Good morning and welcome to the BrainStorm Cell Therapeutics KOL webinar. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations, and as a reminder, this call is being recorded and a replay will be made available on the BrainStorm website following the conclusion of the event. Before we begin, I would like to draw your attention to the Safe Harbor here on slide two. Today's event and presentation will include numerous statements, descriptions, forecasts, and projections regarding BrainStorm Cell Therapeutics and its potential future business operations and performance, including statements regarding the market potential for the treatment of neurodegenerative disorders such as ALS, the safety and clinical effectiveness of the NurOwn technology platform, clinical trials of NurOwn and related clinical development programs, and the company's broader scientific initiatives. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond BrainStorm's control, including the risks and uncertainties described from time to time in its SEC filings. The company's results may differ materially from those projected in today's event and presentation. The company undertakes no obligation to publicly update any forward-looking statements, and with that, I'd now like to turn the call over to Chaim Lebovits, President and Chief Executive Officer of BrainStorm Cell Therapeutics. Please go ahead, Chaim. Thank you, Tara. Thank you for joining us today for this webinar. My name is Chaim Lebovits, and I'm President and CEO of BrainStorm. It's a privilege to speak with you all today as we discuss recent progress being made in the fight against ALS. Today's session would be of great interest because we are joined by Dr. Terry Heiman-Patterson, a leading expert in ALS and an esteemed member of the medical and scientific community. The agenda for today's presentation is here on slide three. Dr. Terry Heiman-Patterson will begin with a review of the current treatment landscape in ALS. It will be followed by Dr. Bob Dagher, BrainStorm's Chief Medical Officer, presentation and update on NurOwn, our cell therapy treatment, including details on the planned phase III-B trial. This will be followed by Dr. Netta Blondheim-Shraga, our Senior Vice President of Research and Development, who will discuss the evidence from biomarkers that support NurOwn's treatment effect. Then Dr. Dagher and myself will return for some concluding remarks before opening the call for questions. Some highlights of Dr. Terry Heiman-Patterson's professional career are summarized here. She's currently the Director of the Center for Neurodegenerative Disorders and a Professor in the Department of Neurology at the Lewis Katz School of Medicine at Temple University. She co-founded and serves as President of the ALS Hope Foundation and is also one of the founders and the former co-chairs of the NEALS Executive Committee. She has been involved in 24 ALS clinical trials, establishing key standards in ALS care. Dr. Terry Heiman-Patterson was the recipient of Forbes Neuroscience Award for the dedication to improving ALS patient care and advancing research. We are grateful for the opportunity to hear her insights on the current landscape and the potential impact of novel therapies such as that's being developed by BrainStorm. Dr. Heiman-Patterson, I will now turn the call over to you. Thank you very much, and it's a pleasure to be here. And I never turned down an opportunity to talk about ALS because I think there's so much hope now and so much going on. And so I'm going to start by talking a little bit. I think everybody here probably knows that ALS is really a devastating disease that is a progressive neurodegenerative disease, and it's really a degeneration of the motor system. And the motor system is a tag team of nerve cells, including the upper motor neuron, which of course transmits information to move from the brain down into the spinal cord, and a lower motor neuron, which transmits the information from the spinal cord out to the muscles. And as a result of the lack of motor nerve innervation, muscle atrophies, the term sclerosis actually comes from the way the spinal cord looked pathologically. We define ALS as having evidence of damage to both that upper and lower motor neuron, and that's what the clinical picture will look like. Although some folks, as I'll describe, can be more upper motor neuron or more lower motor neuron. As a result of the disease, there is progressive weakness and loss of mobility. It can start anywhere, usually in the extremities, an arm or a leg, two-thirds of the time, one-third of the time. It can start with speech and swallowing, rarely with weight loss and breathing difficulties. As I mentioned, the phenotype can look like it's mainly that upper motor neuron from the brain to the spinal cord, or mainly the lower motor neuron from the spinal cord out, or speech and swallowing predominantly. There are other phenotypes where just the arms are involved or mainly the legs or one side of the body. I bring this up only because it speaks to the heterogeneity, which is one of the challenges of treating the disease and designing treatments and the fact that the phenotypes are heterogeneous and it may not be one disease. I would argue that we know it's not one disease. It's simply degeneration of the motor neurons. Eventually people lose all ability to move, to speak, and then to breathe. It's typically two to five years from symptom onset, and people pass due to respiratory failure unless they choose to go on a ventilator. There are really too few treatments and options for people living with ALS, creating a huge unmet need given the urgency and severity of the situation. I've already mentioned this, and I bring it up mainly because this variability is one of the challenges to the design of clinical trials and speaks to probably different mechanisms and different underlying processes that propagate disease. You can see in the plot on the right-hand side of the slide that depending on your phenotype, there are different survival rates. People who have mainly upper motor neuron or what we call primary lateral sclerosis, they have the longest survival, while bulbar onset and green has the shortest survival. Typically, as I said, three to five years, and predominantly lower motor neuron or upper motor neuron and not that really 50/50 mix have the longest survival. 10% of folks do live more than 10 years, mainly in that predominantly upper motor neuron or lower motor neuron, and the disease can have plateaus and quiet periods. There can be other signs and symptoms. We consider ALS a predominantly motor syndrome, but we now know importantly that cognitive changes occur in almost 50%, and they can be very subtle, but people can have frank dementia, frontotemporal dementia in anywhere between 5% and 15%, depending on who you read, and I'm going to show you later why this is important because it's overlap in symptoms. There's also overlap in pathology and likely a continuum of neurodegenerative disease, and as you can see, people can have sensory symptoms, bowel problems, they can get skin breakdown, and they can get eye involvement, but those are quite rare. The incidence is 1.5 per 100,000, which means 10-15 per million. Prevalence is about 100 per million people, the male-to-female ratio, slight male predominance. Typical age is between 50-60, but I have an 18-year-old and I've seen 90-year-olds. Again, familial ALS is when there's a family history of ALS, occurs in 10%. This has really given us a lot of support for the mechanisms that we think are playing a role in ALS, as I'll show you in a few minutes. There can be occupational clusters, most importantly, military service. This has led to the fact that people who have been in the military and developed ALS have a service-connected disability and do get significant care through the VA system. Other things are trauma and head trauma, chronic traumatic encephalopathy as described in football players that can lead to a syndrome that certainly looks like ALS. Many of these associations have been difficult. There's been conflicting evidence, but some are more established than others. Now, I wanted to spend a little time on the genetics of ALS. 10% of ALS has a family. People have a family history. The first gene ever identified was SOD1. That was back in 1993. It provided the infrastructure to create the first animal model of ALS, which is the SOD1 mouse, and approximately 20% of people who have a family history will have an abnormality in the SOD1 gene, which means 2% of all ALS if you look at the whole of ALS, and there's a lot of complexity even within families where SOD1 ALS is found. There can be variable onset, and some people may not even manifest, so again, there's variability, and that suggests a complicated interplay of the rest of your genetic background as well as the environment, and so the complexity of the disease, even in a monogenic form, is clear, and we have now identified more than 40 genes that underlie the familial cases. And in fact, we can identify the genetic cause in approximately 70% of folks. And important to notice in this is on the left in the graph, the dark brown area represents sporadic ALS, and upwards of 15% of people with sporadic ALS also harbor a genetic element or a genetic abnormality that may underlie their disease. The most common of the genetic abnormalities is the hexanucleotide repeat, which we call C9ORF72. And SOD1 is probably the second most common genetic cause, as I mentioned, 20% of familial ALS. And these genes are important because they define mechanism, and we'll get to that in a moment. But I wanted to point out this continuum I already mentioned. We know that 50% of ALS subjects or people have some cognitive involvement. Up to 5%-10% have frank frontotemporal dementia. When you look at the pathologic changes, there's a shared pathology with aggregated TDP-43 in much of FTD as well as ALS. There's many of those 40 genes that are shared that can create either a phenotype that looks like frontotemporal dementia or that looks like ALS or that has a combination, which suggests that many of these mechanisms that are defined by these genetic underpinnings are shared mechanisms. Drugs directed at these and treatments directed at these may be treatments for both ALS and FTD. This just is a way to look at things in terms of what pathways are implicated by the genetic defects that have been identified. You can see 10 major pathways. I point out that the pathways in blue, mitochondrial function and oxidative stress, excitotoxicity are pathways that we now have identified drugs that modify disease. In the case of oxidative stress, the free radical scavenger, Radicava, or edaravone is directed at oxidative stress and has shown some efficacy, at least in one of the trials. Then glutamate excitotoxicity is the target of riluzole, yet another drug that has been approved. Much of the pathways, though, have been identified as being targeted. I'll also point out that we do have, at least for the SOD1 gene, a treatment that's directed at the genetic mechanism, and that's the antisense oligo, tofersen, that blocks the production of SOD1. Turns out that SOD1 is important for reducing oxidative stress and that you don't actually need SOD1 and that mutated SOD1 takes on a toxic function. It's a toxic gain of function so that by knocking down SOD1 production, you can improve disease. And in fact, we'll talk a little bit more about that towards the end of the discussion. And so I would argue that it's really an interplay. ALS results as an interplay of your genetic infrastructure, the things you're exposed to, an environment and aging and chance. And there are many models of this and stepwise models that we can't get into today, but it's this interplay. So how do we treat ALS? And I love giving the lecture, "ALS is a treatable disease." You need to have compassion and hope. And the way you give the diagnosis and you talk to people about what's going to happen is really important in setting the tone for hope and quality of life. You educate about disease and you manage the disease. And that includes a multidisciplinary approach to address symptom management and maximize function. You want to treat symptoms of disease. You want to implement any disease-directed treatments that are available. And you want to take care of people through the continuum, which is the palliative and hospice care. And an important part of compassion, hope, and really quality of life is research. And that includes not only clinical trials of drugs that are potentially going to help, but these are also clinical studies that will be aimed at how to better take care of people and prolong life. The multidisciplinary approach is really an AAN quality parameter. This is important to quality of life for folks living with ALS. And it includes a multitude of team approach with physical therapy and occupational therapy, speech, nutrition, mental health clearly. This is a family disease, and you have to treat the entire family and help support them through this. Respiratory therapy and the implementation of non-invasive ventilation has made more difference to survival than anything else that we have. It also improves cognition and quality of life. Nursing. And then, of course, research is an integral part of multidisciplinary care and implementing clinical trials. And as part of that multidisciplinary care, the physician and nursing staff will manage symptoms like drooling and pain and implement assistive devices. And now we're going to talk a little bit about disease-specific treatments. There's actually four approved drugs. Dextromethorphan/quinidine is really for pseudobulbar affect, and it may have some effect on bulbar function, but it is not approved for disease-directed treatment. R iluzole, as I mentioned, is directed at excitotoxicity and reduction of glutamate excitotoxicity, although it may also modify sodium channels. Edaravone is a free radical scavenger reducing oxidative stress, and Qalsody or tofersen is directed at SOD1. There's clearly all of these have a modest effect, and there is clearly an unmet need. And so again, here is the landscape now of what we have approved. R iluzole was approved in 1995, and it does prolong survival in ALS. People use the three-month term. It may be more in real-world evidence. And that was approved in 1995. And it wasn't until 2017 that the next disease-modifying agent was approved, and that was edaravone, the free radical scavenger, which showed an effect on the rate of decline based on what's called the ALS Functional Rating Score. And so phase III trial that really looked at a modified population to maximize the chance of seeing an effect, there was a 7.5 drop in the ALS FRS score in untreated folks in the placebo group versus five. They used very early folks that would be projected to have a more rapid progression to tease out that effect. And they based that on their first phase III trial where there was a trend, but it didn't reach statistical significance. And they went back and looked at responders. That's how they designed the trial that did show efficacy. And then just recently in 2023, tofersen was approved as a disease-modifying agent for SOD1. And as I mentioned, it's antisense. But the thing that I wanted to point out, again, the primary endpoint was change in the ALS Functional Rating Score. The initial study did not reach its primary endpoint, but it was approved based on the fact that looking at biomarkers, the amount of SOD1 protein and the plasma level of neurofilament light chain, they improved. There was a drop in SOD1 and a drop in neurofilament light chain, which reflected neurodegeneration. It was based on that that it was given tentative approval, and then in the open label, it showed the clinical benefit, so that this change in biomarker preceded the ability to really show the improvement in muscle strength, decline in the rate of progression, and improved respiratory function, and of course, dextromethorphan/quinidine is not disease-directed, but rather directed at pseudobulbar affect and may have some disease modification. This shows you none of these is a slam dunk. None of these is a home run. We've gotten to first base. There's a large unmet need for disease-modifying treatments, and what are the challenges? I've already indicated some of them. First, it may be that if these treatments extend life, we want to get them to people as soon as possible, and we want to test drugs in people as early as possible. But diagnosis is often delayed, as you can see in the upper graph. It takes up to 12-14 months, and it takes longer for women than men. And it's fastest for people with bulbar onset and longest for people with upper limb onset. The presentation is variable, as I pointed out. There's genetic heterogeneity. There's 40 different genes that have been identified as genes that can produce disease. And even in sporadic folks, there's variable progression and survival. And then you get to when you plan and you start to project the power, how many subjects I'll need, that's going to increase the number of subjects you need. You have to even account for the fact that enrollment and retention is low. 22% of folks will withdraw from a clinical trial. Then you've got the clinical heterogeneity. Then what target do you select? I showed you the 10 implicated pathways. What do you use for your inclusion criteria? This becomes a problem. Many trials are now focusing on using earlier people who are more projected to progress more rapidly. What endpoint should you be using? How should you stratify folks? How can you predict who might be a responder to maximize your chance of seeing efficacy? That includes using biomarkers both for target engagement, prognostic, and pharmacodynamic, as well as disease progression. That's best exemplified by the SOD1 trial with tofersen using the neurofilament and the SOD1. And so these kinds of things are all challenges that have to be addressed to maximize funding on good drugs and speed up the production. And so our strategy is just what you'd guess: inclusion criteria, the use of biomarkers. And I do want to mention including people living with ALS with lived experience who can help you in designs that are patient-centric that will mean that more people will stay in the trial than leave the trial so that you reduce the rate of leaving the trial, that 22% rate. And you want to try to continue to. You don't want missing data. So if you can use remote endpoints, that will help. And digital biomarkers may be something in the future that we look at. And as I mentioned, what are you targeting? You've got these 10 pathways, and there have been trials targeting many of these pathways. To start with, the stem cell trials are really neurotrophic and some anti-inflammatory. You'll hear more about phase III-A results in a moment, but it does appear that there's some neurotrophic influence as well as anti-inflammatory. There's other stem cell trials going on as well, including injection of glial progenitor cells right into the spinal cord. There's also cells that will deliver GDNF, deliver to the motor cortex via the cisterna magna or Cedars-Sinai. There's Corestem, which is autologous bone marrow-derived mesenchymal stem cells in Korea. And here in the U.S., the Mayo Clinic system, adipose-derived autologous mesenchymal cells. And so many of these really are neurotrophic and addressing neuroinflammation. And this is the landscape. I'm not going to go through each of these, but you can see there's different mechanisms, as I mentioned, all those mechanisms that we can target. And you can see the landscape. In red are the drugs that are already approved. In green, there's data that phase II efficacy phase III. and in blue, phase III signals. and you're going to hear about the NurOwn signals in a few minutes. But this is the landscape, but we don't have home runs, and we're crossing our fingers that something will hit. So in summary, I've said it several times, there's an urgent need for new treatment. The current therapies are modest in efficacy, leaving that unmet need. ALS is complex, making the design clearly difficult and meaning that we may need multiple drugs on the horizon for multiple different mechanisms. And genetic discoveries, the genes are highlighting the pathways and mechanisms. And this is going to be valuable in terms of insight and confirming targets. Clinical trials have challenges in multiple pathologies, heterogeneity of the disease, both genetically and phenotypically. And we need to find better biomarkers. And it's only through science that we're going to have hope brought to people that the innovations that we have in research underscore that we will get to ALS being treatable, not only through the support of multidisciplinary care symptom management, but through new disease-directed treatments that are going to be guided by our community partners, scientific rigor, and the development of better biomarkers that will inform us earlier whether or not a treatment is effective. The tofersen approval really sets a precedent in that FDA did approve tofersen tentatively based on targeting the underlying disease mechanism and showing biomarker changes reflecting an effect on that disease mechanism that really preceded any clinical effect. And the clinical effect was shown later in the open label. With that, I thank you for your attention, and that was a whirlwind tour. I appreciate it, and I'd like to pass it on to Dr. Bob Dagher, the Chief Medical Officer at BrainStorm. Thank you, Dr. Heiman-Patterson. It was a pleasure listening to your talk. Hello, everyone. My name is Bob Dagher, and I'm the Chief Medical Officer at BrainStorm. As Terry just mentioned, there remains a very significant unmet need in such a rapidly fatal disease, and we are persevering in our efforts to bring an effective treatment to people living with ALS. Today, I'll present our very compelling data and signal of efficacy in early disease group, and I will present BrainStorm's new clinical trial that is designed to maximize the likelihood of success. We are a clinical stage biotech company, small biotech that's focused on ALS and multiple sclerosis. Our lead phase III, NurOwn, is a stem cell therapy that's administered directly into the spinal canal for close access to the spinal cord and brain areas that are affected by the disease. Our platform is novel, autologous. That is, it leverages the patient's own bone marrow to manufacture our treatment. Our team has decades of experience in cell therapy and in drug development, specifically in neurodegenerative diseases. We will share with you today how we were able to leverage this experience, all the learnings from our past clinical trials, our robust biomarker data that we recently published. We designed and are getting ready to start a new phase III-B trial that incorporated all the knowledge from the past few years and satisfied the FDA SPA agreement requirements. SPA stands for Special Protocol Assessment. This is the first of its kind obtained in ALS. It presents a very significant milestone as it sets forth an agreement with the agency on the protocol design, the study population, the primary endpoint, the duration of treatment, all such important components that go into a BLA filing for potential approval. The clinical development plan for NurOwn and ALS you see here had reached a number of trials over the years. These are all clinical trials that we have completed in participants with ALS. And on the far right, you phase III-B trial that's under a special protocol assessment agreement. Also, on the regulatory front, NurOwn had secured orphan drug and fast track designations. We also completed a signal-finding phase II trial in multiple sclerosis as phase III-B trial will focus on participants who are early in their disease course. As I mentioned, important changes were made that basically we want to maximize the effectiveness of the trial and its likelihood of success. Starting with a very important patient population, I will share data with you today on the positive effect of NurOwn in early disease participants. The choice of the primary endpoint is a very important one and a critical one for success of the clinical trial. This has been agreed upon with the FDA and the SPA, and it uses the "gold standard" being used in modern clinical trials in ALS today, and that is the change from baseline in the ALSFRS-R scale. The screening period has been shortened. This is important. There is no longer need for a lengthy run-in period, and this will help us to ensure better control of the population when they reach baseline. So between first screening and baseline, we shorten that lag. And it's a particularly important aspect as the endpoints in the trial refer to change from baseline. So that baseline is a critical criterion to control. The study has been also extended to now incorporate, after finishing the double-blind placebo control period, an open label extension part. So now we have a two-part trial of 24 weeks each, about one-year duration of the trial. I have to mention, though, at the end of the first part, the double-blind one, once we secure that data, we lock the database, we will be filing our BLA while the second part, part B, is ongoing at the time of filing and review of our package. And as I mentioned, this regulatory alignment is a very important aspect of our trial design. We were very excited that we were able to reach that important milestone. Here, I'm showing you a snapshot schematic of the study design. You see it's followed by a nine-week, eight to nine-week screening period. Then we have a double-blind part A phase, NurOwn versus placebo, one-on-one randomization, 200 participants. Then moving into part B, another 24 weeks' duration where the placebo participant will switch to receive NurOwn, and NurOwn participants will continue on NurOwn. Now, we haven't changed the treatment regimen, the amount of frequency. It's the same as in the previous trial. It's one intrathecal administration every eight weeks. So at the end of the trial, some participants would have received six doses of NurOwn. The entry criteria, I'm showing here the important ones, and I'll describe the importance of each one of those. First of all, early in the disease, we are putting a criterion of two years or less from first symptom. Unfortunately, as Dr. Heiman-Patterson just mentioned, it takes a little while, 12 to 14 months to get the diagnosis from first symptom. And then we have another 12 months or so or less to get into the trial. So it's very important to get in the trial as soon as possible. The ALSFRS-R score has 12 items. Each one of them, you can score zero to four, zero being bad and four being normal. So a total of 48 on the scale. And as soon as you get the first symptom, the score starts dropping. So we didn't want it to drop and just hold for a two-year period before coming into trial. So we are mandating a 45 or less total score for that reason that we see signs of progression of the disease. Also important, each one of the 12 items, you cannot score zero or one. So we are requiring a two, three, or four. And this is very important to make sure that the functional disability did not advance too much in the four domains and each item of the scale. The respiratory function has to be relatively preserved. And there is a measurement we call SVC or slow vital capacity that we want it to be at least 65% or more of what's predicted for that participant's age and gender, etc. And yes, we are allowing standard of care that's approved to be taken during the trial. And we will be giving NurOwn on top of that or placebo depending on randomization. The endpoints, the primary endpoint, as I mentioned, is that change from baseline to week 24, so at the end of the double-blind phase. And then we have, I would say, the usual standard nowadays, secondary endpoints, vital capacity, hand dynamometry for muscle strength in the hand, time to death or ventilation, patient reported outcomes, an assessment questionnaire that has 40 questions about PROs and caregiver burden, very important. As well as we'll be collecting blood and CSF and measuring biomarkers since our drug is administered intrathecally. So we have easy access to the spinal fluid. As I mentioned, and it's important, we will be basically in a position to file our BLA with successful completion of the part A double-blind of the study. Now, let me show you briefly before I compare contrast the changes. This is a brief summary of what were the elements of phase III trials, and I will try to highlight for you what has changed. Quickly, you will notice that it was a one-part trial, so only double-blind placebo controlled of 28 weeks' duration, so there was no open label extension. However, and it was 189 patients, so 10 of those 189 went on to an EAP, Expanded Access Program, and the study started with a 20-week run-in period during so the screening was 20 weeks long, and it had three-month measurements of repeat ALSFRS-R run-in to measure that change in ALS and measure the slope of change pre-treatment or pre-baseline. And then we follow that post-baseline, and that becomes the primary endpoint of that particular trial, which was the percent of responders on that change of slope post-treatment versus pre-treatment, meeting more than 1.25 point per month improvement on the ALS FRS over placebo. So it was a stringent criterion, to say the least. That particular study had a cutoff at screening of total score of 25, so relatively low. So participants could come in at 26 and higher at screening. And 20 weeks later, we saw a good percentage of those participants reaching very, very low numbers on the scale, meaning have advanced disease. So the population became a broader population than originally anticipated. The change and the promising data that I will show you next happens early on in the disease course. So we're now focusing on enrolling early disease participants in the next trial. Another important change. The primary endpoint, as I just mentioned, is the responder analysis in the previous trial. The key secondary endpoint will become the primary endpoint in phase III-B, that was agreed with the FDA as well. As well as the other secondary endpoints, I will mention that the CAFS or the combined analysis that takes a combination of the functional scale, the ALS FRS, and survival into a joint metric. That analysis will be done in the next trial. The p-value for the primary endpoint will be basically extracted from that CAFS. That's agreed with the FDA under the SPA agreement as well. I'm showing you here the primary responder analysis in the previous trial. It did not reach p significance. However, we can appreciate a trend in favor of NurOwn on the overall population on the left side, 188 participants. On the right side of the slide, you see the pre-specified population of those participants who came in at baseline with not too advanced disease. They had to have an ALSFRS-R of at least 35 or higher. That was pre-specified, meaning before we locked the database and we looked at the data, we put in the statistical plan that we are interested to see there is a differential response in participants with early disease, 35 and higher. Yes, we can appreciate visibly here a larger treatment. However, it was not statistically significant. We understand that that subpopulation was very small, only 58 participants. There was not enough power to be able to show a treatment effect if such effect is present. This will be capitalized on in the next trial to focus on early disease population. Showing you here quickly that modern trials in ALS. Looking here, you see that their baseline ALSFRS-R total score falls usually around 36- 38. On the very top, the approved Radicava, that trial had a baseline of 42. So clearly, those are early participants. Unlike our trial that I just showed you in orange here, the baseline median came at 31. So clearly, an outlier. And when we look at that population that were above 35 of total score at baseline, on the right here, it's a subpopulation of the total, only 58 participants again. We see a clear treatment effect on that change from baseline in the ALSFRS-R. Very important endpoint, which, as I just said, is going to be the primary endpoint of the next trial. And that reached statistical significance at week 28. You see p-value less than 0.05. But also, you can see and appreciate the treatment difference of more than two points starting at week 12 to 16-20 all the way to the end. So clearly, that's a signal of efficacy that we want to capitalize on in the next trial. When we also did additional sensitivity analyses, now these are post-hoc, not pre-specified, like the previous one, we also can appreciate that not only at 35 total score and higher at baseline, but also across all other cutoffs, 34, 32, 30, 27, we see and appreciate that the blue NurOwn has that benefit over placebo, two points or more on that scale. And those reach nominal p-value across all cutoffs in that sensitivity analysis. So clearly, there is something here that NurOwn is a benefit that is showing the earlier the disease is. Here I'm showing you extending beyond 28 weeks. As I mentioned earlier, we took these 10 participants phase III and continued into an Expanded Access Program that spent two additional periods. In phase III and first period, there was a gap. In between the first period and period two, there was another gap of time. It wasn't continuous. However, we can appreciate first here on the survival side of the 10 participants that started until the end, we only had one participant that died from elective euthanasia. Nine remaining participants were still alive. When we do the Kaplan-Meier curves and we look at median survival, at the end, we had benefit for NurOwn over placebo as well with 5.5 months beneficial survival. Clearly, there is a benefit on survival here that we can appreciate. Also, when we look at biomarkers, which, as mentioned earlier, it takes a long time to see the effect beyond six months on neurodegeneration survival: the measurement of NfL here that I'm showing. As the field has moved into appreciating how the pathophysiology and how changes in the biology happen, we can appreciate that in the participants that received NurOwn phase III, they had already seen benefits on NfL. That was, by the way, significant, and my colleague will show you that data next at week 28 with a p-value less than 0.05, and that benefit continued in the EAP as well to the end. When we look at the participant that started on placebo and started showing some worsening in neurodegeneration, meaning an increase in NfL by a median of 37% phase III, when we put them on NurOwn in the Expanded Access Program periods, we see improvement and basically change in their slope, so that's encouraging as well for us. Again, these are small numbers for participants on placebo, six on NurOwn, so we're looking definitely to look at this data in the next trial. As I mentioned, it's going to have a one-year total duration when we add the open label extension, so promising data, and it gives us additional support that there's a signal there that we have to exploit. On top of that, now when we look at genotyping, particularly the important UNC13A genotype that has been talked about, it's understood now that this genotype, when the mutation happened at a certain SNP part of that gene, and specifically when that mutation carries the homozygous CC, unfortunately, the carrier of that mutation has a worse prognosis. They have more severe symptoms. They have shorter survival time. So when we look at our genotyping phase III trial, an interesting analysis appears as well. Now, granted, these are small numbers relatively. We had a total of 63 participants with that genotyping on NurOwn versus 61 on placebo. But when you dig deeper in the three different genotypes, you see that CC, we only had basically nine participants on NurOwn versus 10 participants on placebo. So small numbers. We could not see a p-value on both the responder analysis, that primary endpoint, and the change from baseline on the ALS FRS, that important new primary endpoint in the next trial. But when we look interestingly at that heterozygous AC population that happened to have the highest number of patients, so you have 23 on NurOwn versus 35 on placebo, we can appreciate a significant p-value there. So 65% responders on NurOwn versus 29% responders on placebo with a p-value of 0.011. So this is important data as well that, by the way, we will be looking at it in the next trial as well. So we'll be measuring biomarkers, genotyping, etc. So here I spoke a lot about before and after. Here I'm putting for you sort of summarize it side by side. On the right side is a new trial. On the left side is phase III trial and why we made these changes and why it's important. Starting at the very top, as I mentioned, the patient population is critical. So we no longer have a run-in period and extended screening of 20 weeks. And we don't have that relatively low cutoff total score of 25 at screening before later baselining. So now we are coming at baseline with we have simulated our data based on the entry criteria I summarized for you earlier with making sure we have a population with earlier disease at screening and also eight to nine weeks later at baseline. The primary endpoint, as I mentioned, is no longer the responder analysis. It's the more understood change from baseline to week 24, ALSFRS-R. The study duration is 24 weeks, double-blind followed by another 24 weeks open label. That additional extension will allow us to better measure survival, biomarkers, NfL, etc. The screening period is now going to allow for better control of the baseline entry criteria. And as I mentioned, it's first of its kind, SPA phase III-B trial that we now have in ALS, unlike the previous protocol that basically had the responder analysis in order to show efficacy. With that, I hope that was a good summary of what we are up to. And we are excited to be in the startup phase of our trial. But it's important that we take a deeper look and look at our biomarker data specifically as the field has evolved so much now. We are learning a lot, as Dr. Heiman-Patterson just shared as well. So I'm going to turn it over to my colleague, Dr. Netta Blondheim-Shraga, who will take us over the biomarker data. Thank you, Bob. I'd like to begin with a word on what biomarkers are and why they might be important for clinical research. Biomarkers are molecules that represent different biological mechanisms or processes. We can learn about them and how they change in disease and in response to therapy by measuring them in samples that we collect from patients during clinical trials. For example, as Dr. Heiman-Patterson mentioned, recently a drug was approved based on an important biomarker that improved in the treatment group, thereby indicating that the drug was working. Our drug is administered by lumbar puncture, and that enables us to sample patient CSF during treatment visits, which enables us to measure biomarkers in the CSF, cerebrospinal fluid, and how they change over time in the placebo group compared to the treatment group that receives NurOwn treatment. Let me remind us all that NurOwn is an autologous mesenchymal stem cell therapy. The cells are derived from the patient's own bone marrow. These cells are intentionally induced to secrete neurotrophic factors that can protect neurons. As you heard from Dr. Heiman-Patterson, ALS is a complex disease and calls for multifactorial interventions. Indeed, cell therapy is different from traditional drugs in that they are not a one molecule to one target type of therapy, but rather the cells are active and interact with their environment by receiving signals and secreting molecules that can affect their surroundings. This unique attribute enables the cells to affect multiple pathways. We utilize this multifactorial effect by designing a therapy that builds on the documented ability of mesenchymal stem cells to reduce inflammation and designed a process that causes the cells to enhance neurotrophic factor production to further enhance their beneficial neuroprotective and neuromodulatory effects. So how will we know if it's working? The ALS microenvironment reflects an imbalance across multiple pathways that NurOwn aims to correct or improve. Pathophysiological hallmarks include enhanced neurodegeneration and neuroinflammation alongside reduced neuroprotection and anti-inflammatory signals. If treatment works, we should see a shift in biomarkers of these pathways. And indeed, as I will show you in the next few slides, BrainStorm analyzed a wide set of biomarkers that represent these important disruptive pathways and found that changes following NurOwn treatment suggest a favorable disruption of pathological processes. We observed a reduction of CSF inflammatory and neurodegenerative biomarkers and an increase in CSF anti-inflammatory and neuroprotective biomarkers. Here we listed the inflammatory and neurodegenerative or neuroprotective-related exploratory CSF biomarkers that we analyzed in the corresponding pathways phase III trial. they were selected based on literature that pointed at relevance of these pathways in ALS. As you can see, most biomarkers had significant overall treatment effect. In bold font, the biomarkers that changed significantly following treatment, and they support an anti-inflammatory and neuroprotective effect for NurOwn. Of these, the best-known marker is probably NfL. Let's take a closer look. NfL is a measure of neurodegeneration and measures how much neuronal loss is happening. NurOwn significantly reduced NfL levels from baseline compared with placebo in the trial. NfL had the largest reduction observed from baseline at week 20 at 11% compared to no significant change in the placebo group. Now, keep in mind phase III was shorter than other studies. And at 20 weeks, we don't see an increase in NfL in the placebo group. And we didn't really expect to see a significant change following treatment in such a short time. So that was a pleasant surprise, and it was very encouraging. We believe that the longer duration phase III-B study will provide even more conclusive evidence of benefit as the graphs are expected to diverge more over time. Our program was so rich with 45 biomarkers, each analyzed at seven time points. I'm summarizing three representatives of neuroinflammation on the top row in the left panels, representative of neurodegeneration in the second row, neuroprotection in the third row, and several additional exploratory biomarkers of interest in the last row. In all of these, you can observe an effect of NurOwn in blue that affects changes in the right direction consistently from the early time points and up to week 20. If we look at these graphs in an overlay fashion, which you just saw playing out, and kind of bunch them together, the effect of NurOwn, while not necessarily significant in every time point, is very much evident. We look forward to extending this data beyond 20 weeks in the next trial. In summary, we set off to design our therapy to address multiple pathways that are driving ALS. Indeed, as I've shown you, NurOwn is a cell therapy of mesenchymal stem cells that are induced to secrete neurotrophic factors that affect multiple pathways, confirming NurOwn's design mechanism of action. Back to you, Bob, for some concluding remarks. Thank you, Netta. I was trying to control going back on camera. So the important question right now, and we are very excited to, as I mentioned, to get started with our next trial. So what are the upcoming milestones? So now we have secured agreements with a number of selected clinical sites at a broader geography in the United States, from the East Coast to the West Coast and in the Middle, North, and South. So very keen about enrolling our patients quickly and give broader access. And we selected top-tier sites that have a wealth of experience in conducting clinical trials in ALS. Our manufacturing is underway. We basically are positioned well for securing product for the clinical trial while at the same time planning for our commercial manufacturing plan as well with top partners. And finally, I will say that we are being in a startup phase is very energizing and anxiety-provoking, and we cannot wait until we get the first patient enrolled. With that, I'm going to turn it back to Chaim for final remarks. Thank you very much, Bob. Before we begin the Q&A session, I want to express my sincere gratitude to Dr. Heiman-Patterson for her insightful and enlightening presentation. I also want to commend Dr. Dagher, our Chief Medical Officer, for his comprehensive phase III-B trial. i'd like to acknowledge specifically Dr. Netta Blondheim-Shraga. Wonderful, outstanding presentation. She serves as our SVP for Research and Development. I think people listening got a far better understanding of what it is, biomarkers related to ALS and the mechanism of action relation. Before starting the Q&A, I want to remind everyone that this is a key opinion leader call. It's designed for researchers, analysts, and investors to engage in a focused discussion with Dr. Heiman-Patterson, Dr. Dagher, and Dr. Blondheim-Shraga to ensure a productive and informative exchange. Today's Q&A session is meant to primarily focus on scientific and medical aspects of ALS and also our NurOwn trial. Business-related questions, such as corporate updates and specific timing inquiries, will be addressed in a separate call that was already announced. It's scheduled for December 30. We'll provide more detailed corporate updates during that dedicated session. Thank you very much. And Tara, I turn it over for you for the Q&A session, please. Great. Thank you, Chaim. At this time, we'll be conducting a question-and-answer session with our speakers. To our audience on the webcast, as a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. Please hold for a brief moment while we pull for questions. Our first question comes from Jason McCarthy at Maxim Group. Please go ahead, Jason. Hi, everyone. Very informative talk today. My first question is about what we think is seemingly more emphasis on overall survival measures in these ALS studies. We saw just as recently as yesterday with another company talking about overall survival and connecting it back to NfL. My first question related to that is, can you control or do you need to control trial design and enrollment around primary lateral, progressive muscular, spinal, and bulbar onset symptoms? You had shown a slide very early on, Dr. Heiman-Patterson, about there was variability in survival, I think, based on those or stratifying patients based on those metrics. Thank you, Dr. Heiman-Patterson. So you know it's really this is where phase I and phase II studies are really important in terms of looking at responder populations. And that phenotype may be important, but it may be that you really want to target more rapid progression so that you can detect a difference in rate of progression earlier. And you mentioned survival has been focused on, but actually, there have been a lot of recent studies that use the ALSFRS-R or a functional rating score as a target, with a primary endpoint being slowing down of the progression or the drop in ALSFRS-R. Because in the old days, and unfortunately, I'm old enough to remember when survival was the primary endpoint, we'd run trials for two years and 18 months. And what that meant is if you're living with a disease and your expected survival is two to five years, you may, A, only have the opportunity to participate in one trial and, B, be on placebo that whole time. And open-label extensions weren't always incorporated. All of these changes to try to shorten the duration of trials and make them patient-centric have led to using more functional scores as the endpoint. And if we can add to that biomarkers, I think that'll really be helpful. But yes, selecting out responder populations, I don't know that it's going to be by phenotype, but more by biomarkers, especially if you can find biomarkers of what you're trying to target as an enrollment criteria. I think that's very nascent. And hopefully, in the future, it's almost like in cancer looking for the receptors and what the treatments are. Right. And we're not. We're not there yet. Trying to discount ALSFRS-R at all as a hard endpoint. Because from a cell-based therapy perspective, I guess any of you can kind of speak to this. We see, having been in the space for so long as analysts, this shifting narrative at the FDA level just mostly in the last year. And it's particularly around cell-based therapies that are unmodified genetically or any other way. NurOwn fits into this category. It's just cell culture conditions that they use. There's nothing else different about the cells that they seem to be much more open to, not to use the wrong phrase, accelerating these therapies to get to patients using kind of totality of data. So maybe survival as a piece in ALSFRS-R and ALSFRS-R combined, the NfL stuff. We're also seeing things in like GVHD. There's a PDUFA coming. This whole shifting landscape where they're open to looking at everything. Even if you missed on one hard endpoint in ALSFRS-R, you have all this other data. And that's something that was not here even two years ago. It's here now in 2024, and we think will continue in 2025. Do you guys want to comment on that? Because we think NurOwn and BrainStorm kind of fit this bucket. I can take that, perhaps. Thanks, Jason, for the question. So I want to take the opportunity to remind the audience, and also, our important meeting with the FDA, by the way, was an in-person meeting to discuss the plan and the SPA agreement and the protocol. And you'd guess easily here that this question and many similar questions like this were raised. So the question of survival is an important one, obviously, to us and to everyone. And as Dr. Heiman-Patterson just mentioned, you have to reconcile long duration of trial with the placebo effect, placebo being on placebo arm, and also basically the reality, the harsh reality that basically by the time you're diagnosed and coming into a trial, already one year has passed. And survival three to five years in a two-year duration trial, unfortunately, many people will succumb during the trial. That's why you need long duration to measure survival. So it's a challenge, but clearly the ALS-FRS complemented by biomarkers. And now neurofilament light is an important one there. It will give us at least that first take at it. And then you know if it's going to be accelerated approval or full approval. But anyways, you get approval, and then you wait longer to get survival while the drug is available for more people. Thank you, Bob. I would just add, Jason, that, yeah, I think you mentioned in your question that we're looking forward for a PDUFA for GVHD. And I think that will be very exciting because it's true. I think FDA has yet to move for a serious stem cell approval. So even though that's not an ALS, it's GVHD pediatric. Right. Yeah, we think these types of therapies, that's a big event for the space. Different indications, but they seem to be more open to all of these much larger data sets. My last question, Dr. Heiman-Patterson, you had a slide that showed, I think it was slide 25 on the very complex nature of ALS, all the different signaling pathways and everything that's involved. And on the next slide, which caught us kind of by surprise in a good way, that there are all these other groups working with MSC-based therapies. And my question is, do you think that not because this is a NurOwn event here, that the complexity of a stem cell and its ability to do all kinds of different things, maybe not all measurable, but it's having this incredible biological effect, is the appropriate approach for something complex like ALS, where targeted therapies maybe not so much? Yeah. It's got multiple effects that may target several of those mechanisms and be additive is what you're really getting at, correct? Yeah, I mean, I don't think it's the only approach. I think it certainly justifies it even more and underlines the importance of pursuing stem cells as a treatment modality. It'd be good if we eventually understood the mechanisms by which stem cells, if they are efficacious, what are the mechanisms that drive that efficacy. But right now, I think that that does make them certainly important to look at and suggests that they may be more useful than a targeted approach with an untargeted population. That is, I'm targeting neuroinflammation, say, but I don't have any biomarkers, and I don't really try to look for responder populations based on making sure that the folks I'm testing actually have neuroinflammation driving their disease. Because I think we all understand that the initiating factors may be variable, and the propagating factors, neuroinflammation seems to be a propagator, but some of those may be shared and others won't if you're not treating the right mechanism. So if you have something that's multifaceted, treating multiple different mechanisms, clearly you stand a better chance of having an effect. And I think to comment, go back a little bit. Some of the ways the FDA is looking, at least at ALS, is driven by advocacy and patient advocacy, which has become very important in that incorporation of the patient voice in design of trials. And there are also joint-rank analyses of survival and ALSFRS-R that have been used as endpoints. I'll just comment. Dexpramipexole, for instance, used that kind of joint-rank methodology. Got it. Thank you for taking all the questions. Great presentation today. Thank you. Thanks for the questions, Jason. So our next three questions come from David Bautz at Zacks and Dr. Terry Heiman-Patterson. These are for you. So with so much variability in disease progression, what do you think are some of the best things that investigators can do when running clinical trials to mitigate that variability as much as possible? Yeah, it gets to the inclusion criteria. And I think not only the present BrainStorm III-B trial, but other trials are also trying to create an inclusion criteria that minimizes that heterogeneity by choosing people that may be predicted to be a little bit more rapid within two years by the capacities at a higher level. I think that there's things that are being developed that may further help with that. And that's really identification of biomarkers. I mean, I feel repetitious, but biomarkers that can stratify people by mechanism. And if your drug is targeting that mechanism, then that would be a criteria for entry into the trial as well to maximize the effect. The fear is always that if you sort of restrict your entry criteria, if your agent is successful, the insurers will probably limit who they'll pay for the drug to that population and not the wider ALS group. And we've seen that with the other approvals. It takes time to fight that. But if you want to maximize your chance of seeing an effect, I hope that answers your question. Yes, thank you. So the next question also from David Bautz. You mentioned all of the, or sorry. How much does proper care of patients play in the progression of ALS? Are things like proper nutrition and meeting a patient's mental health needs things that are usually controlled for in clinical trials? No. The short answer is it makes a difference. Most of what we do in our clinics are pretty standard. So most of the patients entering a trial wouldn't have multidisciplinary care. They would have the standard operating procedure for administration of non-invasive ventilation and the standard recommendations for placing a feeding tube. And those events are captured in the data so that when you're doing your analysis, you could theoretically look at, hey, were all our centers consistent in the way they applied their multidisciplinary care? It is true that multidisciplinary care does improve survival. So people who are better at it might influence survival as well as quality of life. But the centers typically have a similar application of these efforts, and they're captured. At least those major interventions are captured in all trials. When we do a trial, we have to capture that as events, adverse events, placement of a feeding tube. I hope that answers your question. It's a good one because certainly good care is good care. Great. And then our final question from David Bautz. You mentioned all the different pathways and targets for potential ALS treatments. In your opinion, what are the most important mechanisms that should be targeted for drug development? That's a great question. If we knew the answer, we'd have good drugs. I'm not trying to be facetious. I really am not. I think that that points out the importance of biomarkers of mechanism. And I think the drivers, you'll have an initiator and propagation of the disease process. And those are going to be different processes. Knowing where somebody is in the course of their illness and which mechanisms are most operant at that point in time can be reflected in biomarkers. And therefore, that will drive what drugs they are most likely to respond to. Having said that, neuroinflammation is a propagator since we are getting people in trials. So yeah, there are diseases already started. They're typically 12 to 14 months into disease. So the initiators are long gone unless you're doing studies on pre-symptomatic gene carriers, right? Then you have a chance to intervene even before it really gets going. I'm dealing with the propagating mechanisms. So neuroinflammation being one of the major propagators is probably a good target, but wow, they're all targets. I would not want to say one over another. Biomarkers. I know I hate to be repetitious, but biomarkers are the key. Great. Thank you, Dr. Heiman-Patterson. So here's another one for you. Do you find BrainStorm a serious candidate in the race to find a cure for ALS? I think that the data from the III-A study tells me that this has to be looked at. And that we need to explore whether or not this is a treatment strategy. It may be like any of the agents, not work for everyone. But there certainly may be a subpopulation, and certainly it needs to be looked at. I do think it's a serious contender. And I'm hopeful that if the trial goes forward, that we'll see that efficacy and have another sort of trick up our sleeve to help patients. I think that the time has to come for figuring out who responds to these therapies, and you'll see even greater efficacy if we restrict populations to responders. I think some of the biomarker data from III-A and what we'll learn from the upcoming trial will help us to determine who might best benefit, and we're just going to have to do the work, but yeah, it's a contender. Great. Our next question. On less advanced cases of ALS, how much does your drug seem to slow down or stop the progression of symptoms against what would be expected without the drug? I think, Bob, this one might be for you. Thank you. Yeah, I'm getting off mute. So if I hear the question, if you don't mind, I missed the crux of the question. Is it about? Yeah, I can repeat it, Bob. So on less advanced cases of ALS, how much does your drug seem to slow down or stop the progression of symptoms against what would be expected without the drug? Yeah. So as I mentioned, when we look at slowing progression, when we look at what's going to be the primary endpoint, the ALSFRS-R change from baseline versus placebo in the less advanced, in the early disease population, we clearly see a strong signal, and I'll go on to say a statistical significance at week 28. I can go back to that slide to mention it. So that's a very important aspect of the treatment, that this stem cell therapy, for it to exert its anti-inflammatory effect, as Dr. Terry Heiman-Patterson mentioned a minute ago, the propagator of the disease and then the initiator and then the propagator, we have to attack them both. And we know that our treatment is doing that. So we're curbing inflammation. We're halting further degeneration. And we see that effect as early as week 12, and then it continues on to week 28 in a population that basically, yeah, that slide right there on the right side you pass through. So yeah, this one here. So clearly, there is a stoppage of further progression. You see the blue line that basically got better early and then continued while the placebo gray line continued going down. And as mentioned also earlier, the longer you wait, the more extended that effect will be seen with time. But unfortunately, we don't want to keep people on placebo for longer than six months. So we feel good about this effect here that we hope to replicate in the next trial. The next trial is dedicated exactly to do that. Great. Thank you, Bob. Sorry. Tara, go ahead. Okay. Thanks. So our next question. Do you include a genetic profile of each study participant to check further reactions individually? So the genetic phenotyping is optional testing at baseline for exploratory effect measurement. So no, we are not stratifying the population based on genetic background. Let's remind ourselves, as Dr. Heiman-Patterson just educated us here again, that the sporadic disease is the overwhelming number of patients, more than 90% of them. And those 40+, 40 we know today, genetic mutations that largely happened in the 5%- 10% familial ALS have informed us about genetic, but not to the point where we need to stratify populations based on it, especially the sporadic ones, the non-genetically identified ones. Great. Thanks, Bob. So next question. What are the requirements for inclusion? So there was one slide. We can go back to it. It's basically that schematic of the study. I can summarize it here quickly. Less than two years. This one, yeah you just, yeah this one. No sorry, sorry. Can you go back to the other one? Yeah, this one here. So what's important is that you come early as soon as diagnosis is made. Typically, it takes about 12- 14 months. Less than two years from first symptom. The total score cannot be at 46 or 47. So it has to be 45 or lower. Each item of the scale, those 12 items, you cannot have 0 or 1. So it has to be 2, 3, or 4. Vital capacity has to be more than 65%. You can have other treatments allowed. And basically, there are, of course, a long list of inclusion and exclusion criteria, which are, I would call them, the standard in clinical trials in ALS that you have to meet as well. But those are the important ones that were redesigned based on the learnings from the past. Great. Sorry. And ages between 18 and 75. We're not restricting age too much. Sorry. Okay. Great. So we are on our final question. And this one comes from a patient. So their ALSFRS-R score is in the responder category, but they don't qualify for the trial because they are greater than two years since diagnosis. Will you be offering EAP to patients like that in that situation? Well, I'll take that. You want to take it, Chaim? No, you can go, Bob. We are not opening an EAP program today. We are focused all our energy and resources phase III-B trial. and we have an open-label extension for those participants in this trial. But we hear this question a lot. I've heard it with every site. We went to all the sites that enlisted for the trial, have those patients asking them. I would add, pleading them to be allowed in. So we take that with strong consideration. Obviously, we need to have the resources and the efforts to do that. So it's not off the table, but it's not in the plan today based on our situation. Thank you. Great. So that was the last question. So Chaim, I'm going to turn it over to you for some closing remarks. Yeah, thank you very much. I just want to thank everyone for the thoughtful questions and the engaging discussion we've had today. We truly value your input and the opportunity to share our progress with this distinguished group. So this concludes our Q&A session. This concludes our presentations today. And I want to thank you all for your time and attention. Thank you very much.