologists, and then LJ, I'll come to you next. Basically says, in spite of the enthusiastic impressions of the data from the group of you and colleagues in the field. What is biotech and big pharma missing? Why is there not enthusiasm from the rest of the deep pockets in the biotech and biopharma space? What is not translating from your mouth into their ears? Does anybody have any feedback on that?
I'll start if you want to.
Sure. Absolutely.
I think, you know, we need a positive trial. I think that many people don't do what we do and look at the totality of the evidence across multiple studies, and they just look at the top line results and say, "Okay, it was a neutral trial." You know, to convince everybody out there, we need a positive trial. We need that finding based upon the pre-specified primary endpoint. You know, there's always. We're always worried about bias, and that's the way you eliminate bias, by doing a randomized controlled trial, and you have a pre-specified endpoint, a primary endpoint, and you hope that that's how you get a positive trial. I think that's what it takes to generally convince the non-experts that a treatment like this works.
Of course, that's what it takes to convince the FDA. If the FDA isn't convinced and it doesn't get approved, then we can't get a hold of it. So that that's what we need. We're certainly hopeful that MASTERS-2 will be that trial that turns this around. I think once that does happen. For example, David used the tPA example. The first tPA trial wasn't successful, but the second one was, and that turned everything around. This is true of multiple therapies. You could look at mechanical thrombectomy. The first thrombectomy trials were negative. Then the second tranche of trials that were better designed and better targeted were clearly positive. Coronary angioplasty and stenting initially wasn't successful in trials.
The totality of evidence was clear that this was beneficial. These are treatments that are now standard of care. I think once we get the right trials and we get the right results, people will look at the totality of evidence and get on board.
Any other stroke interventionalists wanna add in, or has Larry cornered the market on good answers? Okay. LJ, quick question for you that we actually got two versions of the same question, and I think it's trying to help people understand how to look at the data, the top-line data. Could you explain the concept of imputation in a clinical setting? Because people are trying to understand if someone's treated and then dies at day 180, how does the data that patient could have presented or provided in the final outcome get calculated over the course of the trial?
Willie , if for example the excellent outcome or we call a global recovery outcome and which is a binary. A patient dies before reaching 365 days or even before 90 days, we essentially, that's non-responder. That's very easy. We don't even need it to do any imputation at all. That's a well-defined rule, right? In a clinical.
Right. So basically, if I could just make sure I summarize this and say this correctly. If we had somebody that was getting better and showing a lot of dramatic improvement, and then they unfortunately passed away for some other reason, we wouldn't obviously get them across the goal line for excellent outcome at day 90 or day 365, even though they might have reached an excellent outcome. Is that correct?
That's correct because we actually pretty conservative.
Yeah.
In the clinical trials.
All right.
Rather we give this guy credit. We say, "Sorry, you didn't make it."
All right. Great. I wanted people to understand that not all aspects of trial design and trial management are in the hands of those running the trial. With that, we got a question here. I'm gonna throw this to Tom. Given that there are no material safety concerns that have surfaced during previous clinical trials with MultiStem, should we be using this as an existing stroke treatment right now compared to tPA, where there are extensive safety concerns?
Well, it's certainly safe, safer than tPA. We have these efficacy signals, some of which are quite strong. We have a trial with an expected lower age level, with age being a complicating difference between TREASURE and MASTERS-1 and MASTERS-2. It seems to me we really need to let this have runtime, because if you start to introduce therapies that aren't proven, or more definitively established anyway, you really get into a mess. The current testing plan is really on track to give us an answer here. There was discussion of how TREASURE differed with age, and age is probably the most significant distinguisher in recovery rate and absolute level and so w e have a blip, and now we have a planned trial to really address this. It would be probably dangerous to start instituting a therapy that's safe without further data on efficacy.
Great. Thank you very much. Sean, to you. We know when we compare the TREASURE population to the MASTERS-1 population that the median age is 15 years older in TREASURE than what we had in the MASTERS trial. We have had two questions that have come in regarding. Can you comment or speak about the frequency and/or impact of strokes as we age?
Well, I think, you know, first of all, I mean, age is one of the biggest risk factors of all for us. Unfortunately, as we age, the risk goes up to have a stroke. Even more to the point is that unfortunately, when people are older, when they have a stroke, there is certainly a higher risk to develop complications. Unfortunately, in the very elderly, they have less potential for recovery and to achieve good outcomes compared to people who are at a younger age. What was really interesting and exciting is that, I mean, you have the substantial age difference in the TREASURE trial compared to the MASTERS trial, and yet still we see some really significant findings.
I think very exciting that, you know, people can achieve excellent outcomes at ages that, you know, we would expect there to be limited or less potential for recovery. In addition to that, we also know very clearly that, you know, people, for example, who are over 80 years of age or over 85, have much higher risks for complications, infections in particular, or other types of medical complications. We didn't see that increased incidence of adverse events in the patients that were treated with MultiStem compared to placebo. It's, I think, also concordant and jives really well with the MASTERS trial data, you know, in which this is a younger patient population, and there was less complications in the patients that had MultiStem compared to placebo.
The implications here is that not only could MultiStem have an effect to improve recovery overall and achieve excellent outcomes, but it also that these cells could reduce the chances of us developing a medical complication after stroke. That's possible that this can be achieved in patients who are much older. We didn't know that, I think, and that's something that's, I think, really fascinating, that it's possible people over 80 years of age, for example, could derive those types of benefits from MultiStem.
Great. Thank you very much, Sean. David Hess, we received a question. It's pretty specific, but I think the mRS shift might be able to speak to this. Do we have proof that we saved the life of any stroke patients using MultiStem? The whole Lazarus thing here.
Well, you know, in an older population, you know, severe disability and death are rather equivalent. I'm not sure in stroke you're really aiming to save lives, you're really aiming to save disability. I'd have to look at the death rate. I have to go back and look in TREASURE, but that's not really what we're aiming to do. We're really aiming to reduce disability and move people up to, you know, better recoveries.
Yeah. Independent living. The ability to take care of yourself, just by yourself without depending on others, I think is a really important endpoint. Seems like mRS less than or equal to two is gaining a lot more foothold as an outcome in recent years. Okay. Thank you very much. Let's see. We have a question here. Tom, I'll come to you. We'll focus on the stroke survivors here. Could you discuss, you know, at a high level, the economic and personal sort of costs associated with caring for a moderate to moderately severe stroke patient, over an extended period of time?
Well, they're pretty substantial. As a matter of fact, most of the costs in stroke are chronic care costs. I don't have the statistics straight off the top of my head, but it used to be around $55 billion-$75 billion, somewhere in that range. Something like two-thirds of those costs are in chronic care. The audience will know that the major grouped outcome levels involve one measure, which is modified Rankin. Modified Rankin has specific cutoffs that are directed to need for help, whether it's an assisted device or other things. When you start to climb that scale of higher modified Rankin numbers, you activate caregivers, assistive devices, and considerable cost. That's primarily because these patients won't die of their stroke.
They're now six months or years afterwards. They'll die of a comorbid or existing condition that's worsened by the disability of their stroke. There's really a long time period in which patients are increasingly dependent. They need assistive devices. They need additional resources from friends, family, or support groups.
Yeah, great. Thank you very much. Yeah, those indirect costs, I mean, I think those are calculated when you talk about the big billions, people having to take off of work to go pick somebody up or transport somebody or etc. Those things add up quite a bit. Lots of people, the same question keeps coming in, and it had come in in the earlier questions too. Lawrence Wechsler, what do you think about the use of excellent outcome as an endpoint in TREASURE or in any potential trial?
Yeah. I think that was an unusual choice. Maybe not the best choice from a number of viewpoints. First of all, only a minority of people would be expected to achieve that. There's a lot of improvement that can occur without getting to excellent outcome that you're not measuring there. I think that you know that you want to see that the things besides getting to the excellent outcome measures. I think the Rankin, and particularly what we call the Rankin shift, is a better choice, and that's what's being used in MASTERS- 2. It's a better choice because it covers the spectrum of outcomes, not just getting to that excellent outcome. That's great.
I mean, it's great if we can get people to the point that they have no deficit and no symptoms and excellent outcome. That's great. But the other improvements, getting somebody who can't walk to be able to walk, getting someone who wasn't independent to be independent, that's important too. If you've had a stroke, those things are important as well, and change your life for the better. So looking at the spectrum of change in this shift analysis, I think is the way to go. It's the better measure of whether a treatment is effective. I think not only is it better from a trial point of view, but it's better from a clinical point of view. It's a more clinically important and relevant endpoint.
For us as clinicians, if we have a treatment that across the spectrum of Rankin outcomes causes improvement across the whole spectrum, that's really important to us as clinicians, because we know that's what's important to patients. You know, the excellent outcome probably wasn't the best choice. I think MASTERS-2 is much better in that regard because we are using not only a better trial outcome, but a better clinically relevant outcome.
Yeah. Thanks, Larry. Just one comment. I do know our friends at Healios had intended to have a different primary outcome. In discussions with the regulators, it was decided that excellent outcome would be the primary endpoint. That led someone we spoke with at Athersys recently that they felt that the cells didn't fail the patients, the design failed the cells, which I thought was a prescient comment. Anyhow, moving along. We're down to about the last 10 minutes here. So Dr. Chiu, considering what's available to the stroke patients and community in the time windows, and I think you touched on this in your previous comment, what percentage of ischemic stroke patients could potentially benefit from a therapy like MultiStem in the time window we administrate?
Right. And I think that's again one of the major potential, you know, differences between the reperfusion therapies like tPA and a cellular therapy or neuro recovery therapy like MultiStem. You know, about 10%-15% of patients with ischemic stroke potentially qualify for a treatment like tPA under our current, you know, practice guidelines. Because the time window is so stringent for a therapy like tPA, that excludes a lot of patients. The fact that just simply by virtue of having, you know, 18- 36-hour window with MultiStem, that means potentially far more patients could potentially benefit.
Great. Thank you very much. I have a question I was told I needed to forward to you or to throw out to you guys. David, this will be you. It asks specifically, what are the differences between TREASURE and MASTERS-2 that could result in the different efficacy outcome? I think Larry spoke to it a little bit. David Chiu spoke to it. Does a younger population in the U.S. make patients more likely to have a good outcome? Are there other differences between the United States and Japan, like diet, etc., that could factor into the chances of success in MASTERS-2? That's a mouthful, but if you could tick some of those boxes, I'd appreciate it.
Yeah.
Oh, I'm sorry. I meant that for David Hess. I'm sorry, Dave. You can certainly chime in afterwards.
Why don't you let David Chiu? He was doing so well. Let him go, and I'll follow him.
Okay. That's fine too. David Chiu, you go ahead, and then we'll come circle back around to David Hess.
Yeah. Well, I mean, a number of the panelists have already mentioned this, and this is indeed an extremely important and potent predictor of stroke outcome, which is age. We know that the two most important prognostic factors for stroke outcome overall are age and the stroke severity, the NIH Stroke Scale, which makes sense. You know, in the TREASURE trial, you had a population of patients who were very elderly, who had moderate to severe strokes. It comes as no surprise that it turns out that only 10% of the placebo patients in the TREASURE trial had excellent outcomes as a result. The trouble is really when you start to talk about the potential treatment effect.
Not only is the overall, you know, prognosis worse for older patients with moderate to severe strokes, but the potential to respond to any form of therapy, whether you're talking about tPA or a new cell therapy, a neuroprotective therapy, you know, the concern is that for very elderly stroke patients with severe strokes, that nothing that you can do may really result in a major difference. That puts you know, any kind of study of a novel therapy behind the eight ball to start off with. The amazing thing is that in spite of these you know, being hamstrung by this type of study design and this patient population, that TREASURE still managed to show such strong signal of benefit. That's what's really remarkable.
I mean, I might take this time to elaborate just a bit on what I said before about the treatment effect sizes that we saw, you know, in the tPA trials versus what was seen in TREASURE. You know, the mean modified Rankin Scale shift or change with tPA in the NINDS trial was about 0.5. The mean modified Rankin Scale difference in the ECASS III trial was close to 0.2. If you look at just the TREASURE study, the overall cohort in the TREASURE trial showed a 0.2 modified Rankin Scale shift for all patients in TREASURE, including those 80 years of age and older. That would mean that the effect of MultiStem was comparable to the effect of tPA in the 3-4.5-hour time window.
If you look at the quote-unquote "target population" in TREASURE, those patients 80 years of age or under, and you provided some of the data in that subset of patients, about 60% of the patients in the TREASURE trial. The average modified Rankin Scale change afforded by MultiStem therapy was on the order of 0.4-0.5. Again, quite comparable to the effect size seen in the NINDS trial, which is thrombolytic treatment with tPA within three hours of onset of symptoms.
Thank you, David. Dr. Hess, would you like to add anything?
No, I mean, I think David covered it really well. Like you said, I think the TREASURE population. It's the oldest stroke population that I'm aware of. Like it's been said, to expect an excellent outcome, a bar in a population that old, I think it just shows that Japanese people are much healthier than we are. I mean, don't Japanese have the highest life expectancy in the world?
Yes.
It was really a surprise to me that you could have a stroke population that old and that made the choice of the primary outcome, you know, unfortunate, but.
Yeah. Question here from Kurt. We'll address this to you, Larry. When it comes to FDA and/or other regulatory approval criteria, does a drug or a therapy's lack of safety concerns lower the threshold required to bring a new treatment to the market?
I think it does. There's no doubt they take that into consideration, you know, something that's safe has virtually no toxicity, has a much lower threshold for approval. As it should be. I mean, that only makes sense. However, it still has to be efficacious in addition to being safe. They will be less stringent about the proof of the efficacy side given the fact that this treatment is very safe, but the efficacy still has to be there.
Great. Thank you very much. Sean, if you had the choice between a hard baked excellent outcome or shifting outcomes to get more people able to live independently, which would you prefer? That's a question that we've gotten different versions of.
Well, I think, you know, if it's a binary decision, you have to pick one choice or the other, I would certainly want, you know, for more people out there to be able to shift, so that, you know, they can achieve more. I think that's a real benefit, you know, for people. We just had some good discussion here. Somebody going from dependence to independence, transitioning from one health state to another, I think is very valuable and very impactful. If we could do that for more people and shift people down in health states that are more desirable, I think that would be, if given a choice, that would be the one that I would wanna see more focused on compared to getting everybody to an excellent outcome. Everybody's different.
We talk a lot about individualized, personalized medicine these days. I think that we should be thinking more about what is the target goal for individual people. People are different in terms of what they can achieve to get better. I think that if people can get better to go to a lower score, I should say, a better health state, but that may not necessarily be an excellent outcome as defined, you know, by us in the scientific community. I think then I would certainly prefer the shift.
Great. Thank you very much, Sean. We're almost at the top of the hour here. I'd like to give everybody, if anybody has any closing statements or would like to make a comment before we close things out here, I would give you the opportunity at this time. LJ, is there anything you'd like to say from your comfortable chair in Boston?
Thank you, Willie . One thing I just like to emphasize what Sean just saying. Interesting enough, everybody knows if you have a binary outcome, right? Just yes or no, or responding or not responding. From a statistical point of view, it's not really a good outcome to give us the most power. On the other hand, if you have more choices, more than just binary, like we call mRS shift. mRS shift, in fact, it's just basically you classify people to seven categories, zero to six, and the lower the better. Okay? So you have a six bucket for treated arm, and you have placebo people also have a 6 bucket. You basically compare the frequency after trial is done. So that's more powerful, the outcome we can use to detect the treatment effect.
I'm just using the statistical point of view to say mRS shift, so-called shift model, could give us more powerful statistical results if we still live in the p-value world. Thank you, Willie.
Yeah. Thank you, LJ. Sean and Tom both sent their best. They had to log off. Larry, do you have any closing comments or anything you'd like to say?
Yeah. I just wanna make one point that goes back to the very first question you asked about, you know, what was striking about the study, and particularly, to me, the difference between 90 days, the improvement between 90 days and 365 days in the treatment group. You know, one of the reasons, there are many reasons, but one of the reasons why we've kind of taken 90 days as the standard for measuring outcome after acute stroke therapy trials is that after 90 days, so many things can happen that have nothing to do with the treatment. You know, the groups tend to come together after 90 days just for no reason related to treatment. It's not really a fair assessment of whether the treatment really worked.
You know, that's why we don't carry it out later. Here, even despite that, despite the fact that all of those things can happen that can mess up your experiment after 90 days, even despite that, we saw an increase in the spread between the placebo group and the treatment group, which makes it, to me, even more powerful.
Great. Thanks, Larry. Dr. Hess, last comment?
Yeah. I mean, I think it is remarkable, the separation. Don't forget that this was a relatively small stroke study of only 200 subjects, 100 in each arm. You know, mostly we're used to having much larger stroke trials, and you still see these signals, which are interesting in a relatively small trial of 200 subjects, you know. It's quite remarkable.
Great. Thank you very much. Last comment to you, Dr. Chiu.
Last comment. Well, maybe I should try to go back to, you know, what I saw as a historical significance of what we're trying to do here. It's really you can't exaggerate how important the stakes are. You know, stroke research is a very, very difficult slog. The few times that, you know, stroke researchers have hit it big, with thrombolytic therapy, with reperfusion therapy, with the advances that have been made in stroke prevention, the effects on public health have been enormous. Again, I go back to, you know, the importance of what we're doing and the overarching historical significance, the large number of firsts that MultiStem would potentially represent in the field of stroke therapeutics.
Great. Thank you very much. Again, thanks to everybody that participated this afternoon, either by typing in questions, listening, or supporting Athersys. Thanks to our panelists. Karen, I'll turn it back to you to do whatever needs to be done.
Well, thank you, everyone. I just, again, wanna thank the panelists for your time and for everyone for joining. Thank you very much. Bye-bye.
Bye-bye. Thank you.