Good morning, everybody. Thank you for joining us. We are thrilled to be here today to talk further about our mind-blowing data, pun intended, in treating our first three GBM patients. For those of you who don't know me, my name is Raphi Levy. I've been CFO of Alpha Tau for seven years, following over 12 years in investment banking at Goldman Sachs. I'm joined today by three distinguished guests in this conversation. Uzi Sofer, our Founder and CEO, has led the company since founding it in 2015, following over 10 years as Co-founder and CEO of BrainsWay, a medical device company in the mood disorder space. He brings with him many years of business management experience across a range of industries as CFO, CEO, and Chairman. Together with him is my colleague, Dr. Robert Den, who serves as an Associate Professor of Radiation Oncology, Urology, and Cancer Biology at Thomas Jefferson University Hospital in Philadelphia, where he did his residency after finishing medical school at Harvard. His true passion lies in serving as Chief Medical Officer of Alpha Tau, which he has done also for about seven years. Last but not least, we're joined by Dr. Joshua Palmer, Professor of Radiation Oncology and Vice Chair of Advanced Imaging and Experimental Therapeutics at The Ohio State University Comprehensive Cancer Center, also known as The James. Dr. Palmer also did his residency at Thomas Jefferson University after finishing medical school at the University of Miami. Thank you again to all of us for joining us, and I'm gonna turn the mic over right now to my colleague, Dr. Den. Thank you very much, Raphi. It's my pleasure today to be joined by Dr. Palmer and to be speaking with you today about our exciting technology. Just to begin, Alpha DaRT is a unique product in that it focuses on the utilization of alpha emitters for its treatment. Alpha emitters have many unique properties, one of which I would like to start with, is its safety profile. The alpha particle is unique in that of all the radiation types, it can be stopped by something as thin as a sheet of paper. What this means is that we are able to deliver this treatment in any clinical setting, whether it's an operating room, an endoscopy suite, a clinic room. This versatility allows us to utilize the Alpha DaRT across multiple different indications. This is coupled with the knowledge that the alpha particle itself is the most potent way to cause DNA damage, the main form of cell death generated through radiation treatment. Alpha radiation is unique in that it directly damages the DNA and works independently of oxygen, causing irreparable double-strand breaks. This independence of oxygen is crucial, especially as we talk of a disease such as GBM, which is known pathognomonically for having necrosis. Necrosis is the pathological indication that there is a lack of oxygen or blood flow to the tissue. Many people have asked, "If this is so potent and safe, why hasn't it been previously utilized?" The main limitation in utilizing alpha radiation itself is that the alpha particles have an extremely limited range in tissue. An alpha particle can only travel between 40 - 90 microns in tissue. The obvious question is there a way in which we can deliver alpha radiation, but on a clinically pragmatic scale? This is what has led us to develop the Alpha DaRT. As you can see in the video, the Alpha DaRT consists of a biocompatible, inert, metallic, and in this case, titanium seed, which serves as a scaffold by which we introduce a radiopharmaceutical, Radium-224. Radium-224 is co-coated on the exterior of the seed, and upon its insertion directly into the tumor, it begins a process known as radioactive decay. This decay process releases the daughter atom, Radon, from the surface of the seed and allows it to move by both diffusion and convection in the tumor. Radon continues its decay chain, decaying to its subsequent daughters, with each daughter decay, releases an alpha particle further and further into the tissue. By relying on the movement of the atoms as opposed to the movement of the alpha particles themselves, we are able to create a clinically pragmatic range of cell kill within the tumor until we get to stable Lead-208. This is the particular pathway that we utilize. We start with Radium, it decays to Radon, Polonium, Lead, Bismuth, and finally stable Lead-208. This process releases multiple alpha particles directly into the tumor. From Radon to Lead, this entire process of decay takes 12 hours for 50% of the Radon to decay to stable Lead-208. We are not only delivering a more potent form of radiation, but we are overwhelming the tumor and not allowing it the time factor by which it is to repair this damage that we have brought. Because we are directly inserting the sources into the tumor and we are utilizing alpha radiation, we are able to deliver radioactivity levels that are on the order of microcuries. Typical systemic radiopharmaceutical is delivered on the order of millicuries. What this means is that the amount of lead that we end up with at the end of this process is two orders below normal blood levels of lead. This means that we can re-treat patients without concern for toxicities. When we start a new clinical program, in this case treatment for the brain, we always start these programs in the in vivo and in vitro setting doing preclinical studies. What I'm showing you here is a glioma model, the U87 cell line, where we grew a tumor inside a mouse. We inserted a single DaRT source here and here. What we were able to do was to confirm and compare the autoradiography showing the spread of the radiation dose on the left to the histopathology shown here on the right. What we consistently see is a death zone of cell kill 4 mm- 5 mm in diameter with an extremely sharp dose falloff. As you can see here, no damage to the surrounding tissue. We've subsequently shown and published that we can deliver this to retard the growth of these GBM tumors in an in vivo model. We have shown that we can safely deliver this in combination with first-line chemotherapy temozolomide. Subsequently, we've shown that we can deliver this also with biologics. Here we're using Avastin, a VEGF inhibitor, where we are treating with either DaRT alone, shown here in blue, or the combination of DaRT and Avastin, shown here in green. As you can see, these mice are living significantly longer time with minimal to no regrowth of their tumor, and we have previously published this. We have shown that we can deliver this in an orthotopic manner, meaning we can put it, a source directly into the brain of a mouse as well to further mimic the clinical scenario. Based on all of this, we then moved towards the large animal studies, which we have previously published. I'm going to show you now the way in which we deliver this in the clinical setting and preclinical setting. [Presentation]. [Presentation]. We have utilized and built a special applicator, the radial applicator, that works with a standard neurosurgical biopsy needle. We work with both major vendors. It has fixed rotation angles labeled one through seven, which allows us to place these clusters, umbrella shapes of seeds through a single insertion into the brain. We have spaced them such that the dose is matching at the most distal end, and the dose is much hotter as you move more interiorly. We can create clusters between 1 cm- 3.5 cm in diameter and place clusters vertically as much as we want. Here you can see one of the neurosurgeons performing this procedure on a porcine brain. We can clearly see the insertion of the neurosurgical navigation biopsy needle, as well as the deployment of the seeds shown here on CT, as well as coronal MRI. It's important to note that on MRI we did not see evidence of artifact, allowing for proper evaluation of the tumors. Importantly, in this trial we saw that there were no tissue changes in distant sites, thus all of the effects were occurring extremely locally, matching our other preclinical data. I'm now gonna turn it over to Dr. Palmer to discuss the clinical trial. Thank you very much, Dr. Den. To kind of go through the clinical trial patients, I want to touch briefly on the trial design. Like you've heard, this is for recurrent glioblastoma patients, so they've actually been treated before with radiation and failed in field from their prior treatment. The key eligibility, they have to be 18 - 85 years old. This tumor size based on the implant and technique has to be less than or equal to 3 cm with more than six months between the very first course of radiation and treatment, up to three or less recurrences, so you have to have four-week interval from a prior treatment, and then they have to have a RANO defined disease progression. The primary endpoint of the study is safety and feasibility of the implantation, with secondary endpoints, the treatment response and overall survival. The feasibility is defined as having more than seven out of 10 patients having appropriate placement with grade 3 or higher CNS adverse events as the safety signal. MRI local response will be determined by the treatment physicians. Again, there's three patients planned to enroll within an interval of one month in between for safety monitoring, and then that gets reviewed by the FDA. Once cleared, we'll enroll the remaining seven patients. All patients are monitored in the hospital for 24 - 36 hours. No additional treatments are really required outside of steroids. The first three patients that we enrolled were 56 - 71 years old, all male patients, Caucasian. They each had a WHO grade 4 IDH wild type tumor. The first two patients were unmethylated. The third patient, which is important, was hypermethylated. They were treated between 2021 and 2025. The first patient that came to us had three prior recurrences. Patient two had two recurrences. Patient three had one prior recurrence. For patient one, this was a 56-year-old gentleman, like you heard, with an unmethylated WHO grade 4 tumor. He had the postoperative course, had a gross resection with no remaining tissue at Stupp regimen, 60 gray and 30 fractions, which completed in April of 2024. He had his first recurrence with LITT, followed by a clinical trial with gallium maltolate. His second recurrence was an additional surgery, which did show viable tumor. Upon his third recurrence of additional new enhancement, he was then enrolled on the Alpha DaRT trial. Just to note, he did have a left homonymous hemianopsia from his original surgery. You can go to the next slide. This is the area that was demonstrated as per RANO, a new focal enhancement with a FLAIR encapsulation. We did perform an amino acid PET to confirm this, and it was active. If we go to the next slide. This was the pre-implant treatment plan. I think we can highlight here the two colors that you can see within the actual treatment zone, sort of the teal and pink colors are the gross tumor volume with the CTV of 1 mm clinical treatment volume, where we're trying to obtain good coverage. Highlighting here that this was able to, we were able to show that the sources can be placed in a safe and reasonable location in this area. The MRI defined sort of tumor volume. You can go to the next slide. You can see that on CAT scan, we could also identify this region of safe zone to implant. If you go back and forth between the last slide and this slide, you can see that the coverage that we did on the pre-plan and the post-plan on CAT scan were essentially identical. We had adequate coverage with really no zones that we would consider under-covered. We were able to highlight this area even on CT and MRI, even with in human placement of the seeds like you saw in the preclinical studies. What you can see here on the top left is the seeds immediately same day demonstrating adequate proper placement with no artifact. You can still identify the tumor in the central zone of the seeds. The X-ray or the X-ray fluoro that was taken during surgery shows that they were all adequately deployed during surgery. The post-implant CT, you can see, has really no artifact, but does allow us to see the seeds very well. The post-implant MRI shows the essentially pre-implant coverage was obtained, and then this was the pre-treatment PET scan, like we mentioned. Going to the next slide. We can move to the next. This is our three-month post-treatment scan. What we can see is that there is now no longer a tumor in the region of interest, so we can no longer identify the tumor. Along the seeds, there is no more edema in the area. There was edema from his surgeries, which was chronic, but the area of implant has no swelling. The seeds enhance along the seed, but the actual disease itself has regressed. This was confirmed by multiple neuroradiologists. We can go to the next. He developed no dose-limiting toxicities, no AEs, no adverse events in the CNS. He remained symptom-free throughout the course of follow-up without evidence of disease progression, both of the site of treatment or outside, with a complete response in his lesion. He's done extremely well, able to travel and do his normal activities. We can go to the next slide. Patient two was a 71-year-old gentleman, again with a WHO grade 4 tumor. Had Stupp protocol originally to a gross resected location in the right frontal region. He had developed seizures post this initial surgery in 2021, for subsequent to that, for several years, had stability in that area. He recurred with a left frontal lesion, a contralateral distant recurrence. In May of 2025, he underwent a gross resection with no residual tumor, was treated with focal proton radiotherapy with our team to avoid the prior treated area. About 5.5 - 6 months later, patient had a local recurrence in the prior treated site from 2021 in the right frontal lobe. You can go to the next slide. This is the original treatment seen on the left for the right frontal lesion, and then the recurrence that was treated with focal proton radiation therapy, trying to minimize dose to the original site of the right frontal lobe, which we were able to do here. Going to the next slide. This demonstrates that you can identify this new and focal nodular enhancement seen in the upper right around the resection bed with FLAIR encapsulation, and then the amino acid PET did highlight this area of focal recurrence. This again shows the pre-implant dosimetry, where we're trying to avoid critical areas. The blue is the area for his motor function, and then we're trying to spare his ventricular system. We're able to adequately and safely plan this in a location where obviously it's quite complex of that area of brain and entry. If we go to the next slide. We were able to, on the post-implant dosimetry, essentially recreate that. There was no areas that we were concerned were under-covered. He had a very safe and feasible implant. Going to the next slide. This is where you can see the day zero CT and MRI showing no artifact. You can actually still identify the tumor within the areas of the seeds. If we go to the next slide. On his one-month post treatment, you can see that the seeds similar to the patient one, that there is some slight enhancement along the outside coating of the seeds, but there is no further lesion in the area, so we could not find the area of original tumor. This was confirmed by several neuroradiologists. There is also no additional edema. This is an area that had previous surgery and encephalomalacia that did not change. The edema from the procedure did not increase on this scan. We go to the next slide. The three-month post insertion, the patient did also show now the enhancement around the seeds has diminished. There is no lesion seen in the area. He continues to be without disease. He did develop, day 10 post the insertion of the radiation seeds, grade 3 seizure with Todd's paralysis, which just means that he had a focal seizure that led to weakness, on the affected side for 48 hours. Patient was placed on an elevated dose of steroids, this resolved to his baseline after approximately five to six days. Since then he's been doing well, returned to his neurologic baseline. Patient three, this is an additional 56-year-old gentleman with a WHO grade 4 wild-type tumor. His was hypermethylated. He underwent a subtotal resection and for his original diagnosis in 2024, which was incomplete. He came to our center and had a reoperation for a completion surgery, which was complicated by an empyema with Klebsiella infection, which then cleared. He had a history of seizures after that second surgery and underwent postoperative chemoradiation with a Stupp regimen. During this adjuvant temozolomide, he was seen to have progressed. He underwent another surgery demonstrating active tumor. We performed an amino acid PET and showed that there was a RANO-based progression at the level of the surgical resection. If you go to the next slide. This is what you see here is the original radiation volume to that right sort of fronto-parietal region. Go into the next slide. This is that focal area of progressive disease seen in the original site of his tumor that was delivered back in 2024. This area was focally hot on the PET imaging and nodular growth along that area and enhancement. Going to the next slide. The pre-implant dosimetry was very easily able to cover the full disease and spare the motor region, which again is in the blue. We were able to get an appropriate location to place the seeds away from critical regions. Go into the next slide. We were able to recreate that during the actual implant. You can see there was maintained full coverage of the gross tumor volume. If you go to the next slide. This is the patient showing the deployment of the seeds. This is the day zero same-day scan, CT and MRI. You can still identify the lesion there in that right fronto-parietal region. If you go to the next. Three days post the procedure, he did have a breakthrough seizure, in what was called on the MRI as a pseudoprogression event, which is most common in patients that are MGMT methylated like he, his tumor, which is this swelling event or the very common inflammation that occurs after a radiation treatment, where the lesion actually got slightly larger and the edema got slightly larger, leading to his breakthrough seizure. Next slide. He was placed on an increased dose of antiepileptics and steroids, which then resolved his symptoms. He's back to his neurologic baseline. The tumor itself, because of that sort of increase in size that occurred from a pseudoprogressive event, the lesion itself was still present one month, but 30% decreased in size, which is a stable disease per RANO, but obviously a clinically relevant decrease due to the treatment itself, which was confirmed by neuroradiology with no additional worrisome edema. Next slide. He did develop a grade 2 seizure, so a breakthrough seizure due to the pseudoprogressive event, which was then managed quite simply with steroids and antiepileptics, returning him to his neurologic baseline. He's currently still doing very well, with again, that 30% decrease in size of the tumor. So far, all three patients have been appropriately treated as feasible and safe to do the implant. There was no unanticipated associated high-grade CNS side effects. All patients had tumor responses, which two were complete responses, one a 30% reduction or stable disease, which clinically these are extremely good responses in a highly pre-treated patient population, which we typically don't see. The plan is to complete the enrollment of 10 patients for the rest of the pilot study. Thank you. Excellent. Thank you very much, Dr. Palmer. Really appreciate that intro, and the detailed overview of what you saw. Just to wrap it up, and we're going to open up to questions in a second, I want to put this in context of where we are now and how we're seeing this fitting into our broader program. As many of you know, this is one of a number of different things that we're working on, and we've seen great progress across all those things, with our most important studies in the U.S. right now being our recurrent cutaneous SCC ReSTART study, where we just announced last week that we finished the completion of the recruitment of those patients in that pivotal study, looking for data to come out later this year, around the end of the year. As well as the U.S. IMPACT trial in pancreatic cancer, where we announced just a few weeks ago that the FDA expanded that study to include additional forms of chemotherapy and a larger number of patients, looking to finish their recruitment there roughly in the next quarter. Finally, of course, the recurrent GBM, the REGAIN study that we've discussed today, where we just had the initial safety readout, and as discussed, looking to have additional patient recruitment done as soon as the FDA gives us the clear, the all clear following the review of the safety data. With that, we're gonna pause here for questions. I'm gonna ask the moderators here to help us in doing that. I believe our first question is coming in from Jeff Cohen from Ladenburg. Can we please turn the mic over to him? Good morning. Can you hear me okay? Yes, we can. Wonderful. Couple questions for you, Raphi and Dr. Den, and then maybe one question for Dr. Palmer. Talk about, it sounded like the timing of the seven additional patients will be in the coming months. Can you talk about number of DaRTs that were used in the treatment so far, and how you think about that and its power over the surface area or total area? Yes. Each patient's treatment was built specifically for them. We have different variations in terms of the number of DaRT and the configuration that we can use. We can either use 1 cm or 2 cm lengths along the axis that we treat. And we can plan that based on the trajectory that the neurosurgeon chooses. In terms of the total number, the number of DaRTs we've used have been anywhere between 25 to about 40 DaRTs. Again, we've done different configurations depending on where the normal organs at risk are, vis-à-vis where the tumor is and what gives us the most optimal coverage along the trajectory that the neurosurgeon wants to use in his approach. I'm sorry, what was the second part of your question? It was related to the timing. Yes. Should we expect the balance of the seven patients? Yes. We've submitted to the FDA a request to increase to an additional seven patients. In addition to that, we have also requested to have two additional sites join Dr. Palmer's site in the enrollment onto the trial. Because we have FDA Breakthrough Device designation for this indication, we will have responses within 30 days from the agency. Assuming that everything moves as we anticipate it will based on, as you can see, the very favorable safety profile that we've seen, we anticipate being able to begin recruitment immediately, and I would anticipate that we can recruit rather quickly. The delay in recruitment thus far has really been to allow for that one-month interval between each patient in order to fully assess safety. Now, as you can see, with the first patient, we have them with at least five months of follow-up and no new safety signals. The second patient now having close to three-month follow-up as well, excuse me, close to four-month follow-up. As you can see, we have some longer duration follow-up, especially if we remember that this patient population generally has a median survival between six to nine months. That's helpful. As a follow-up, I guess a question for Dr. Palmer and/or Dr. Den, if you could hypothesize with us about, you know, where you see this therapy being, fitting for GBM as far as recurrence or front line or second line or third line patients at some point, if or when approved. Sure. I think what we're seeing based on this, assuming the data continues to follow, I would anticipate that it will because we've utilized a common practice approach that is very familiar for the neurosurgeons and works very well with their radiation oncology colleagues, that we will become front line as the go-to treatment for recurrent GBM. I think that in the future, we may see some different IITs, investigator trials, where they're looking at different combinations with DaRT. I would also say that we would anticipate moving DaRT even into the front-line setting. I would think that we would probably initiate it with those patients that are either unresectable or in patients in whom a subtotal resection is only achievable. That third patient that Dr. Palmer noted, where they initially only had a subtotal resection. If that patient was unable to undergo a gross total resection for whatever reason, I would see the DART having a major role in that patient population as well, especially as we're seeing the tumor response to the therapy. I think that just broadly within the context of CNS tumors, you know, with this, we are going to be looking towards other CNS tumors, whether it's brain metastases or other high-grade lesions, that we would be looking to utilize DaRT in that area. I think we're gonna go deeper within the high-grade glioma space, and then we'll also expand into other tumors within the context of the brain. Perfect. Thanks for taking the questions. Thank you, Jeff. All right, I think now we're gonna go to Yigal from Citi who asked to share some questions. Yeah, thanks. I was just wondering with the third patient, the fact that they had a hypermethylated tumor, if that was in some way, relevant in terms of not getting a complete response or was it related to the fact that there was just a partial resection? Good question. He ended up getting a completion surgery to a GTR, did have a recurrence in the cavity. I would relate probably the change in why this one wasn't a CR was, like you mentioned, likely due to the biology of the tumor. I think clinically though, still seeing a shrinkage that early, because, like, just having treated many of these patients over the years, most of our therapies like re-irradiation, Avastin, all these drugs, don't really cause a true clinical response. They stabilize disease or elongate potentially some of them may elongate the patient's survival. We very rarely get, like, a true complete response even to, like, upfront treatment with chemoradiation. Seeing the first two patients disappear was just sort of a little bit shocking of like, "Well, this is a great response." Even the 30% response comparing to the having sort of the swelling event that made the tumor even larger, I think shows us that there's something happening where the immune system is impacting it, and it's not quite there yet. Obviously, we're still getting the additional three-month scan then following them longer. It's possible some patients respond quickly, and others may take a little more time based on their biology. With the hypermethylated tumors, would you suggest or consider doing more DaRTs to increase the radiation field or that wouldn't be recommended? Right now, probably not. I think if there are the current way we do it's very personalized to the patient and how the procedure's being done. It's adding more, I wouldn't expect is needed unless we see marginal failures or something strange like that down the road, then we'd probably modify the procedure. Right now, we're implanting the gross disease appropriately, wouldn't add additional seeds. Okay. Thank you. Yeah. Great. Thank you, Yigal. All right, I see we have quite a number of questions here. Let's pass it off to Yi Chen from H.C. Wainwright, please. Hi. Thank you for taking my question. Regarding the grade 3 side effect, seizure with temporary paralysis, have you determined whether it is related to the insertion procedure or related to the radiation treatment? Good question. We related it to the actual radiation therapy, given the timing. The majority of patients, and this is why it was a little bit interesting to see it happen in that particular patient, is that there were really no side. Like we implanted the patient two and three near, but not within the motor region. We were somewhat happy to see that there was no motor changes from the procedure itself, placing the DaRTs in and around that motor region away from where we are trying to stay away from for safety. They had no kind of immediate post-procedure problems. When they ended up coming in with sort of their seizure event, the MRI showed this inflammatory response. Between that sort of 48 hours, 'cause you saw we showed the one-day MRI, like the same day or within 24-hour scans. There was actually no immediate inflammatory changes that you could see, so like no change in edema around the implant, no change in enhancement around the seeds. Once you get to that sort of seven to 14-day time point, which like for radiation oncologists, we see this sometimes with like high-dose radiosurgery for brain lesions. You can get like a week later a FLAIR-up or a seizure breakthrough or something from a delayed immune response. What we sort of anticipate is the radiation as it was getting through that phase of delivering kind of an intense treatment within that first two weeks, we think there was an inflammatory response that led to the swelling change and then the breakthrough seizure. Again, the first patient didn't ever have a history of seizures, so he never developed one even with sort of the likely inflammation that was occurring in the area. The second two patients having a little bit higher risk given their history of seizure, we think that it was an inflammation from the radiation delivery as opposed to the actual procedure. All the patients really got out of the hospital about one day later. We required keeping them for some of the trial-related procedures a day later, so they all had to stay at least one day. After that, they all left the morning after the procedure. They did great with the actual delivery, biopsy, needle, everything, with no complications. In your view, it cannot be completely avoided, but it should not interfere with the efficacy in these patients, right? Right. That's my thought. I think that it's sort of an anticipated potential problem with any radiation that we deliver, is that you can get breakthrough seizures. The way that the trial's worded, but also just clinically, this wouldn't be an unanticipated higher grade toxicity. We get these occasionally if the radiation, you know, quote-unquote, "is working." If you actually get a good response and start seeing treatment changes or inflammation in the disease, you can see this sort of breakthrough in headaches or seizures or symptoms related to the actual lesion location. I would view it as sort of an anticipated but higher grade toxicity that we shouldn't impact efficacy. Thank you. Great. Thank you, Yi. Let's move on to Jason Bednar from Piper. Jason, good morning. Hey, good morning. Maybe as a follow-up just to one of the prior questions on next steps, can you talk about how you're currently thinking about what a more robust trial would look like after this safety and feasibility study? How large of a trial would we be thinking about? How quickly could you look to, you know, initiate such a trial? Sorry for packing a few in here, but Dr. Den, I think you referenced moving to, you know, more frontline, newly diagnosed. You know, is that something that's in, like, the next two to three-year time window, or how should we be thinking about that? 'Cause that's a much bigger opportunity, of course. Of course. In terms of the next trial for the recurrent GBM setting, you know, I think that what we will do is we'll complete this 10-patient pilot and see what the response looks like. In addition, we'll look at what the survival looks like for these patients. If the patients continue to follow the same trend that we've seen thus far, we would be extremely bullish and could move to a potential pivotal trial immediately. I would anticipate that since we are a member of the TAP program for our GBM indication, the Total Product Lifecycle program with the FDA, that enables us to have very frequent discussions with the agency, specifically around this diagnosis. I would anticipate that we would move very, very quickly to a pivotal trial. In terms of the size of the trial, I think it really will be dependent on what we see in terms of the pilot data. If the pilot data continues to follow the same trend, we would not need necessarily a large trial if based on the differences that we would see, whether we have power to survival or response against current standard of care. I would anticipate that we'd be able to move very, very quickly, and again, through the Breakthrough Device designation pathway, we would be getting reviewed in a very expeditious manner. In terms of moving to the frontline, we would take it step by step, first completing this pilot, then looking towards the indication in the recurrent setting, and simultaneously to that, consider moving to the frontline. I apologize for not giving a definitive answer. I think this is very exciting and early, and definitely I am very bullish about this. But we will continue to follow this very, very closely, and again, if the results continue to follow as we are seeing, and I don't see any indication that they won't, considering the diversity of patients that Dr. Palmer and his team has treated thus far, I would anticipate we will see, and as we've seen also in our preclinical data, that we're not seeing that there is any specific genotype or phenotype that makes us consider any different results. I think it's also important, and maybe Dr. Palmer can just touch on the IDH wild type nature and the expected prognosis for these types of patients as well. Yeah, even for upfront IDH wild type tumors, the overall survival is typically somewhere between 14 and 20 months, depending on molecular, other molecular features. In recurrent GBM, it's typically six to 12 months as a range. It's typically a very difficult disease to treat, many times because they continue to recur. I think that's where, you know, this therapy is potentially that huge breakthrough of can you actually eradicate the disease locally? Because this is a local disease. They die of their local disease progressing, and we just don't have therapies, any therapies so far, that have demonstrated a true response, I would argue. I think that's the true power of this device, is that this isn't like a gene therapy or an oncolytic virus trial where you have to be, like, an extremely talented academic, you know, neurosurgeon to do this. You can do this procedure once trained well and do it a couple times. This is something that utilizes already available resources and is a procedure that can be trainable across the entire United States. It can be across Any neurosurgeon throughout the world can likely learn this quickly and utilize it quickly. I think that the uptick of it and the ability to use it in a real-world situation is just much more likely than something like an oncolytic virus or something there where we have to have catheters placed and all these things that people are running trials in for GBM. I think that this is a unique aspect that's actually delivering true responses. Very, very helpful and comprehensive. Maybe just as one quick follow-up, Dr. Palmer, you referenced, I think, enhancements around the implanted seeds on follow-up scans. I think you addressed the seizure part, your adverse event risk here, very well. Is the enhancements around the seeds, and sorry if I'm mischaracterizing it, but are those of any concern for you? Is that something you need to monitor, as you go along, or not an issue at all? Good question. The way I've looked at it with the first few patients in the first six months, I don't really view it as a necessarily negative thing, because for patient one was a good example. You see this, the seed enhancement, but there was no swelling at all. I think what we're seeing is the local reaction of the really intense radiation, and you see this with a lot of our radiation treatments. You get this new enhancing region typically because of inflammation. I view it as sort of it delivering such an intense dose, especially at the seed surface, that you're likely getting really significant leakiness around those seeds, allowing for an immune response, which is why I think you're getting some of the patients get this sort of delayed immune kind of swelling or edema in some of them, which is not a bad thing because most of these tumors are essentially immune sort of cold. They don't allow an immune response, which is why immune therapies haven't ever worked in any of our brain tumors. I think this is just highlighting there's a uniqueness to how alpha particles interact, both with the tumor and the microenvironment, that's creating potentially an immune milieu that's allowing us a better response. 'Cause, one, many times glioblastomas probably aren't changing in size because the immune system is unable to go in to remove the disease. That's one reason we think potentially you don't really see complete responses outside of CAR T-cell therapy, like if you've ever heard of or seen CAR T-cell therapies. Like, within 24 or 48 hours of a CAR T-cell therapy at some of the trials in Seattle and in Penn, you could see the tumor essentially go away. Like, all the enhancement goes away 24 - 48 hours after CAR T-cell. Unfortunately, within, like, a week of the CAR T-cell, all those patients recur. There's something happening where the GBMs or the immune system, if it can actually interact, that's when you're seeing the actual responses. I think what my sort of, you know, this is with the first few patients, we're creating this immune system milieu, killing off the tumor and allowing the immune system actually in. For me, it's not a big deal to see the enhancement along the seeds. Obviously, we need to mitigate some of the breakthrough symptoms, which I think is doable clinically, but overall, not a huge problem. I think it's really just telling us a little bit more of how it's working and that it is working. All right. Very helpful. Thank you. Thank you, Jason. All right. We've gotten a bunch of questions here. I'm gonna go through some of the questions that were submitted in writing. A number of them, I'll turn to you, Dr. Den, relate to the expected future use cases for this product in the brain. Some of the questions we've received have been around, number one, whether the product would be used in or explored in other brain cancers besides the recurrent GBM, or other settings in the brain. Number two, whether we expect to use this only on its own or also in combination with other therapies. Wonderful questions. I'll give you a brief preview that we are anticipating a submission to the FDA to utilize the Alpha DaRT for the management of brain metastases. As you know, this is a much larger market and equally as important as the high-grade glioma market. It will utilize the exact same applicators and approach as Dr. Palmer noted. In fact, we anticipate we might see even better results in the setting of brain metastases, as these tend to be more circumscribed lesions. Brain metastases will be anticipated submission within the next month or so to the agency, utilizing the safety data that we presented here today. That will be our first indication in that regard, and that will then open up a wide array of possibilities. As you know, many patients, while receiving with brain metastases also have systemic disease or have been on systemic therapy. I think one of the exciting areas that we have to highlight, and this was alluded to in Dr. Palmer's answer, is the combination of different immunotherapies with our DaRT treatment. We have and will be presenting data at one of our upcoming head and neck meetings on the combination of the checkpoint inhibitor, KEYTRUDA, pembrolizumab, with DaRT for patients with recurrent or metastatic head and neck squamous cell carcinoma. Just that will be coming up in July. I think what we will look to do, especially in brain metastases, but as Dr. Palmer mentioned, also potentially in high-grade gliomas, is looking at the combination of checkpoint inhibitors with the DaRT. I think it's important to note that, based on our pancreas data that we presented last week at DDW, we have shown that we can safely deliver systemic therapy with the DaRT in combination. We would anticipate being able to do this. This is an important paradigm shift because what it means is that we can deliver local therapy at the same time as systemic therapy. One of the challenges we currently have with our current local therapies is that it generally requires a break in systemic therapy. In a sense, it's a balancing act, as Dr. Palmer could speak to more eloquently than I, right? Between determining which should take precedent, the local therapy in the brain or the systemic therapy. The beauty here is that the ability to deliver both simultaneously means that we do not have to compromise on either. It gives our patients an even better chance. I think the enhancement that we see around the sources that Dr. Palmer alluded to indicating a increase in immune profiling would suggest that we would get even more robust responses to both biologics and immunotherapy moving forward in the future. Great. Thank you, Dr. Den. Speaking about the DDW data that you mentioned and the responses that we've seen in the skin, the pancreas, and elsewhere, one of the questions we got is in light of those various responses we've seen and the general physics nature of the treatment, are there tumors that we've seen that have been resistant to Alpha DaRT? We've yet to find a tumor that has been resistant to Alpha DaRT, both on the preclinical side as well as clinically. As you see just from this presentation, we can have differences in responses, and we are currently studying the underlying biology to try to tease apart if there is something specific. Thus far, we have yet to determine any histology or tumor type that is truly resistant to DaRT therapy. Okay. Great. Thank you. I've got a question here regarding recurrences and re-treatment. How do we think about potential recurrence after DaRT treatments? How do we think about the potential to re-treat if that happens? Recurrence can always potentially occur. Dr. Palmer can talk more about their specific monitoring them. However, what we would do in terms of re-treatment, as you saw previously when we designed the DaRT umbrella, we do a half shift of the umbrella itself as we go up layer by layer in order to increase the total dose within the area. And importantly, and I'll let Dr. Palmer address this even further, is that when we looked at all of the organs at risk that we measured in the DaRT treatment, we essentially saw all of them receive close to, if not, zero gray. In general, one of the main challenges with re-treatment of any tumor, especially in the brain, is the concern in the brain for radionecrosis, and that is generally not because there is too much dose going to the tumor, but rather too much dose being received by one of the organs at risk. In this case, since we're giving no dose through the DaRT treatment, we would be able to re-treat. I think the only limitation that we may have would be if there's any steric hindrance from a previous DaRT seed. Dr. Palmer, do you wanna comment any further? Yeah. Exactly. I think, kind of highlighting even one of the patients on the study, you know, it's always a challenge to try to re-treat a patient, and we had to use a proton approach. Even with that approach, there still is overlapping of some of the radiation treatment because it's external. Even with protons, you're getting some robustness where dose is overlapping with the prior treatment, and that does lead to a lot of safety concerns, but is doable with appropriate time intervals in between treatment. Like, thinking about how we would manage a patient after Alpha Tau is really, we would just, if in a, you know, several months have gone by, because the dose is so confined to the region, there really isn't any limitation for us to then apply additional treatment if there's, say, a new disease nearby or something close to the prior alpha treatment. I would not be too concerned about it, just because the safety to the kind of critical areas of the brain that we worry about with additional radiation treatments is just not there. I think it's something that opens us to a more, we're probably more at ease of treating somebody after an alpha treatment than sort of this brachy treatment than an external treatment. I think that's sort of how I would look at it. Great. Thank you. I think we have another question here for you, Dr. Palmer, and Dr. Den as well, if you'd like to comment. The question is around alternative therapies. If these patients hadn't received Alpha DaRT, what else would have been available to them, and what do you expect or what do we typically see as outcomes for those kind of therapies? Good question. Right now, there's no technical true standard of care for recurrent glioblastoma. I think depending on where you are in the world, it can either be Avastin or re-irradiation or surgery. The data does, they've run one study showing that Avastin versus Avastin plus re-irradiation was equivalent, so there really wasn't a huge benefit to one or the other treatment. Right now, most of the treatments, whether it's surgery, re-irradiation, or drug therapy, they all get you about six to nine months of progression-free interval, and then those individuals tend to progress again locally. From a treatment standpoint, outside of Alpha, the Alpha DaRT study, the options are really limited. Similar to, like, some of the patients that come on this trial, they have one to three prior already attempts at trying to stop the recurrent tumor. You know, many will then continue to progress. Usually, it's re-irradiation, surgery, or a drug therapy. Yeah, I would agree. I think anytime you look at the National Comprehensive Cancer Network guidelines and you see that the first level 1 recommendation is a clinical trial, you know that there is no true standard in the space. I think that I would agree with Dr. Palmer. Remember also for a lot of these other alternatives, they come with additional concerns for safety over and above what we've seen with the DaRT. Remember, these patients were able to go home within 24 - 36 hours after their procedure and are all now back at their neurologic baseline. I mean, I think those are huge steps, and I know we focus a lot on the efficacy results, which are phenomenal, but I think it's also important to demonstrate both the feasibility of this approach, the safety of the approach, and the ease at which it was done, and as Dr. Palmer noted, that it can really be done out across the community. One of the challenges is that when you have therapies that are so complicated, where it only is able to be done in centers of excellence, it means that you've limited the total population that can benefit from such a therapy. The beauty here of the Alpha DaRT, because we've designed it around the normal workflow of the neurosurgical community, it means that it can be done in and across multiple different geographies and patient settings. Great. Thank you. And then I have a related question I received, Dr. Palmer, if you can comment on this. To what extent do you see other therapies generating complete responses as well? Again, I assume you talked a little bit about the goal really being more about the survival, but are there any other experiences you could point to where in this setting you would've normally seen a complete response? No, the only other time, like I mentioned, the only other time I've ever seen a recurrent glioma study show a complete response is with CAR T-cell therapy, which obviously had caused, like, a huge uproar, was published in The New England Journal and all that you could see something within 24 hours just make a GBM disappear on an MRI. Outside of those initial kind of you know, responses that, like I mentioned also, were not sustained, so they don't go the tumor went away, but then comes back because of a currently unknown immune sort of response and how the GBM is working. Outside of that, there really haven't been trials that show complete responses. That's why I think this therapy, because of, like you saw the preclinical data and how this mechanism works, I think it just tells us this is an exciting area that's causing responses that we otherwise have never seen. Most individuals have stable disease or worse, so, like, that pseudoprogressive event. Sometimes we view that as a positive thing for glioblastoma patients because it means that, hey, it may be working, they may live longer even though it looks worse, it's okay. This is like one of the few diseases where that is sort of a clinical way that we manage patients is, "Oh, it's all right that the imaging looks worse. It looks like it's growing, but in fact, you may still do okay. This is one of the few times we're actually seeing true responses in the lesion, leading to, so far, a sustained response, and so I think that's the exciting thing about it. Great. Thank you. All right, I know we're running close on time here. I'll try and stick in some of the last questions that we can before we get cut off here. Question to both of the doctors, if you have a view on what percentage of GBM tumors are or are not reachable by Alpha DaRT. Dr. Den? I think, in terms of reachability, I think the vast majority are reachable by Alpha DaRT. I would say perhaps the only one that we would probably hesitate would be kind of a diffuse intrinsic pontine glioma at this point. I think what we would need to do is to get more experience before going after this, you know, truly devastating disease. I think otherwise we have multiple areas to treat. I think one of the areas that we really, when we go to the frontline setting, which is quite exciting for me, will be when we look at kind of butterfly lesions, which are lesions that actually cross the corpus callosum and actually are on both sides. These are exceedingly challenging, patients, as Dr. Palmer can speak to eloquently, have an extremely poor prognosis. I think this would be an area where we would see a huge benefit for that patient population. Yeah. I agree. I'll chime in just from a neurosurgical standpoint, as a non-neurosurgeon, what you'll likely hear from them is that you really there's almost nowhere that they can't put a biopsy needle. Like, a technically ability to treat a lesion should be open to anywhere in the brain. The question will be the safety. That's why I think this trial will be quite useful. We're gonna be using and treating mostly the safest locations, but as this becomes a more broadly used, larger setting, we'll be able to see how can we tailor it to each patient's lesion and treat even larger or more difficult locations. I think that becomes more appropriate as we go down the road of, like, should we do a lesion? You can from a technical standpoint, the biopsy region can be placed anywhere. That includes brain stem, thalamic, frontal, everywhere. The challenge will be is it safe and feasible, which is what the trials will show. Great. I know we're running short on time here. We have a ton of questions here. Maybe I'll end off quickly with a question. Dr. Den, can you talk a bit about the follow-up that we're expecting to need with these 10 patients to wrap up the study? Surely. As you know, the primary endpoints in this trial are both feasibility and safety. Feasibility, we, as Dr. Palmer has noted, we know basically immediately after the procedure. That is an immediate known. The safety, we have both one month and three months. I would anticipate that we would be reporting out final results approximately three to four months after the last patient was enrolled onto the trial. Now remember, our secondary endpoints are survival, so we will still be monitoring these patients for survival. I anticipate if we will have at least one patient. If patient one, God willing, will still be alive, you know, we'll have a patient out close to one year on survival follow-up at that point. We will have a median survival probably on the order of, six months, assuming all the patients continue to follow these, with our anticipated, overall timeframe, for reporting out and completion of the trial. Great. All right. With that, we're gonna stop. I know we still have people waiting for questions. I apologize for those that we didn't get to. Obviously, a very exciting set of data here that we're very happy to share with you. Thank you everybody who joined us. Thank you, Dr. Palmer, Dr. Den, and Uzi Sofer for the time. Have a great day, everybody.