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spk01: The next presenting company is Brainstorm Cell Therapeutics from New York, New York, United States. Brainstorm Cell Therapeutics is focused on CNS neurological gene cell therapy inflammation. Presenting for Brainstorm Cell Therapeutics are their CEO, Haim Lebovitz, and co-CEO, Dr. Stacey Lindbergh.
spk02: Good morning. Dr. Stacy Lindberg is my co-CEO as of late week or so. And so we don't want to change the presentation or send someone else to present me. So we can do this together. This is a very exciting moment for us. And I'm sure many of you know that late in the week, we're having a meeting with the FDA type A meeting. But for now, we'll be focusing and explaining our narrative of our data, why we think approvals warranted here. And just will Stacey please take this forward and move the slides, and I will jump in different slides, right?
spk00: Sure. Thank you. It's a pleasure to see everybody here. We have our forward-looking statements. And we've presented quite regularly here and on our own are very excited about the evidence we've generated. We'll be focusing, as Haim said, on the Phase III ALS data. but wanted to offer a little bit of background and perspective. Neuron is an autologous treatment. It's consistent, reliable, and convenient. And by nature of not using animal proteins, antibiotics, or any genetic modifications, and with Culture Rescue, we have the ability to effectively make this an off-the-shelf product. With one bone marrow harvest, we can produce several years of treatment. And we have successfully completed tech transfer of manufacturing to our commercial manufacturing organization, Catalan, which was done in 2021, and really have had great success and have superb manufacturing quality across all the transfers for production and academic centers and our clinical trials, demonstrating really robustness with our manufacturing process. You look at our pipeline, ALS is the furthest progressed. We have been studying ALS, and I'll show you in just a few minutes, have completed four clinical trials. The phase three trial was published in Muscle and Nerve. It appeared in print in January of 2022. But even more importantly, we started with a number of animal models preclinically, which really gave us a foundation and understanding of Neuron. and an ability to really understand the mechanism of action and the breadth across different neurological diseases. We've completed clinical trials in two different diseases. So we have a progressive MS study that was completed and also was published in a peer-reviewed journal, generating a lot of excitement at ECTRIMS and also amongst the MS community. It was published in a multiple sclerosis journal in September of last year. We also have new technologies coming. So as you see on the bottom, we have an Exosome platform. We have published data from ARDS and really are looking forward to sharing in the future different diseases that we believe really are incredibly promising, and this would enable growth beyond the neuron technology.
spk02: As you can see here, we usually focus, and like this presentation, we'll also focus mainly for our ALS trials because that's our, of course, most advanced program. But we have many additional programs. There's a very strong published preclinical and clinical results. Of course, progressive MS is a huge market, over 500,000 patients in progressive MS in the United States only. So once the ALS will be approved, at least once we get that upcoming and proceed to get an approval, of course, that will come into play in the market cap as well and these other different diseases. And each one of them can be, of course, blockbusters. And, yes, and I would like to say kudos to our team on the exosome platform. It's not trivial to be able to have the quantity and the quality of exosomes as our team were able to, and it took quite a few years, but we're very professional with that, and we have the clean room facilities, of course, in addition to Catalan and Israel, both in the IHLF Center and in ADASA. They will support us for ALS when needed in the initial after a possible launch, but also that's where we're able now currently to do different various trials with exosomes, which we'll be announcing later in 2023. But again, this presentation will focus mainly on ALS. And I'll hand it back to Stacey. Thanks.
spk00: That's great. Thank you, Haim. So this slide really just illustrates when we began preclinical development with Neuron and really the culmination across all of our clinical trials published in three different peer-reviewed papers, but with a muscle and nerve paper that was the last published and based on our Phase III data. So first and foremost, when I think about, you know, really the designing of these trials, what's been really superb for me entering the company just about three years ago is seeing really the caliber of the institutions we're working with and our principal investigators, really the most well-known researchers and clinicians treating ALS patients over time, Merit Sedkiewicz, Mass General, and Bob Brown at University of Mass. Tony Windebank, really just phenomenal, phenomenal researchers, as well as really prestigious academic sites that served as the manufacturing sites. We're also very pleased with the engagement in the patient community. We did have grants that supported this trial. We had the ALS Association and IMALS, which sponsored a grant for biomarker studies, which we'll spend some time talking about today. probably one of the most exciting aspects of our trial. And California Institute of Regenerative Medicine also contributed a substantial grant. So this trial, the Phase III trial, was extremely well conducted and was well designed. It featured some unusual patients, which we can really show through this trial. We included a very broad, real-world set of patients. which is a real strength when we get to and think about the biomarker data and what we can glean about patients across the spectrum of advanced ALS all the way to those that are much earlier in the disease course. But if you look at this little kind of sigmoidal shaped curve, the red dots highlight phase three trials or trials that are under review right now of therapies. And you can see we're graphing actually the baseline functional rating scale, the ALS functional rating scale, from each of these trials. So, Neuron is in the blue in the far left. We can see that our baseline level of disease by the participants in the trial was lower than the other trials that have been conducted, the other late Phase 2 and Phase 3. But predominantly, if you focus on the products that are approved or under review, we're five points lower than Amaleksa's registration trial. We're six points lower than Terforsen, which is currently under review by Biogen, and Adderiva in the J19 trial is 11 points higher, the baseline average. So the reason this is important is that we can see, if you look at the gray box on this slide, when you have participants coming in with advanced ALS, you have individual attributes, all of which are incredibly important. There are 12 items on the ALS functional rating scale. all very important in assessing function, physical function that we're trying to show and assess the treatment effect in. In these patients, our study has shown in those that were starting with advanced ALS, and I'm specifically highlighting data in patients that had a score of 25 or lower, we actually observed that there are patients that on average about 40% of patients started with zeros on the fine and gross motor items of the scale. So that means each of those items ranges from zero to four. If you're beginning a trial with a score of zero, it means you can't measure disease progression in those patients. So this is actually a really small, relatively small percent of the trial. And we'll be highlighting and showing how the overall results compare to when you are able to account for this effect, which is a floor effect. It's a plateauing of the ability to measure and quantify ongoing disease progression that is continuing in this universally fatal illness. Patients are worsening. It's simply a scale assay sensitivity problem, but it can be overcome, and we'll show you the effect of it.
spk02: Simple layman language for some of the laymen here. I'm a layman. So, of course, we don't argue that our treatment is not effective for the lower part of the score of patients there. We just argued that we discovered, unfortunately, we were the ones who discovered because we went to the lowest, as you see, compared to other trials, that there's a floor effect that's higher than what's thought. Everyone knows in every score there's a ceiling effect and a floor effect. The ceiling effect for ALS or for RSR is very well established because all or most of the trials stay very high. So we know that over 45, you cannot draw any conclusions because patients can be stable not because of treatment, just because it's still the ceiling. The floor effect, We show that our data, Clary and Stacey will present it soon, clearly suggest that there's a floor effect far higher than what was thought. The biomarker data, which we'll show later, will show you that patients under 25 in the score and over 25 have the same biomarker effect versus placebo zero. So that's what we're arguing here. And this is something that we're paving the way, like just like we're paving the way in biomarkers, we're paving the way in understanding the score better. That's one thing I wanted to point out. Also, another thing is the other two approved products were not approved only for the patient population they studied. So they studied only the early patient populations. They were approved across the board. Just a comment I wanted to make. Thank you.
spk00: So I'm going to highlight two very critical endpoints from this trial. So on the left of the slide, you can see the primary endpoint. On the right is an endpoint which has been used in regulatory approvals and is a very logical, it's very easy to interpret clinically. It allows you to assess how much function is lost on average from baseline through the end of the study. And in both of these plots, on the far left, you can see the results in all participants. So if you start with the primary endpoint, you can see that there's the blue bar is the neuron-treated participants, and we can see that there's A larger percent of neuron-treated patients compared to placebo, which is in red. But we expected a 20% difference between treated and controlled. What's interesting, if you go to the next set of bars, which is showing a pre-specified subgroup. So we specified a subgroup for common and neurodegenerative disease you want to be able to assess. if there's a different treatment effect in patients that are earlier in disease course versus later in disease course. And what's very interesting is that the assumptions that really went into the trial, which is based on historical data and really what we would expect from other clinical trials, we actually see these results aligning almost identically to the power assumptions, which show a 20% difference in response rate with Neuron compared to placebo. We look at the secondary endpoint, which again is allowing us to look at specific function that's lost. And this is really critical when you look at one point loss in any patient that's living with the disease. They would say that this means the difference between being able to turn over in bed, being able to feed yourself, take care of yourself from a hygiene perspective. Each point is incredibly important. And again, what we see in this data is the influence of a small percentage of patients, it was less than a quarter of the patients, that had this floor effect, and we see a five-fold improvement in the treatment difference when we go between all participants and the results where we couldn't actually measure decline, to now when we're looking above 35, we see that the difference in the function that's maintained and not lost with neuron treatment is over two points. So this is a really, really important clinical finding. And we also note that from a regulatory standpoint, the p-value associated with this comparison is 0.05. So what's very important also is to understand, okay, this was a pre-specified subgroup. It was smaller than we expected because the baseline average turned out to be lower in the trial. So we wanted to, and this was published in Muscle and Nerve for full transparency and really to be able to understand how consistent are these results across the trial. And you can see, whether you like pictures or numbers, you can look at the version you like, but you can see that there really is a very consistent effect as you proceed from the pre-specified threshold of 35 and you go down to the level where we know very objectively where patients have a preponderance of zeros on items. And so we see here there are some of these thresholds on the primary endpoint are statistically significant, but really most importantly is that we see a 15 to 20% difference in response rates between neuron and placebo consistently across what is almost 80% of the data. Okay, and then similar analysis for this secondary endpoint Again, if you look at the treatment difference, these two points, you can see when you're above 26, we consistently see two points or higher function, level of function that is preserved across patients in the trial. And this endpoint is statistically significant in every single one of these thresholds. So clinically meaningful and statistically significant. So I do want to say a few things and show you some of our biomarker data. We actually have a manuscript that is drafted, and we expect to be submitting soon, which will really be a very important contribution to the field. As Haim mentioned, really when you look at the baseline scores of all the trials that preceded this trial, we really haven't studied patients that have advanced ALS. And so it's extremely important not only that we're continuing to work and validate biomarkers so that we can accelerate and progress drug development in the future. But what's also important is that we have an ability where we don't have the assay sensitivity with the ALS functional rating scale to be able to see what happened in these patients and to be able to actually have a rigorous placebo-controlled trial to do so is a real asset, I think, for the community. Another part that I have to say really makes this study a landmark trial Often what you'll see with biomarker studies is that they are sub-studies of large trials, and Brainstorm decided very smartly to conduct biomarker studies in every single participant in the trial, and we collected CSF samples seven times throughout the trial, so we have an incredibly rich set of data and a very precise, much more precise measure than when we, for many of the biomarkers we know compared to if we were sampling through SARM or other samples. So what is very exciting, if I go back to the broader portfolio perspective, we are going to focus on the data from our ALIS study But we have confirmed the mechanism of action and really what we understand from preclinical studies and from phase two in phase three. And what's very exciting is that the mechanism of action aligns really very closely with what we understand not only of ALS disease, the underlying pathology, but also other neurodegenerative diseases. So we know that there's increased inflammation. We know that we see cell death and markers of neurodegeneration. that are classic hallmark of the disease, and also a lack of this neurotrophic support in really enabling cell vitality. So this is true certainly of ALS, but is true of other diseases. And when successful with ALS, it does allow us to move very rapidly with really an expectation of being able to demonstrate clinical relevance in other disease states, but expecting our mechanism of action to be effective. So I'm going to show some very specific data, but you will find the conclusions on the right, which is that Neuron very effectively lowered markers of neuroinflammation. We elevated markers of anti-inflammation, so very consistently impacting inflammation in these participants in the trial. We also reduced markers of neurodegeneration and markers of cell death. I will show you some neurofilament light data, which is a very relevant marker in many diseases. And also we improved very significantly the neuroprotective factors and other markers that we will fully report on in our manuscript. So these are meant to simply give you an illustration across a very broad set of biomarkers that we analyzed. We did this very rigorously. We submitted to the FDA in advance of the study on blinding a second analysis plan. so that we would have an ability to be very thoughtful and planned, not only in how we would analyze the biomarker data, but also how we would formally connect the relevance of biomarkers to clinical outcomes. This is very important because certainly from an ALS perspective, I think there are emerging biomarkers, and there's a lot of interest in the scientific community, but I think we're shy of a true surrogate. So our rigor in really defining how we would connect these became very important. And what you can see if you look at the top row, this is MCP1 is a pro-inflammatory marker and LAP is an anti-inflammatory marker. In all of the graphs, placebo continues to be read. So if we start with really just that we observed exactly what we expected, which is in these participants, we would not expect these markers to change over time in an untreated population. This matches what we see in the literature. We see very flat and stable. which we're presenting in log scale. But we can see with Neuron in the blue, we see very rapid. So the very first circle that's on here, if you can note the legend, is actually at week two. So it's the only time we measured really out of not wanting to have undue burden for patients in the trial. We did want to see how quickly we would see the response, the biological response. Every other time after treatment at weeks 0, 8, and 16, you see their four-week increments. So we may in fact have a similar response after future treatments, but we did not insert that burden in the trial. So we see with MCP-1 and LAP, we see significant changes with impacting inflammation, and we actually see significant values at every single time point where it's measured. This is true across many inflammatory markers that we collected. If you go down to the bottom row, we have neurofilament light, a marker of neurodegeneration. We collected death receptor 6, phosphorylated neurofilament heavy, and many other neurodegenerative diseases. we see that there is a steady decline of neurofilament light values with Neuron compared to placebo, with placebo staying relatively flat. We see a slight increase at the top, which is also expected with an intrathecal injection, so we believe, and the experts that we speak to are completely, we're expecting to see this finding. And we really have quite a sizable reduction, about 15 percent, actually slightly more, from baseline. And then VEGF-A, which is an important marker that we have used over time for quality release with our manufacturing, and it's a very important neuroprotective marker, we see very fast elevations, actually well above 300 percent from baseline, and significant changes across the study. So the last two slides, which I really am not planning to present, but as Haim actually went through with the remarks he made partway through our talk, really what we see when we look at, as we are interested in understanding what's happening in these patients with advanced ALS, this is showing you the same biomarkers I just presented, but looking at patients that had a 25 or below at baseline. and above 25, and we see basically very similar effects, the same effects across all four of these biomarkers. And the very last point is that we used a machine learning approach that actually identified biomarkers that could accurately predict and were relevant to the clinical outcomes observed, and were able to find three very important markers that we'll be displaying more of in the future. Thank you.
spk02: Thank you very much. It was very well done.
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