Brainstorm Cell Therapeutics Inc. (BCLI) Earnings Call Transcript & Summary

Good morning, and welcome to the Brainstorm Cell Therapeutics KOL Webinar on NurOwn for Alzheimer's disease. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Brainstorm website following the event. I would now like to turn the call over to your host, Chaim Lebovits, CEO of Brainstorm Cell Therapeutics. Please go ahead, sir.

Thank you, Sarah. Good morning, and good afternoon to everyone. On behalf of my colleagues at Brainstorm and life science distinguished professors, Scheltens and Dubois. I would like to welcome you all to today's KOL call and to introduce you all to Brainstorm's program in Alzheimer's disease. As you all are aware, Alzheimer's disease is a growing health burden, robbing individuals of their identity and creating a huge demand on families, caregivers, health care resources and society. At the same time, it's important for me to also reassure those who are suffering from ALS that based on recently received EU SME status, and we are in active dialogue with the EMEA to find the best regulatory path forward for NurOwn in ALS in Europe. As you are aware, our proprietary cellular technology platform, NurOwn, has great potential to address the unmet need across several neurodegenerative disease, including ALS, progressive MS and Alzheimer's disease. Based on leading Phase III ALS program that's now fully enrolled and fully dosed, we're on track and expect top line data in the fourth quarter of this year. The Phase II progressive MS trial has also restarted after COVID-19 delays. In the call today, Dr. Kern, our President and Chief Medical Officer, will describe how Brainstorm leveraged NurOwn's mechanism of action, proof-of-concept ALS biomarker data and shared disease mechanisms in ALS and Alzheimer's business, to initiate a biomarker-focused Phase II clinical program in Alzheimer's disease in Europe. Also joining us on the call is Dr. Stacy Lindborg, Executive Vice President and Head of Global Clinical Research. She will provide an overview of the clinical trial in Alzheimer's disease, that Brainstorm will soon begin. We are extremely privileged to be joined on today's call by Professor Philip Scheltens from the Amsterdam University Medical Center; and Professor Bruno Dubois from the Neurological Institute of the Salpétrière University who will discuss the current Alzheimer's treatment landscape, therapeutics in development and the potential role of NurOwn. Both Professor Scheltens and Dubois and will also be available to answer questions at the conclusion of the call. Brainstorm is fully committed to advance best-in-class cellular therapy to address unmet need in neurodegenerative disease. Our new program in Alzheimer's disease in Europe confirms that commitment. Before handing this over to Dr. Kern, I would like to take this opportunity to thank the entire team at Brainstorm that worked so hard in the run-up to submit our trial application to the relevant European regulatory authorities timely. Our CRO of WCT, Worldwide Clinical Trials, told me that this is a record first time for them to submit any application within 22 days. And I should also thank WCT's wonderful team for coordinating everything to make this happen timely. So without further delay, I would like to introduce to you Dr. Kern. Ralph?

Thank you, Chaim, and welcome, everybody, to this webinar today. On today's call, I would like to share our thinking about how important learnings in our over 10-year preclinical and clinical journey in neurodegenerative diseases has shaped our thinking. And I also want to acknowledge our opportunity to partner with 2 leading European Alzheimer's centers of excellence. Both of these events have shaped our approach and our decision to pursue a European clinical program in Alzheimer's disease. In today's webinar, I'll be giving you a brief overview, and then I'll hand off to Professor Bruno Dubois, who will be speaking about essentially the unmet need, the great progress in diagnostic procedures and the current status of Alzheimer's treatment. Professor Dubois will then hand off to Professor Philip Scheltens, who will be speaking to you about new emerging therapies, great progress in biomarkers in Alzheimer's disease, which is really supporting our efforts. And essentially, what is unique and attractive about Brainstorm's approach. Professor Scheltens will then hand off to Stacy, who will go through our study protocol and some of the thinking that we've put into what we believe is a very strong approach to use biomarkers to study Alzheimer's disease. And then, of course, we'll be available for Q&A. So without further ado, could I have the next slide, please? Thank you very much. So as you can see in this pipeline slide, our proprietary cellular technology platform has great potential to address the unmet need across several neurodegenerative diseases, including ALS, progressive MS and Alzheimer's disease. In the preclinical studies across several neurodegenerative diseases, NurOwn has consistently demonstrated a number of features: First of all, the enhanced delivery of neurotrophic factors; secondly, the protection of neuronal tissues in different models; and finally, improved behavioral outcomes and increased survival. Brainstorm's leading Phase III ALS program is now fully enrolled and fully dosed. We are on track, and we expect to have top line data in the fourth quarter of this year. The Phase II progressive MS trial is well underway, restarted after a few COVID delays and is on track for completion by the end of the year. And as you will see -- as you will hear today, we hope to treat the first Alzheimer's clinical trial participant with NurOwn before the end of the year. Can I have the next slide, please? The Phase II randomized placebo-controlled trial of NurOwn in ALS essentially provided us with proof-of-concept that intrathecal administration of our proprietary cell therapy was safe, that it was well tolerated. And very importantly, it impacted known ALS diseases biomarkers. We were very encouraged to see, particularly in the preselected rapid progressor subgroup, that the rate of ALS functional decline could potentially be slowed or improved. In this slide, you can see on the left, in the entire study population, which included 46 participants; and on the right, in the rapid progressor population, which were defined as greater than 0.7 points per month decline of ALSFRS-R in the run-in period, and that was 21 participants, that the rate of ALS functional decline improved post-treatment compared to pre-treatment. These changes were also reflected in the responder analysis. While this was an important observation, we asked ourselves a critical question of was this reflected in the biomarker analysis that we had performed in the CSF? May I have the next slide, please? So one remarkable aspect to NurOwn technology is the consistency of the mechanism of action from in vitro preclinical data to in vivo animal models and finally to CSF biomarkers. And the fact that we can read this through and translate the science through all different dimensions is critical. This slide gives you a very good example of the delivery of neurotrophic factors that play a role in neuronal repair and neuroprotection. And we don't distinguish between those 2 because they're both important. In the slide, you can see on the top row that the neurotrophic factors delivered by the cells, which include vascular endothelial growth factor, hepatocyte growth factor or scatter factor and leukemia inhibitory factor in the CSF of NurOwn-treated ALS clinical trial participants greatly increased several weeks after a single intrathecal administration. The implication of this is really profound. And that is that high levels of these neuronal repair molecules, weeks after a single injection, confirms that there is ongoing secretion of NurOwn's cargo or if you will, the fingerprint of continuing presence and activity of NurOwn or MSC-NTF cells in the ALS study participants. Can I get the next slide, please? A second way of looking at the effect of NurOwn in patients or in clinical trial participants is to measure the effect on pharmacodynamic biomarkers. In this case, we looked at inflammatory markers or MCP-1. And literally just this morning, today's webinar, there was a very -- there was an excellent publication showing the parallel between ALS -- MCP-1 as a biomarker in ALS and MCP-1 as a prognostic biomarker in Alzheimer's disease. We know that NurOwn reduces the production of inflammatory factors in vitro. And we also know that it induces immune regulatory cells in IL-10. And MCP-1 is one of the -- it was one of several inflammatory factors that's known to be associated with worsening function and reduced survival in ALS. And recently, it's also been shown to correlate with cognitive decline in Alzheimer's disease. And as you can see in this illustration, that a single injection of NurOwn reduced this important inflammatory factor by 40%. We saw similar reductions in other inflammatory biomarkers. They all move together, in other words. And this essentially also correlated with NurOwn cargo delivery. What was really intriguing about our biomarker data was that the post-treatment MCP-1 levels correlated with improvements in functional decline. And that was really an important point that we want to pursue in our Phase III ALS trial and also look at how that plays out in Alzheimer's disease. Can I get the next slide, please? This is my last slide, and this is really a summary of our thinking in how we translated what we learned in ALS and how we're applying it in Alzheimer's disease. And in this slide, what you see on the left are essentially the pathways or the targets of disease that we feel are tractable and can be addressed by our technology. As you can see, neurodegeneration, loss of neurotrophic function and inflammation are key elements of all neurodegenerative diseases. They play out very strongly in ALS, and they play out very strongly in Alzheimer's disease as well. And I think our panelists today will tell you more about that. What I want to impress upon you is that NurOwn may directly address each of these pathways in turn, through an increase in microRNA, in this case, miR-132 by reducing caspase-3, which is a silent executioner or driver of neuronal degeneration, delivery of neurotrophic factors and also immunomodulation. We accomplished immunomodulation both through secreted factors, through release of microRNAs, in this case, miR-146. And also some cell-to-cell contact effects and secretion of factors that increase regulatory function. The other rationale, obviously, for our ability to pursue Alzheimer's disease aside from the very strong rationale is the unique opportunity that we have to partner with 2 of the leading Alzheimer's centers in Europe. And today, we have Professor Scheltens and Dubois, and their talented teams able to join in. I'd like to just take a moment to introduce our speakers, and then I'll hand it off to Professor Dubois. I want to be very brief. I know this is -- they're both -- both of the speakers have very long CVs, but I'll just highlight a few important points. Professor Philip Scheltens is Professor of Neurology at VU University Medical Center in Amsterdam. He has served as the Dutch National Principal Investigator for over 35 Alzheimer's and dementia studies. Professor Scheltens founded the Alzheimer's Center at VU University in 2000. And he's Co-Editor in Chief of Alzheimer's Research & Therapy, one of the leading journals in the field. Professor Scheltens has authored more than 1,000 peer-reviewed papers and more than 75 book chapters on this topic. He's a leading and participating European expert in various European Alzheimer's disease research initiatives. Professor Scheltens was elected to the Royal Dutch Academy of Arts and Sciences and recently was also awarded the European Grand Prize for Alzheimer's Research, and we welcome him. Professor Bruno Dubois is Professor of Neurology at the University Salpétrière in the hospital in Paris at Sorbonne University. And he's Director of the Institute for Memory and Alzheimer's Disease, the Expert Memory Center in South of Paris, and the research unit on Cognition and Neuroimaging in Brain Diseases at ICM in Paris, and I had the privilege of visiting ICM myself. It's a brilliant institution. Professor Dubois has published more than 600 Alzheimer's preclinical and clinical peer-reviewed publications. He leads an international working group of experts on the new criteria for Alzheimer's disease. He is principal or co-investigator of several research programs focusing on Alzheimer's disease. He is leading and participating in various European Union Alzheimer's research initiatives. And a great accolade is that-- Professor Dubois is a President of the French Society of Neurology, and he's a member of the National Academy of Medicine. So welcome, Professor Dubois. And it's with great pleasure that I now welcome Professor Dubois, to take the presentation. And thank you very much for your attention.

Thank you, Ralph Kern. Thank you very much for this introduction, and thank you for the neutral slide that you have shown and for the efficacy of NurOwn in ALS, and we hope that we will have the same efficacy in Alzheimer's disease. So my job now is to present to you our truth, the reality of Alzheimer's today, that can be summarized as follow. Can you show me the first slide, please? Yes. The high prevalence of the disease worldwide, great progress in diagnostic procedures and a certain disappointment with current treatment. Next slide, please. So the high prevalence. I think that everyone knows the numbers, over 7.5 million in Europe, over 5 million patients in the U.S. And if we focus on the U.S., there is apparently every 65 seconds per new patient that developed the disease in the country. 300 -- I'm sorry, I'm sorry, 35% of Americans over 60-year-old are most afraid of developing Alzheimer's disease or dementia. This is higher than for cancer. And it has been shown that $7.5 trillion is a potential cost saving from early diagnosis only for current population in the U.S. And besides these numbers, the estimated numbers are rather impressive and what we're in for the next few years, over 13 million, both in the EU, in Europe and in the U.S. at the end of the next 20 years. And interestingly, there is a significant higher interest in the low and middle-income countries, this is shown in the figure and around. Next slide, please. So if we look at now -- next slide, please. Thank you very much. As I told you, there is also, in the landscape, a significant progress in the diagnostic procedures during the last 20 years. And this is mainly due to the discovery of biomarkers. The discovery of biomarkers constitute a major breakthrough for at least 2 reasons. First, because biomarkers can be considered as a surrogate of the Alzheimer brain lesions; and second, because it can be assessed in vivo. And because of that, it is now possible to certify the presence of Alzheimer's disease lesion in the brain of someone in it during his lifetime. As you know, Alzheimer's lesion can be characterized by their nature or by their location. Nature, there is 2 types of lesions, the amyloid plaques and the neurofibrillary tangles. And these can be assessed by what we have called, pathophysiological biomarkers, that can be investigated by CSF. And we can look at the level and the concentration of abeta and tau levels of CSF or by molecular neuroimaging, and we can look at the tracer retention in amyloid PET or tau PET. But interestingly, if these lesions occur in more or less specific region of the brain, it can be responsible for local changes due to inflammatory process, due to synaptic dysfunction, due to neuronal loss. And these local changes also good markers of the presence of Alzheimer's disease. So at the end, it is possible to distinguish 2 types of biomarkers, the pathophysiological marker that we should consider as diagnostic markers, because they reflect in vivo pathology in case of Alzheimer's amyloid and tau changes. They are present at all stages of the disease, that's very important. We will come back on that later on. They can be observable even in the asymptomatic state of the disease. And they might be a bit correlated with clinical severity. They are indicated mostly for inclusion protocols of clinical trials and for the accuracy of the [indiscernible]. On the other hand, you have topographical markers that are more progression markers. They are downstream markers. They have probably a less disease specificity, but they indicate the clinical severity and they are mostly indicated for disease progression. May I have the next slide, please? So based on a better knowledge of the clinical phenotype, and thanks to the discovery of biomarkers, Alzheimer's disease is now considered as a clinical biological entity defined by specific clinical phenotype that can be typical, and this is mostly characterized by an amnestic syndrome of the or hippocampal type or atypical and varies at least 3 different atypical forms of Alzheimer's disease. This is maybe more the posterior cortical variant, the logopenic variant and the frontal variant. And this clinical phenotype should be associated with the presence of the biomarker -- the pathophysiological biomarker positivity that can be assessed by CSF abeta, CSF tau and phosho tau and amyloid PET and tau PET. Next slide, please. So there is a trend today to turn to the left. That is to diagnose Alzheimer's disease at the earliest stage of the disease before dementia, at the pre-dementia or prodromal stage or even before at the symptomatic stage of the disease. This is now possible because we know that -- I've already told you that Alzheimer's lesions are already present in the brain several years before the onset of the first symptoms. Indeed, there is a synaptic dysfunction, microglial and astrocyte activation, a progressive abeta deposition and an increased pathology with neurofibrillary tangles long before the onset of the clinical disease. Therefore, thanks to the biomarker, it may be possible in the future to identify the disease before its clinical onset. And this will, as a consequence on our definition of Alzheimer's disease, should it be defined as shown here in the first box, should it be defined by the onset of the first clinical symptom or should it be defined as shown in the lower box by the presence of Alzheimer's disease pathology. This is an open question, and we will have to discuss this later on in the next few years. Next slide, please. At the same time, there was a great disappointment with treatment. During the last 20 years, since the approval of Tacrine trials inhibitors and memantine, more than 100 clinical trials were performed and all were negative. They include serotonin receptor antagonist. They include gamma-secretase inhibitors, monoamino acid -- MAO-Bi inhibitors, beta-secretase inhibitors, amyloid-targeting antibodies, PDE9, among others. However, I should mention that the BAN2401 and aducanumab showed promise in slowing of cumulative decline in addition to target engagement, and we heard this morning that aducanumab has a supposedly [indiscernible] small. Next slide, please. So despite all these failures, there is still an important activity in the field as shown here on the left, by the high numbers of clinical trials that are currently running. A few in the preclinical stage, around 10, most at the prodromal mild dementia stage of the disease. On the right, you can see that 39% of these are directed against symptomatic -- the symptoms of the disease. There are symptomatic treatments directed against the neuropsychiatric symptoms or cognitive symptoms. But the majority are disease modifiers, including anti-amyloid, anti-tau, anti-inflammatory and neuroprotection treatments. So this is what I wanted to tell and on the landscape of Alzheimer's disease today. And now I will leave the room or at least the virtual room to my dear colleagues and -- dear colleague and friend, Philip Scheltens. Philip?

Great. Thank you very, very much, Bruno, for this excellent overview. And I'm very proud to be here with you because you and I, we actually -- we were witness of this whole development of the biomarkers. We were there in the late '80s and early '90s when this all started. And now we are actually having the fruitful sort of results of all this biomarker research and I can actually implement it in the -- in clinical trials, such as we are discussing today. So my task. Next slide, please. This is my name. I will talk briefly about the new emerging therapies. I will talk about biomarker progress, a little bit building on what Bruno has said already, and also discuss a little bit about the Brainstorm approach, what I think is what we have learned today and what we are going to do tomorrow. Next. So I think one of the most important things that we have learned over the past few years, and I think most of you will share the disappointment that Bruno voiced about the failure of many of the therapies that were directed only at amyloid beta. And this is -- this may have many, many reasons, and I will discuss that later. But what I'm going to focus now is that there is not only a focus on amyloid beta. If you look in the middle, this is about neurodegeneration in general. You can focus on the misforming protein like amyloid or tau or TDP-43 or any other things. But around it, there are so many other things that actually go sort of at the same time. I think especially relevant for the discussion of today is everything that revolves around neuroinflammation and neuronal death. So those are important targets as well. And I think nowadays, we have many therapeutic approaches that we can use not only in the monoclonal antibodies, an example of aducanumab, is one of them, but also antisense therapy trials are ongoing. We have gene therapies starting, and we are also discussing stem cells therapy as today. So many more targets and many more approaches than ever, ever, ever before. And I think that is why this field is so extremely exciting, because of all these new targets and new approaches. Next. This is reflected also in this graph, also from Jeff Cummings. Despite the failures that Bruno showed you, there's an increasing activity, basically. There are more agents than ever, and there are more trials running than ever before. There's an increase since 2016 into 2019 of at least 12%. And we are now in 2020. I can tell you that this is actually progressing even more. Next. So looking back on the failures. On every failure, there's a lesson to be learned. And I think one of the things that we are now more critical about is the issues in drug development. And Jeff Cummings and myself, together with Howard Feldman, we have called this the 5 rights. And this is basically -- not a recipe or a cooking book of how to design a proper clinical trial, but it is actually sort of almost checking whether you have checked all the boxes, whether you can proceed with a certain intervention into the next phase. So is it the right target? Is it the proteinopathy you're targeting or any other process that is relevant to the disease, which is extremely important? Do you have the right drug? Have you shown in the early phase, before Phase I that there is activity, that it enters the brain for instance? That sort of thing. The right biomarker, extremely important, not only for target selection, not only for patient selection, but also for the readout, biomarkers can be extremely useful. So pick them carefully. The right participants. I think it is commonly known that in previous years, participants were included in trials that didn't even have the disease because not always the biomarkers were used as they should have been used. So people were not having the disease. And this is, of course, killing your trial. And of course, the right trial. And this is also have you gone the right power and have you sort of conducted the trial properly. Have you made sure that all the patients that adhere to the protocol, et cetera, et cetera. This seems very 'as an open door', as we say in Holland, but this is if you look at every trial in the past, some of these rights were actually not present or not fulfilled. Next. So coming to the right patients. And I think building on what Bruno said, I think we are now in the position by using the biomarkers, to at least identify whether the patient that you include in the trial actually has the disease. Of course, they have the clinical science and symptoms, extremely important. They have to have a certain level of cognitive impairment. But even in the early stages, you can already define the patients by the presence of the pathological hallmarks of Alzheimer's disease, amyloid and tau, by looking at the biomarkers. This is what is now called as the ATN system. A+ and T+ means that the patients are amyloid positive and tau positive, which makes them eligible for inclusion in an Alzheimer's disease-related trial. And this is, I think, the next step and the next level of targeting the right patients and which is now sort of almost custom and almost normal to do. Next. So Bruno already mentioned CSF amyloid and tau, which is nice. With one number function, you get information on 2 important proteins in Alzheimer's disease, and there are many, many publications have actually shown that it's not only useful to characterize disease by looking at amyloid and tau, but they are also linked to some form of cognitive decline. If you look at the -- if you compare patients who are diagnosed, whether they have the abnormal biomarker profile or not, of course, you can see already that those who have abnormal abeta and tau are the ones who decline cognitively over a period. And this is in the ADNI, from the ADNI cohort already in 2 years. So it is important to characterize the patients and it also tells you that the patients ultimately will decline over time. Next. Now coming -- zooming in a little bit to the other processes that are taking in place in the brain in Alzheimer's disease. You heard about MCP-1 already. Another one is neurofilament light, which is an extremely important aspecific but extremely sensitive neurodegeneration marker, which can be measured in CSF and in serum. And neurogranin is a specific marker for synapse loss. And all 3 markers here, as you can see, are somehow related to the presence of amyloid and tau because they are increased whenever you have A+ and T+, especially in the NFL and neurogranin. It makes it very, very clear. So it only means that pathology measured in vivo is linked to other pathologies also measured now in vivo in patients who have Alzheimer's disease. Next. And this is a nice link to neuroinflammation, playing a key role in Alzheimer's disease. This is, of course, too busy to read, and this is only a selection of just papers that good emphasis on the inflammatory process taking place in the Alzheimer's disease brain. Nothing new basically because we knew this already, but now it's much more easier to measure this also in vivo, like I showed you with the CSF markers. Now it becomes really a target as well. And it's one of the main factors that plays a role in the progression of Alzheimer's disease if you have amyloid and tau already present. Next. And one of the elements is that the microRNA 132, as was mentioned by Ralph, is a key player also in the cellular phase, which is coined by Bart De Strooper as an important phase already before plaque deposition, so before amyloid plaques, which is quite a late phenomenon. But in this pre sort of clinical space, the cellular phase of Alzheimer's disease, inflammation plays a major role, and this is mediated by microRNA 132, as you can see here, and it has direct influences on the neuronal component of the disease. So it has an influence on dendritic and external sort of macrogenesis and also neurogenesis and also on abeta deposition. But it also plays a role in the inflammatory component and also in the vascular component, which altogether makes the picture of Alzheimer's disease and ultimately leads to neurodegeneration. Next. And if you look here at the microRNA 132, it was mentioned already. We know that this is one of the microRNA studies down regulated in Alzheimer's disease as well. As you can see in the left upper graph here, it's downregulated. It correlates also with AD severity, again, which means that when you have more downregulation of microRNA 132, it means that you're further down in the process of neurodegeneration, so more severe disease. And it is upregulated also in the NurOwn NTF cells, which is the proprietary of Brainstorm's cell, of course. And interestingly, also is shown to be increased and in the responders in the ALS trial. So the intervention NurOwn actually directly involves, among others in the microRNA 132, in the upregulation and that is very useful if you look at the basic science being downregulated in Alzheimer's disease. So it makes a perfect sense to try this specific therapy already proven in ALS to do this and also try this in on Alzheimer's disease. Next. So to conclude, I think NurOwn, as you have shown and seen before, has shown promising results by -- in ALS by increasing [ NTF ] and microRNA 132. 132 is now regulated in AD and is also considered to be the right target. Remember the one on the right. And this microRNA relates also to a large array of other pathologies, namely neurodegeneration and neuroinflammation in AD. So from my perspective, looking at the trial that we are discussing in a moment now, it includes the right patients because they're selected on the basis of biomarkers in the clinics that Bruno and I direct, use the right biomarker to select these ones and also to look at the biomarker effects over time of this important intervention. Of course, we will collect safety information, but also efficacy signals in this particular next phase in the open study in order to program and to plan for the next Phase III in the development of this particular intervention. And with this, I would conclude and give the floor to my colleague, the next speaker, Stacy Lindborg.

Yes. Thank you, Professor Scheltens. Stacy Lindborg, Head of Global Clinical Research at Brainstorm. And I'm excited to walk you through the core components of our first clinical trial in Alzheimer's disease. The study is designed to investigate Brainstorm's proprietary and innovative stem cell therapy and technology within Alzheimer's disease. And Professor Dubois has really nicely summarized the challenges that we faced over time with clinical treatment research and the ongoing medical need and need for patients. So at Brainstorm, we're really excited to bring a new approach to this arena, to the Alzheimer's arena, one that leverages autologous mesenchymal stem cells, which are differentiated to produce neuro traffic -- neurotrophic factor secreting cells. We really think we've laid out some of the science already Professor Scheltens and Dr. Kern have really walked through many of the benefits that we believe really will prove to be very promising within Alzheimer's disease. So my job has been made very easy by the motivation of the importance of biomarkers and how we identify patients. What I'd like to do in my -- in the next 3 slides that I'll cover is really take you through the specifics of how we will select the right patients. It's very important that we're delineating across our sites, how we will target patients correctly, what the study design, the key components of the study design is, as well as what the measurements are that we will collect across the study. So Sarah, if you'll go to the next slide. We've already heard described that the field has been moving more to the left. It won't surprise you that in this study, we've chosen to focus on stage of the disease, where there really is the largest dynamic range observed across clinical measures as well as Alzheimer's biomarkers. It's a stage where we also see a dynamic range for some important neuroinflammatory markers. You've seen reference to MCP-1 or it's also known as CCL2. And really, what this means is this is where we observe many of these measures actually having their greatest inflection and really where patients are worsening. And so we believe that our treatment will have the largest benefit for patients in this period. So the study will be run at medical centers in Europe, in both France and the Netherlands. And the criteria that we've outlined, which you can see on the slide, is using established clinical diagnosis criteria from the second international working group as well as from the International Institute on Ageing and Alzheimer's Association. And those criteria help us ensure that we're identifying patients that are prodromal to mild dementia. And this criteria needs to be established at least 6 months prior to enrollment. And then combined with this criteria, we also will be confirming the clinical diagnostic criteria using baseline scores of the Mini-Mental State Exam. We're looking for scores between 20 and 30, and the global score from the Clinical Dementia Rating scale between 0.5 and 1.0. And then because of the emphasis and really what biomarkers -- Alzheimer's biomarkers have done for the field, we, of course, are using CSF biomarkers of abeta and Ptau, which we've already spoken to, really, of the importance of their association with progression of the disease and brain of Alzheimer's patients as well as correlating with clinical symptoms. So we'll confirm, we use these biomarkers to really confirm that the patients we're selecting are consistent in profile with Alzheimer's patients that are prodromal to mild dementia. And the objective is to study the safety and preliminary efficacy of neuron in Alzheimer's disease patients. So next slide. So we will plan to enroll 40 patients in a study that will be 52 weeks for every clinical trial participant. So once the inclusion criteria is met for a patient and they're enrolled, there will be a 10-week run-in period, during which time, the bone marrow aspiration will occur and the differentiated mesenchymal stem cells is manufactured. And during this period, we will collect important baseline clinical and demographic characteristics. We'll conduct a neurological exam, collect pretreatment CSF and serum data and in pre-treatment cognitive endpoints. And then each patient from the time period that they're enrolled will then enter a 16-week treatment period where they'll receive 3 treatments, each 8 weeks apart. And during this period, we'll collect really critical biomarker data in the form of CSF and serum samples. It will be collected at each visit where a treatment is administered. And then following this treatment period, all patients enter a 26-week follow-up period that will include 2 in-person visits. And during this period, we collect -- we continue to collect biomarker data, serum data. But this is when we will collect our clinical outcome measures, which I will summarize in just a minute, as well as activities of daily living. So in total, you can see across the schematic, with the 10-week run-in period, the 16-week treatment period and then the follow-up period of 26 weeks, each participant will be in the trial for 52 weeks. And the primary objective, as we've also already spoken to, is to evaluate the safety and tolerability of the 3 intrathecal administrations of neuron. And secondarily, it's important that we're able to understand the modulation of our CSF and blood biomarkers as well as evaluate the clinical outcome measures so that we can begin to understand how these are associated with our early insights into efficacy in the Alzheimer's population. So my last slide allows me to walk through some more specific information around the biomarkers that we're focusing on as well as the clinical outcome measures. And these really represent very important study measurements for us to give us insight into this -- into what we'll learn from this trial. So we are collecting paired serum and CSF samples on all trial participants. We will collect them pre-treatment at baseline, which is what we consider week 0, so it's when the first treatment is given, and then at 8 and 16 weeks post treatment. And we do have additional serum sample collection. That's in the follow-up period at weeks 28 and 42. And we're interested in a host of biomarkers that really allow us to explore how these biomarker levels change over time, which include neurotrophic, neurodegenerative and inflammatory markers. And I've listed a couple of them here that we certainly have explicit interest in. And because Professor Scheltens and Dubois and Ralph have really already spoken to many of these, I think I'll hold my comments really about their importance. But we're also interested in markers associated with amyloid and tau deposits in brain, which, as we've shared, or believed to be predictive of clinical decline and conversion to Alzheimer's disease or dementia. So those are additional very important biomarkers. Turning to the clinical outcome measures. So in order for us to evaluate how patients evolve clinically, we've selected a battery of scales that have been designed to be used with patients with Alzheimer's disease or have been shown to be effective in measuring important clinical outcomes in patients with Alzheimer's disease. They're validated and sensitive to changes observed in early stages of the disease that we're targeting. And really each measure that's included here is being included because they focus on different aspects of cognition, covering memory and executive function and attention. And equally as important, our aspects of understanding how the participant is able to function in their daily life. And so included in this list is a measure of activities of daily living. So to quickly run through them. The Clinical Dementia Rating Scale Sum of Boxes will allow us to explore the abilities of patients with Alzheimer's disease across 6 different domains, including memory, orientation, judgment and problem solving, community affairs, home hobbies and personal care. And of course, as we know, the global scale, the CDR global scale is actually used as part of the key inclusion criteria. The Free and Cued Selective Reminding Test is a neuropsychological test of memory that can detect changes in cognition based on free recall, total recall and cued recall in normal participants as well as mild AD patients. The neuropsychological test battery is designed to measure memory and executive function. The Delis-Kaplan Executive Function System measures higher order thinking and executive function, specifically focusing on attention and verbal fluency and cognitive flexibility. The Mini-Mental State Exam, as you know, is included as a key inclusion criteria. It's a very standard assessment instrument for diagnosing presence and severity of cognitive impairment and will be a critical assessment also for the treatment period of our trial. And then lastly, the Amsterdam instrumental activities of daily living measures functional impairment in terms of the activities of daily living. So I will now turn back the conversation to Sarah, our moderator, for Q&A.

[Operator Instructions]

This is Corey Davis. And while we're polling for questions, we also have them coming in through the Q&A feature. Hopefully, everybody is navigating this relatively new Zoom interface well. But I'm going to read one of the first written questions that's come in. It's from Jason McCarthy at the Maxim Group. And he's asking, has the FDA been more open to using changes in these biomarkers and specifically inflammatory markers that you've talked about in Alzheimer's disease, particularly the ones in the CSF, and using them as surrogate markers in earlier stage trials for the more cognitive markers that you would use in later stage trials? And how does that position you for these larger Phase III trials? And I think importantly, how definitive or how predictive are the biomarkers in some of these earlier stage trials versus the clinical endpoints that Stacy just went through right at the end of the talk? So if you could just speak to the balance between using biomarkers and clinical outcomes as endpoints in Alzheimer's studies -- [ as neural ] Alzheimer's study, especially given that you're starting in more mild patients.

Thank you. I will direct the question to 2 people because one part is how the FDA looks at biomarkers versus [ net connection ]. And that I think Dr. Stacy Lindborg would be best based on her experience with Alzheimer's and they have different previous experiences. And I will direct to Dr. Scheltens the question of the trial focusing on biomarkers versus clinician being an open label. So we'll start with Stacy, please.

Yes. I guess the simple and most concise answer is that the -- it shouldn't surprise you that the measures that we've selected are really widely used by other industry trials, which have received regulatory-based feedback. The scales that we're using for clinical outcomes are primary endpoints in multiple trials that certainly have been respected and viewed as important measures and reliable measures from a regulatory standpoint. And I think also from a field perspective, they're viewed as really representing changes in patients that are clinically relevant and that can be observed in patients so.

Yes, but the question was also how does the FDA or the regulatory in the U.S. specifically look at inflammatory markers for a Phase II trial in Alzheimer's.

I was going to allow Professor Scheltens to respond to the components of inflammatory markers.

Yes. Thank you. So my point of view is I think...

We don't see you. We see only half of your face.

You don't see me. But I should be -- do you hear me now?

Yes, we hear you well. But the camera a little bit -- go ahead.

Okay. My video is on. But -- so I think the question is very relevant, and it's always difficult to predict what the FDA will do. But I think for this particular stage where we are in, in the early Phase II, it's basically collecting the right data in this patient group. So all the biomarkers are used to see what kind of signal that you can detect based on the intervention that you do in an open-label to collect as much as information on the target engagement and on the efficacy of the intervention, coupled to those clinical measures. So I think this is the perfect way to do in this early Phase II trial to collect as many and much information as you can. And this is quite standard now in the Phase II in the clinical trial world and very well accepted by FDA and EMA as far as I'm aware.

And may I add a point? I think it's a very interesting question because I totally agree with your answer, Philip, for Phase 2. But besides that, as I said before, it tries the question of what is a disease? And at the end, we need to show that your treatment is improving the symptoms. Not only the lesions, we are not treating lesions, we are treating symptoms. So it's -- there is several steps for reaching the ground. The first step is to show an efficacy on inflammatory markers, that's very important. And in a second, we need to show that this is associated with an improvement of clinical symptoms. That is the notion of clinical relevance.

Yes. I might add one more component, Chaim. This might be what I think you were perhaps looking for. But really, as we interact with regulators around our drug applications, certainly, regulators are looking for consistency of signals, whether there are clinical outcomes or its measures of disease progression through biomarkers imaging, and you're really looking for consistency of signals. And so the work that we're doing in this trial begins to help us draw the appropriate relationships that exist in Alzheimer's patients and ultimately will enable us to describe what we believe we're learning about this treatment in Alzheimer's patients and the consistency of how it's working.

Thanks, everyone. And thanks, Jason, for that question. And another -- a couple of written questions here about the U.S. versus the EU. And so I would ask first, paraphrasing some of these questions is, why start in Europe first? And to our 2 KOLs, how aligned are you in the EU with, say, U.S. institutions in terms of using the team in clinical trials? Is it somewhat of a harmonized approach these days? Or do you sense that there still are differences in how both medicine is practiced between the 2 different geographies and how clinical trials are conducted?

I will allow first for Professor Dubois and Professor Scheltens to talk about their scientific cooperation with U.S. centers, and then I will talk about the strategy of Brainstorm, why we went first to these centers. So Professor Dubois, please. Bruno?

Philip, please go ahead.

Okay. Well, I think it's a very, very good question, but I think the trial design that was presented is really the standard of what we do nowadays in 2020. It's, by far, I think, very balanced between the biomarkers and the clinical readouts, very diligent and also sort of very, yes, almost a safe way in order to get as much data in order to proceed to the next phase. So I would say this is perfectly in line with everything that we do nowadays in at least all the trials that I'm involved, and I think Bruno has the same opinion. And for us, this is quite standard. And I think I like it. Perhaps for some of your American audience, they noticed that the ADAS is missing and this is exactly on purpose because we think that the ADAS is not sensitive at all in this early phase of the disease. So that's why we have targeted more sensitive clinical scales to pick up the clinical signal that Bruno was pointing at. So I think this is standard and up to the standard of the modern times.

But we have the chance to participate in the elaboration of the clinical trials. And it was very interesting, and I would like to thank Brainstorm to have -- to get our advice. So it was very interesting, and we could put in the clinical trial, as Philip said, for example, new, new, new batteries such as the Amsterdam IADL, such as the Free and Cued Selective Reminding Test, which is very, very interesting for including patients with Alzheimer's disease and [indiscernible] with NBT and many, many subtle tests that have been included to evaluate the efficacy of the drug. So I think it was a real cooperation between the company and the PI of this -- and the nature of the clinical PI of this trial. So it was very interesting. And I think it turned a very interesting trial.

Thank you very much, both Philip and Bruno. And of course, for the U.S. audience, you should know that both Professor Scheltens and Dubois are principal investigators for most of the Alzheimer trials in the last few decades. They're international trials. Now we, as a company, we have to choose a site for a Phase II trial. This is an open-label trial. Similar to what we did with ALS, our first open-label trials were in [indiscernible]. And we have many strategical reasons why we wanted to go to Europe, including that we really wanted to work with these principal investigators. And I'm not saying that because they're on the line now. You will see that these are international renowned key opinion leaders when it comes to Alzheimer's. We have other strategic reasons in Europe. I'll just mention one at least. So we did the ALS trial only in the U.S. and we have [ toured ] Europe. And there's a huge European population with ALS patients. And we believe with our run-up with our ALS trial, and hopefully, we'll be successful, it will be very important that the EMA institutions would know our product. It's the same product. So they will know our safety profile, and we already have a good collaboration and perhaps added a local trial in Europe. It will help regulatory-wise both for ALS. And yes, to the questions of many that I see asking, would there be a respect results by the investigators, Scheltens and Dubois? The answer is, of course. Just the BLA that was mentioned that was filed today, both professors are part of that trial. So definitely, the FDA would look very seriously at results from these very respectable centers. Corey?

Thanks, [indiscernible]. A number of questions asking about timing. And so first would probably be more directed to Chaim in the company, which is do you have official time lines for finishing this trial? But then tied into that for Doctors Scheltens and Dubois, how eager are your centers, in particular, to enroll patients? How much competition is there for Alzheimer's studies among other therapies that may be in development and already on the market?

So again, I will allow -- you're right. There's a part of the question to the company, but I'll allow first either Bruno, either Philip to answer the question directed to you.

Interestingly, yes, because we already have a discussion with other centers in France in order to create this -- an input about the recruitment of patients and all the centers were rather positive in saying that it will -- there is a real will for patients to participate in cell therapeutic treatment. This is a new avenue and several patients already heard about this approach. And it seems to us that it would be -- it will be possible to point patients based on some media broadcast and there is several ways to recruit this kind of patient. But I think we will be able to do the job in a short time. What do you think, Philip?

Yes. I agree. I think there is indeed a competition. I mean this is the group that is targeted by most trials. So mild and prodromal patients are the patients that are very much in demand for many trials. And one of the advantages here that, of course, it's a very unique mechanism. It's an open trial as well. So there's no placebo, and that is an advantage for many, many of the patients. So they will directly get good stuff, as they say. So I think it will be no issue to recruit patients for this particular trial.

Yes. Ralph, you would like to address the timing of the beginning. At the end of the trial, I would say, we were going to finish yesterday. But I think [indiscernible] the timing of the beginning.

Yes, yesterday sounds great. So look, we're making -- we've broken records so far in terms of how we've gotten the submission to regulatory groups. I think that we have a very ambitious time line. We like to treat the first patients before the end of the year. In other words, have the cells in patients before the end of the year. That's our plan, and that's what we're working on. It's a 52-week study. So you can imagine that the study -- each participant will be enrolled in the study for 52 weeks. And then we need a few months to ramp up and recruit. So you can do the math based on that. I don't want to give any more specifics, but I think that's our general thinking.

Yes, don't dare give more specifics, and they get out for you if you're a day -- late with a day with 40 patients, yes. Next question, please, Corey.

And just to let everybody know, we actually do have quite a few interesting questions on the line. So we'll probably go right up to 9:30, if that's okay. And then hard stop at 9:30 Eastern Time, if that's okay with everybody. So interesting question here. It's from Dave Sherman of LifeSci Capital and asking about differences between Alzheimer's disease and ALS patients in terms of how the cells, the treatment would penetrate the tissues and how long the cells may survive? And if you would expect differences between those 2 different populations for whatever reason.

Ralph?

Yes. So David, thanks for the always giving us tough questions. Appreciate it. No, look, the cells are the same. So the fundamental properties of the cells are the same in both groups. Both ALS and Alzheimer's are an inflammatory environment. As you know, the cells home to areas of inflammation. That's one of the properties of MSC cells. They also are licensed, and they respond to the environment. In other words, when the cells are in an inflammatory environment, they have a biological propensity to immunomodulate to a greater extent. The secretion of neurotrophic factors would be the same. The relevance of inflammatory markers in ALS and Alzheimer's diseases is uncanny. I mean it's quite surprising how much overlap there is. And I think the way to look at it is the brain only has so many ways to get sick and so many ways to respond to treatment. And I think there's some shared pathways that are there. And I think some of the microRNA profiles, I think Professor Scheltens very eloquently described miR-132. We're also quite interested in miR-146. We know that it's a very important regulator of the innate immune system, and microglia play an important role in ALS and Alzheimer's disease. So we think that there's sufficient overlap that the mechanistic properties of our treatment will play well. And we don't believe based on first principles, that there's any difference in terms of the persistence or the ability of the cells to perform in these environments. And also in preclinical studies, we've seen that the cells, particularly the differentiated cells, have similar neuroprotective properties across different animal models. So we would think that that's also a vote of support for this being a technology platform. And that, obviously, there may be some unique attributes of each disease, but we will obviously be looking very carefully at that in biomarkers. One notable difference between Alzheimer's and ALS is there may be more vascular involvement in Alzheimer's. We know that miR-132 and other factors that are released by neuron are able to stabilize or repair the blood-brain barrier or maintain endothelial and pericyte function. We'll be measuring that. And it may be that, for example, the APOE4 group in Alzheimer's may have more vascular involvement, and we'll be looking at subgroups afterwards to see if there's some biomarker differences. And obviously, these are all very good questions that we'll be looking at. So thanks for the question.

Yes. I know others may [ ask for an answer ] on this question, but if you want to fill in a few more questions. Corey, please, let's file the next. question.

Yes. So another follow-on question from Jason McCarthy at Maxim is asking to discuss the importance of neuron being intrathecal and direct administration into the CNS, whereas plenty of other therapies, obviously, Alzheimer's is a brain disease, other therapies having challenges of crossing the blood-brain barrier to kind of speak to the -- perhaps the mechanistic advantage that you have on the delivery of this -- of neuron.

Yes. Ralph, do you want to go again or Philip, either?

Yes. I don't know. Would Philip or Bruno care to comment?

No. Well, I can comment on the feasibility and the practicality. We're currently doing a study with intrathecal administration of another compound, and it's very well accepted by patients. And it's even more [ LPs ] than in this particular trial that we're discussing now. And of course, it has many advantages. So there is no blood-brain barrier sort of problem at all. So you directly go to the target. So I think there are many advantages, and it's not -- for this particular phase, it's feasible. I mean, if you look into the future, whether we can treat all millions of patients without some disease with intrathecal therapy, that's a different story. And I think we need to think about other ways of administrating these cells. But for this particular trial in this space, it's extremely important and again, it's feasible.

Yes. But Ralph, maybe you have a look at that, and you may have the answer comparing the efficacy with blood brain -- blood or largely by cell intrathecal. Do you have the answer?

Not yet. Well, we hope to. No, I think I just would add one comment after Philip's very eloquent point. And that is that there's increasing awareness that the CSF pathway is a privilege delivery system for various macro molecules and in this case, cells as well. And that some of the best work was done in Alzheimer's disease by Jeffrey Iliff at Washington State University. And really showed very clearly that when you administer molecules into the CSF, there is a delivery system in place using the CSF pathways that travel along blood vessels, and it does have access to deeper brain structures. And some of the preclinical models in Alzheimer's have shown very good delivery in the hippocampus after intrathecal administration. So we think this is a reasonable approach. And obviously, I think the point that Philip made that it can get around the blood-brain barrier is really an important attribute that needs to be explored further.

Thank you. I know there's more to talk about this, but let's squeeze in one more question.

I want to take advantage of the time that we have with Dr. Scheltens and Dubois. This is an -- comes from an anonymous person. But I want to ask your outlook globally on the treatment of Alzheimer's disease. I know those of us involved in the drug development world have seen so many failures over the years. But just kind of ask an open-ended question how you're feeling right now about what you've seen across the continuum of drugs in development. The question is, how are you feeling about whether or not we're going to see drugs that are transformational in terms of treating this disease over the next 5 to 10 years? Maybe Dr...

Yes. Okay. Bruno, shall I go? So I'm quite optimistic, and Bruno knows that as well. I think aducanumab is a good example. I think that will be probably the first in line, but it will never be the ultimate answer. So we need many, many approaches differently, as I showed in the graph earlier. And I'm optimistic because I see so many new leads and so many companies that are sort of developing drugs in the early phases. And we have now the possibility of targeting disease so much earlier than we could ever before. And we are much more conscious of how to design the trial much better. So we have learned from all of failures. So I'm actually quite optimistic in that within a certain time frame, I won't mention any numbers, we will be able to have more than one therapy to treat this disease. I will not say cure, but at least treat the disease.

I would just would like to add something. I totally agree with you -- more or less, up to the -- of my friend. Now the point is that -- the question is very important. We are -- the time now is very important. Is it possible to think that we will treat someone who is already clinical? In other words, when it's -- when there are clinical symptoms isn't too late. That's a fundamental question, fundamental question. It appears that, as you know, that when the symptoms appear, there is already a large amount of, I mean, lesion in the brain and tau is spreading out the [indiscernible]. So we probably need in the future, if we want to stop the disease, to treat before the occurrence of the symptom. But then this asked a very important question, how can we define that someone has already a lesion will develop the disease? So that's a very interesting discussion now. Is it possible to define those who will progress to a clinical disease? 100%. That's the question today. If we can do that, then I'm sure that we will have treatment that can [ block ] the lesions before the symptoms.

All right. Thanks. We've got time for one more question, quick one to squeeze it in because there's a number of questions coming in about partnership discussions. And Alzheimer's is obviously a big disorder. And what's the state of any potential partnership discussions? And how should the Street view your engagement with a potential bigger pharma partner for this indication?

Yes. David, you would like to take this?

Sure. So David Setboun, I'm a Chief Operating Officer, and a big part of my role is to manage the ongoing discussion with potential partners. We do favor global partnership, and we do favor our leading development in ALS. And that's what can I say. It's a strategic part of the development of Brainstorm for us to work on potential partnerships. Thanks.

One more question then, Corey?

Well, the -- lots of questions about funding and how Brainstorm is positioned to be able to fund this study and all future studies.

Definitely. So Brainstorm is well positioned to fund this study. And it's one of the reasons we went to Europe. We know where the price is coming in and going out. And we also have potential non-dilutive grants that we're looking at. So yes, the Alzheimer trial is well-funded. And of course, our ALS trial is well funded, including the progressive MS trial, too. So I think that, that concludes it because we are after 9:30. So I do want to thank the LifeSci team for running a wonderful Zoom meeting. I think COVID brought us this technology, is far better than the audio calls we usually do. And I want to thank all participants. We had a very big crowd that listened in to us, and we are looking forward to having additional discussions with you after we have some maybe internal results, an open-label trial. So we'll have to decide when we're going to share data from this Alzheimer trial. Definitely, we're going to have data before from our ALS trial in the last -- this year. So thank you very much, and I'm sure you all wish of the best with the ALS results. It's wonderful speaking to you. Thank you very much.

Thank you.

Take care.