Conference Transcript - DRTS 2026-09-14

Operator

Is that showing up on the stream for you guys?

Operator

Just a second.

Operator

I don't want to keep him in the waiting room too long. Looks pretty good to me.

Operator

It's fun to be here. Thanks, Micah.

Operator

All right, cool. Let me let him in now.

Rafi Levy, CFO

Hey, 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 Rafi Levy. I've been CFO of AlphaTau for seven years, following over a dozen 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 a decade 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. But his true passion lies in serving as chief medical officer of AlphaTau, 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. So thank you again to all of us for joining us, and I'm going to turn the mic over right now to my colleague, Dr. Den.

Dr. Robert Den

Thank you very much, Rafi. So it's my pleasure today to be joined by Dr. Palmer and to be speaking with you today about our exciting technology. So just to begin, AlphaDart 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, 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 important 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 pathognomotically for having necrosis. Necrosis is the pathological indication that there is a lock of oxygen or blood flow to the tissue. Now, many people have asked, if this is so potent and safe, why hasn't it been previously utilized? And 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 to 90 microns in tissue. And so the obvious question is, is there a way in which we can deliver alpha radiation, but on a clinically pragmatic scale? And this is what has led us to develop the alpha dart. So 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 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, and with each daughter decay, releases an alpha particle further and further into the tissue. So 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, then 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. Thus, 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 retreat patients without concern for toxicities. Now 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. And 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, four to five millimeters in diameter, with an extremely sharp dose fall-off, and 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, and we have shown that we can safely deliver this in combination with first-line chemotherapy, temozolamide. 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 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.

Dr. Robert Den

How it is used. A stereotactic navigation biopsy needle is inserted into the brain until it reaches the desired depth and location. the alpha radial applicator is affixed to the biopsy needle hub. The surgeon opens the needle's window and pushes the flexible applicator tube into the tumor. Once the tube is in place, the surgeon pushes the stylet forward and retracts the tube. Once the seed is deployed, the needle is rotated to the next position. This way, a layer of alpha dart seeds is evenly distributed around the needle without the need to reinsert the needle repeatedly. After the first layer of seeds has been inserted, the biopsy needle and the applicator are drawn upwards to deploy the next layer of seeds, as may be necessary per the relevant treatment plan. At the end of the procedure, the biopsy needle and the applicator are removed, while the alpha dart seeds remain in the tumor and release alpha emitters into the tumor. The alpha emitters diffuse into the tumor and emit alpha radiation that creates double-strand DNA breaks in the cancerous cells and destroys the tumor.

Dr. Robert Den

So 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 1 through 7, 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 one to three and a half centimeters in diameter and place clusters vertically as much as we want. Here you can see one of the neurosurgeons performing this procedure on 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 distance sites. Thus, all of the effects were occurring extremely locally, matching our other preclinical data. I'm now going to turn it over to Dr. Palmer to discuss the clinical trial.

Dr. Joshua Palmer

Thank you very much, Dr. Den. And so to kind of go through the clinical trial patients, I want to touch briefly on the trial design. So 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 to 85 years old. This tumor size based on the implant and technique has to be less than or equal to three centimeters 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 Raynaud 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 three or higher CNS adverse events as the safety signal. MRI local response will be determined by the treatment physicians. And again, there's three patients plan to enroll within an interval of one month in between for safety monitoring, and then that gets reviewed by the FDA. And once cleared, we'll enroll the remaining seven patients. All patients are monitored in the hospital for 24 to 36 hours. No additional treatments are really required outside of steroids. So the first three patients that we enrolled were 56 to 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. So for patient one, this was a 56-year-old gentleman, like you heard, with an unmethylated WHO grade 4 tumor. He had the post-operative course, had a gross resection with no remaining tissue, had stoop regimen, 60 gray and 30 fractions, which completed in April of 2024. He had his first recurrence with lit followed by a clinical trial with gallium maltolate. His second recurrence was an additional surgery, which did show viable tumor. And then upon his third recurrence of additional new enhancement, he was then enrolled on the ALPADAR trial. Just for note, he did have a left hematomous hemianopsia from his original surgery. Go to the next slide. And so this is the area that was demonstrated as perreno, a new focal enhancement with a flare encapsulation. We did perform an amino acid PET to kind of confirm this, and it was active. Go to the next slide. This was the pre-implant treatment plan, and 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 one millimeter 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 and the mri defined sort of tumor volume and you can go to the next slide you can see that on cat scan we could also identify this region of safe to zone to implant if you go to the and so this is our kind of 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 undercovered. We were able to highlight this area even on CT and MRI, even within human placement of the seeds like you saw in the preclinical studies. And so 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. And then 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. And so this is our three-month post-treatment scan. And 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, but along the seeds, and there's no more edema in the area. There was edema from his surgeries, which was chronic, but the area of implant has no swelling, and the seeds enhance along the seed, but the actual disease itself has regressed. This was then confirmed by multiple neuroradiologists. We can go to the next. And so 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 at 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. I can go to the next slide. Patient 2 was a 71-year-old gentleman, again with a WHO grade 4 tumor, had stoop protocol originally to a gross resected location in the right frontal region. He had developed seizures post this initial surgery in 2021, but then subsequent to that for several years had stability in that area. He then recurred with a left frontal lesion, so a contralateral distant recurrence. In May of 2025, he underwent a gross resection with no residual tumor, which then was treated with focal proton radiotherapy with our team to avoid the prior treated area. And then about five and a half to six months later, patient had a local recurrence in the prior treated site from 2021 in the right frontal lobe. We 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 flare 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 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, and we were able to, on the post-implantosimetry, essentially recreate that. There was no areas that we were concerned were undercovered. We 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. fact, 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's also no additional edema. This was an area that had previous surgery in encephalomalacia that did not change. The edema from the procedure did not increase on this scan. 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 three 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. The patient was placed on an elevated dose of steroids, and then this resolved to his baseline after approximately five to six days. And since then, he's been doing well, returned to his neurologic baseline. And then patient three, this is an additional 56-year-old gentleman with a WHO grade four wild-type tumor. His was hypermethylated. He underwent a subtotal resection for his original diagnosis in 2024, which was incomplete. He came to our center and had a re-operation 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 post-operative chemoradiation with a stoop 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 rhino-based progression at the level of the surgical resection, if we go to the next slide. This is what you see here is the original radiation volume to that right sort of frontal parietal region. Going to 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 in 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. So we were able to get an appropriate location to place the seeds away from critical regions. Go into the next slide. And we were able to recreate that during the actual implant. You can see there was maintained full coverage of the gross tumor volume. Go to the next slide. And then 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 frontal parietal region. We go to the next. Three days post the procedure, he did have a breakthrough seizure, and what was called on the MRI is a pseudoprogression event, which is most common in patients that are MGMT-methylated, like his tumor, which is this swelling event or 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 anti-epileptics 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 rhino, but obviously a clinically relevant decrease due to the treatment itself, which was confirmed by neuroradiology, with no additional worrisome edema. Next slide. And so 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, so far, all three patients have been inappropriately 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. And the plan is to complete the enrollment of 10 patients for the rest of the pilot study. Thank you.

Rafi Levy, CFO

Excellent. Thank you very much, Dr. Palmer. Really appreciate that intro and the over-detailed overview of what you saw. So 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 by 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. And then 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. So with that, we're going to pause here for questions, and I'm going to ask the moderators here to help us in doing that. I believe our first question is coming in from Jeff Cohen from Leidenberg. Can we please turn the mic over to him?

Jeff Cohen, Analyst — Ladenburg

Good morning. Can you hear me okay?

Rafi Levy, CFO

Yes, we can.

Jeff Cohen, Analyst — Ladenburg

Wonderful. So a couple questions for you, Rafi, and Dr. Dan, and then maybe one question for Dr. Palmer. So talk about, it sounded like the timing of the seven additional patients will be in the coming months. Can you talk about the number of darts that were used in the treatment so far? And how do you think about that and its power over the surface area or total area?

Dr. Robert Den

Yes. So each patient's treatment was built specifically for them. We have different variations in terms of the number of darts and the configuration that we can use. So we can either use one centimeter or two centimeter lengths along the axis that we treat, and we can plan that based on the trajectory that the neurosurgeon chooses. So 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-a-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. What was the second part of your question?

Jeff Cohen, Analyst — Ladenburg

It was related to the timing. We should expect the balance of the seven patients.

Dr. Robert Den

Yes. So, 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. Once we, and because we have FDA breakthrough device designation for this indication, so 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. But 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, or excuse me, close to four-month follow-up. So 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.

Jeff Cohen, Analyst — Ladenburg

That's helpful. And then as a follow-up, I guess a question for Dr. Palmer and or Dr. Dent, 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.

Dr. Robert Den

Sure. So I think what we're seeing based on this, assuming the data continues to follow, and 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 frontline 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. But I would also say that we would anticipate the moving DART into the frontline setting. And 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. Like 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. So I think we're going to go deeper within the high-grade glioma space, and then also expand into other tumors within the context of the brain.

Jeff Cohen, Analyst — Ladenburg

Perfect. Thanks for taking the questions. Thank you, Jeff.

Rafi Levy, CFO

All right. I think now we're going to go to Yigo from Citi, who was asked to share some questions.

Chia Yi Chen, Analyst — HC Wainwright & Co.

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?

Dr. Joshua Palmer

Good question. So 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 to CR was, like you mentioned, likely due to the biology of this one, 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-radiation of acid and 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. But we very rarely get like a true complete response, even to like upfront treatment with chemoradiation. And so 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 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. And 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. And with the hypermethylated tumors, would you suggest or consider doing more DARTs to increase the radiation field, or that wouldn't be um recommended right now probably not i think there are right the the current way we do it it's very personalized to the to the patient and how the procedure is being done so it's a uh adding more we don't have i wouldn't expect is needed unless we see marginal failures or something like strange like that down the road then we'd probably modify the procedure but right now uh we're implanting the gross disease appropriately wouldn't add additional additional seeds.

Chia Yi Chen, Analyst — HC Wainwright & Co.

Okay. Thank you.

Dr. Joshua Palmer

Yeah.

Rafi Levy, CFO

Great. Thank you, Hugo. All right. I see we have quite a number of questions here. Let's pass it off to Yi Chen from HC Wainwright, please.

Operator

Hi. Thank you for taking my question. Regarding the grade three side effect seizure with temporary paralysis, have you determined whether it is related to the insertion procedure or related to the radiation treatment?

Dr. Joshua Palmer

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. And so 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. And when they ended up coming in with sort of their seizure event, the MRI showed this inflammatory response. So between that sort of 48 hours, because 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 the no change in edema around the implant, no change in enhancement around the seeds. But once you get to that sort of seven to 14 day time point, which like for as a racial oncologist, we see this sometimes with like high dose radio surgery for brain lesions, you can get like a week later, a flare up or a seizure breakthrough or something from a delayed immune response. And so what we think is 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. Because 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. But 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 a day later. So we required keeping them for some of the trial-related procedures a day later. So they all had to stay at least one day. But after that, they all left the morning after the procedure. And so they did great with the actual delivery and biopsy needle and everything with no complications.

Operator

So in your view, it cannot be completely avoided, but it should not interfere with the FXC in these patients, right?

Dr. Joshua Palmer

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. So the way that the trial is 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. Like 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. So like I would view it as sort of an anticipated but higher grade toxicity that we would shouldn't impact efficacy.

Rafi Levy, CFO

Thank you. Great. Let's move on to Jason Bednar from Piper. Jason, good morning.

Jason Bednar, Analyst — Piper

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 initiate such a trial? And then sorry for packing a few in here, but Dr. Dent, 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? Because that's a much bigger opportunity, of course.

Dr. Robert Den

Of course. So 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. And 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, then we would be extremely bullish and could move to a potential pivotal trial immediately. I would anticipate that we would, since we are a member of the TAP program for our GBM mitigation, the total activity lifecycle program with the FDA. That enables us to have very frequent discussions with the agency specifically around this diagnosis. So 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 based on the differences that we would see, whether we are powered to survival or response against current standard of care. So 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 front line 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 front line so i apologize for not giving a definitive definitive answer i think this is very exciting and early and definitely i am very bullish about this um 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.

Dr. Joshua Palmer

Yeah, so even for upfront wild-type tumors, the overall survival is typically somewhere between 14 and 20 months, depending on other molecular features. In recurrent GBM, it's typically 6 to 12 months as a range. And so it's typically a very difficult disease to treat, many times because they continue to recur. And so 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. And so I think that's the 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 you could do this is something that utilizes already available resources and sort of is a is a procedure that can be trainable across the entire United States. It can be across, you know, any neurosurgeon throughout the world can likely learn this quickly and utilize it quickly. And so 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 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.

Jason Bednar, Analyst — Piper

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, adverse event risk here very well, but 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?

Dr. Joshua Palmer

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 even for patient, like for patient one was a good example, you see the seed enhancement, but there was no swelling at all. And so 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. So I view it as sort of the disease, delivering such an intense dose, especially at the seed surface, that you're likely getting this really significant leakiness of the, 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. Because one, many times glioblastomas probably aren't changing in size because the immune system is unable to go in to remove the disease. So 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. So like all the enhancement goes away 24 to 48 hours after CAR T-cell. But then unfortunately, within like a week of CAR T-cell, all those patients recur. So 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. So 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. And so 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.

Jason Bednar, Analyst — Piper

All right. Very helpful. Thank you. Thank you, Jason.

Rafi Levy, CFO

All right. We've got a bunch of questions here. I'm going to 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. So 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 herocardium GBM or other settings in the brain, and number two, whether we expect to use this only on its own or also in combination with other therapies.

Dr. Robert Den

Wonderful question. So 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, so brain metastases will be anticipated submission within the next month or so to the agency, utilizing the safety data that we presented here today, and 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 we'll 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, and just that will be coming up in July, but I think what we will look to do, especially in brain metastasis, but as Dr. Palmer mentioned, also potentially in hygrigliomas, 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. And so we would anticipate being able to do this. Now, this is an important paradigm shift because what it means is that we can deliver local therapy at the same time has systemic therapy. One of the challenges we currently have with our current local therapies is that it generally requires a break in systemic therapy. And so 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. And so it gives our patients an even better chance. I think the enhancement that we see around the sources that Dr. Palmer alluded to, indicating an increase in immune profiling, would suggest that we would get even more robust responses to both biologics and immunotherapy moving forward in the future.

Rafi Levy, CFO

Great. Thank you, Dr. Dent. Speaking about the DDW data that you mentioned and the responses that we see in the skin, in the pancreas and elsewhere. One of the questions we got is, in light of those various responses we've seen in the general physics nature of the treatment, are there tumors that we've seen that have been resistant to alpha dart?

Dr. Robert Den

So 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 in biology to try to tease apart if there is something specific. But thus far, we have yet to determine any histology or tumor type that is truly resistant to DART therapy.

Rafi Levy, CFO

Okay, great. Thank you. I've got a question here regarding recurrences and retreatments. So how do we think about potential recurrence after DART treatment? And then how do we think about the potential to retreat if that happens?

Dr. Robert Den

So recurrence can always potentially occur. Dr. Palmer can talk more about their specific monitoring them. However, what we would do in terms of retreatment, so 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. So we would be, 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. So in general, one of the main challenges with retreatment 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 retreat. And I think the only limitation that we may have would be if there's any steric hindrance from a previous DART seed. Dr. Pomer, do you want to comment any further?

Dr. Joshua Palmer

Yeah, exactly. I think kind of highlighting even one of the patients on the study, it's always a challenge to try to retreat a patient and we had to use a proton approach. And 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 a prior treatment. And that does lead to a lot of safety concerns, but is doable with appropriate time intervals in between treatment. So thinking about how we would manage a patient after alpha tau is really, we would just, if 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. And so 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. So I think that's sort of how I would look at it.

Rafi Levy, CFO

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. So if these patients hadn't received alpha darts, so what else would have been available to them? And what do you expect or what do we typically see as outcomes for those kinds of therapies?

Dr. Joshua Palmer

Good question. So 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, so 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. And so from a treatment standpoint, outside of the AlphaDART study, the options are really limited. So 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. And, you know, many will then continue to progress. So usually it's re-irradiation surgery or a drug therapy.

Dr. Robert Den

Yeah, I would agree. I think anytime you look at the National Comprehensive Cancer Network guidelines, and you see that the first level one recommendation is a clinical trial, you know that there is no true standard in the space. And so I think that I would agree with Dr. Palmer. And 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 to 36 hours after their procedure and are all now back at their neurologic baseline. So, 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 AlphaDARP, 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.

Rafi Levy, CFO

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 have normally seen a complete response?

Dr. Joshua Palmer

No. The only other time, like I mentioned, the only other time I've ever seen a recurrent glioma studies 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, 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 let, 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. So 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. And so 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, there's some, it may be working, there 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 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 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 with the last questions that we can before we get cut off here.

Rafi Levy, CFO

A question to both of the doctors, if you have a view on what percentage of GBM tumors are or are not reachable by alpha-dark? Dr. Day?

Dr. Robert Den

Yeah, so I think in terms of reachability, I think the vast majority are reachable by alpha-dark. I would say perhaps the only one that we would probably hesitate would be kind of a diffuse pontine glioma at this point, but I think what we would need to do is to get more experience before going after this, you know, truly devastating disease. But 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 cavernous cavernosum, and actually are on both sides. These are exceedingly challenging and 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.

Dr. Joshua Palmer

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. So 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 going to 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? But you can, from a technical standpoint, the biopsy region can be placed anywhere. And so that includes brainstem, thalamic, frontal, everywhere. The challenge will be, is it safe and feasible, which is what the trials will show.

Rafi Levy, CFO

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. Dan, can you talk a bit about the follow-up that we're expecting to need with these 10 patients to wrap up the study?

Dr. Robert Den

Surely. So as you know, the primary endpoints in this trial are both feasibility and safety. Feasibility, as Dr. Palmer has noted, we know basically immediately after the procedure. So that is an immediate known. The safety, we have both one month and three months. So 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. And I anticipate if we will have at least one patient, if patient one, God willing, will still be alive, we'll have a patient out close to a year on survival follow-up at that point. So 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.

Rafi Levy, CFO

Great. All right. Well, with that, we're going to 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. Dan, and Mr. Sofer for the time. Have a great day, everybody.