Plus Therapeutics, Inc. (PSTV) Earnings Call Transcript & Summary

Good morning, and welcome to the Plus Therapeutics KOL event. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Plus website following the conclusion of the event. I'd now like to turn the call over to Corey Davis, Managing Director at LifeSci Advisors. Please go ahead, Corey.

Thanks, Tara, and thanks to everyone for joining us on this call to discuss the new data that was presented at the SNO conference a few days ago. It will be my pleasure in a second to turn the call over to Dr. Marc Hedrick, the CEO of Plus Therapeutics. But I'd also like to welcome the 3 KOLs that we have joining us on this call, we have Dr. Andrew Brenner, who is a Professor, Department of Medicine, Neurology and Neurosurgery at the University of Texas Health San Antonio. We have Dr. John Floyd, also Professor at University of Texas, San Antonio, and we have Dr. Toral Patel, who's at the University of Southwestern Medical Center. With that, I will turn it over to Marc.

Thank you, Corey, and good morning, everyone. Thank you for joining us. If you go to the next -- I think, 2 slides or 3 slides please, Tara. Next -- one more. There you go. Okay, perfect. Thank you. So the agenda is that I will speak briefly and just provide an overview of the company. And then Dr. Floyd and Dr. Patel and Dr. Brenner will talk about convection-enhanced delivery and then talk about case planning and how we affect the treatment on a patient and then we'll go over the most recent data that was reported just this past week at the Society for Neuro-Oncology Conference in Vancouver, Canada. So just a little bit about the company. Those of you that follow the company know that our focus is on developing targeted radio therapeutics for patients with CNS cancers. And we have the crazy goal that we could take these very deadly cancers and turn them into chronic diseases like many cancers have now become. To do that, we've assembled a number of technologies in the targeted radio therapeutic drug development space to both be where we are today and then kind of look to the future, what we might do downstream. Our 2 lead indications are for recurrent glioblastoma, which we'll focus on today, and the other is for leptomeningeal cancer, which is about 10x more common. In aggregate, these represent very significant U.S. market opportunities. Thus far, we've shown what I think is very compelling survival signals in these 2 trials. And we'll focus on what we know today about the Phase I and Phase II glioblastoma trials. But I could mention that at the SNO ASCO meeting in August, we showed a 10-month median overall survival early in the Phase I for patients that have about a 4- to 6-week life expectancy with no treatment. It's a very difficult disease with nothing approved. The company continues to be in solid financial footing. We benefit from over $15 million in grant funding from the NIH and CPIRT, State of Texas, and we have a number of other programs and trials that are in development. Next slide, please. Thank you. So first, a little bit about the technology. So Rhenium obisbemeda is a 3-part drug. It contains Rhenium-186 isotope that has very unique properties, and those will be illustrated both in my slides and throughout the remainder of the panel today. But it's Rhenium that's chelated by a small molecule and then loaded into 100-nanometer liposome, and what that sort of 3-part drug formulation does, it just fundamentally changes the pharmacokinetic properties of the drug. And that -- the rubber meets the road really in 2 specific things. First is tumor retention, in that you put the drug via convection-enhanced delivery into the brain, it stays in place and fully delivers all of its radiation throughout the decay cycle. So there's essentially no systemic toxicity. And the second thing is that it moves through or convex through the brain in a very positive way, it distributes throughout the tumor very well with that formulation versus drugs that are much smaller or small molecules. Next slide, please. So CNS cancers are quite radio-sensitive, the problem with external beam radiation, which has been the standard of care for these patients for decades is it's limited in the amount of doses you can give to patients. It requires fractionation, multiple trips to the radiation-oncology suite and off-target toxicity fundamentally limits how much of the radiation you can get. Molecularly targeted radiation has promise but still has the blood-brain barrier to contend with. And these are delivered systemically. They're relying on receptor specificity, which is never 100% and so off-target toxicity remains a problem. It's our view that for CNS cancers, the sort of direct targeted delivery is ideal. And I'll show you why in a moment, but it overcomes 1 of the key challenges of getting drugs to the CNS, and that's the blood-brain barrier. Next slide. So as a drug developer and thinking about targeted radio therapeutics for CNS cancers. You have the sort of simple model that we think about. You can divide the CNS cancers from this perspective into two things. There's the parenchymal disease, the disease, the cancer that's in the brain and the spinal cord, the mid-brain and so forth. That's kind of one animal. The other animal is the fluid containing space. You could sort of divide cancers of the CNS into one of those two areas. And it just so happens, we have 2 well-developed surgical procedures that allow us to get to the brain for parenchyma or get to the cerebrospinal fluid. And we're going to focus today on brain parenchymal delivery for recurrent glioblastoma. Next slide. So I'm sure we'll talk about how this looks from the patient perspective. But to just kind of simplify it and I think specifically, Dr. Floyd is going to talk about this from a GBM perspective, is that the treatment planning is done prior to the patient coming in. And it's a couple-of-days procedure to get the -- to get the drug infused, to get the catheters placed to confirm that they have cancer, and they go home. And that's a short hospital stay relative to the alternative external beam radiation therapy, which is day after day radiation visits to the hospital for many weeks. As it relates to leptomeningeal cancer treating the cerebrospinal fluid, that's actually a much simpler procedure. It ends up being about a 5-minute injection in the clinic as an outpatient. Next slide, please. So in the spirit of a picture is worth a thousand words, I'd like to show this because one of the key aspects of this drug that makes it unique is that it elaborates a gamma emission. So it allows you to see where the drug is and then quantify how much radiation you're getting to the tumor. And as someone that's been doing translational medicine for a long time. And I've seen this now over the course of the development of this drug is that it allows us to iterate and to develop the drug in a much more accelerated fashion because we look at each individual patient we can make changes to drug delivery, dose planning and so forth to improve the outcomes of these patients in a very sort of rapid cycle fashion. Next slide. So then finally, let me just, as a last slide, talk about the company's portfolio and clinical pipeline. So we have 3 trials that will be ongoing fairly soon, early next year when the third trial gets on board for malignant gliomas. We have a Phase I that continues to enroll patients to a maximum tolerated dose, which we have yet to reach. We're giving very high doses of radiation, but that Phase I continues to explore both those doses and the size of tumors we can treat. We have an ongoing Phase II trial using a recommended Phase II derived in the Phase I, and that trial is roughly about half enrolled and should be fully enrolled by the end of 2024. And then, as I mentioned, the pediatric brain cancer trial should be starting here in the next few months. We also have a leptomeningeal basket trial that's enrolling -- Part A of Phase I is complete, and we're now in Part B of Phase I. So next slide, please. So now I'd like to turn it over to Dr. Patel, who's going to talk specifically about convection-enhanced delivery in neurosurgery. Dr. Patel?

Thank you very much, Marc. Thank you all for joining us today. My name is Toral Patel. I'm a neurosurgeon at UT Southwestern, my specialty is in the management of adult brain tumor patients, specifically eloquent location, gliomas. And I'd like to speak to you about sort of the challenges in drug delivery to the brain and then more specifically about this technique called convection-enhanced delivery. Next slide. So this figure sort of nicely outlines the issue with getting drugs effectively into the brain. So this model is the blood-brain barrier with blood on the top of the slide, brain on the other side. And then when you are in the blood vessel, what the drug is seeing is this tight network of cells that prevents the drug from getting into the brain space. And that tight network is formed in large part by tight junctions between the endothelial cells. And so the ways that drugs can get from the blood into the brain space are either through receptor-mediated transcytosis. So a drug or a particle has a specific [indiscernible] on it that a receptor will recognize or through absorptive-mediated transcytosis, like clathrin-coated pits, et cetera, that lets you transcytose through the cell. These methods and these movements are relatively inefficient. And so you will reduce the concentration of drug in the brain by several log-fold, relying solely on intravenous delivery of medications. Next slide, please. Because of this, people have been investigating for several decades now methods to directly infuse drug into the brain. And that method in short is called convection-enhanced delivery, or CED. The figure on the top right of the screen over to the far right shows what happens if you put a catheter into the brain and then just quickly inject all of the drug immediately without any sort of pressure gradient. And what happens is that you get a very high drug concentration immediately at the site of the infusion but the falloff is very rapid, and so the distribution local, regionally is poor. By delivering things via convection-enhanced delivery, that bottom figure, which involves a specific catheter design to prevent backflow of the infusate and then also a specific gradation in the flow through the catheter, you can get square-shaped concentration curve where you maintain very high concentrations, but you can distribute them over large volumes with the volume of distribution over a volume of infusion approximating 5, which is considered ideal. And so you get a square-shaped curve, these particles and drugs move through bulk flow instead of just passive diffusion. Next slide. And so what this might look like is if you had a convection-enhanced delivery of a nanoparticle and the top 2 figures, and you just infused free drug via a catheter then you would move that free drug over a large period of -- a large volume of brain. But immediately after the infusion, that free drug would slowly and relatively rapidly disappear. But if you took that free drug and then encapsulated it into a nanoparticle and then delivered it again via the same convection-enhanced delivery setup, you would get a good local, regional delivery of the infusate as modeled by those green particles, but then because the particle slowly release the drug, and this can be engineered to anywhere between 2 to 6 to 8 weeks, depending on the particle formulation, you'll get sustained large volume and a long period of time drug delivery to that part of the brain. Next paragraph -- or next slide. These technological improvements have really addressed the issues with the PRECISE trial, which those in the audience might remember, was published over a dozen years ago now, but it was a large Phase III randomized trial of convection-enhanced delivery of an IL-13 conjugated to Pseudomonas exotoxin versus Gliadel for recurrent GBM. And there was a lot of promise for this trial but ultimately, the trial showed parity to Gliadel wafers. And the issue is really one of drug distribution. The catheters that were used in that trial did not have the appropriate design for good convection. And so the drug moved largely via passive diffusion and had that very steep concentration gradient right next to the catheter, but very poor local, regional delivery, which explains the failure. Next slide. Since that study, there has been rapid developments in catheter design and Brainlab acquired a company MRI Interventions, which developed this catheter, which we were developing at the same time in lab that has a very important step-down design that allows for good convection infusion without backflow and the ability to get that square-shaped curve. Next slide. This is what the tip of the catheter looks like. It's a ceramic coated catheter. And then as you can see at the tip, there's a step down and that step down along the last 5 millimeters of the tip of the catheter remarkably changes the type of infusion that you get. If you have only 1 caliber of catheter the whole way through the infusate will just zoom up the back of the catheter tract and you won't get distribution into the parenchyma, but this kind of step down remarkably changes that profile. I will say on the prior slide, the remainder of the setup for placing 1 of these catheters in the brain for convection-enhanced delivery was shown and I've done a dozen of these cases now and the sort of learning curve is quick and pretty easy, a standard neurosurgeon should be able to handle this. Next slide. And the way that we put these catheters in our operating room and also in Dr. Floyd's operating room is using a system called VarioGuide, which is a frameless stereotactic system that Brainlab makes through which you can stereotactically place these catheters. Each catheter placement takes about 10 to 15 minutes, and so not an overly burdensome period of time. Next slide. I'll hand it over to Doctors Brenner and Floyd.

Great. Thank you. Dr. Floyd, Neurosurgery, specialize in neurosurgical oncology at UT Health San Antonio. Been there for 16 years now working alongside Dr. Brenner as well. And I'll go through part of our early Phase I trial and some of the lessons learned. Next slide, please. So this is the setup for the Phase I dose escalation trial. I'll just make a note here that prior to this trial starting, we did an FDA-approved animal study in a good lab practices, laboratory in [ Model 1, in Michigan, ] to prove that it's safe before going into humans. This is our first-in-human trial. And so really 1 of remarkable things about this trial is it's first in human, but yet now we have a lot of human experience. And this started in first case cohort 1 in 2016. This is an FDA trial with a dose escalation paradigm where each cohort has 3 patients. We start off with very small volumes of treatment of tumor volume and then small injections of Rhenium. As you can see there, the first injection cohort was not even 1 ml and not even 1 cc. So these are very small volumes and very small targets. That was for the first several cohorts of patients and some of the lessons that we learned through the progression of this trial was that you were doing certain techniques with glass syringes and using intraoperative CT scans and certain procedures to be as accurate as possible. As we escalated through the trial and treating larger volumes, we were able to then adopt more standard neurosurgical techniques. And as we got to cohort 6, we're treating a larger volume of tumor, up to 20 ccs. And then now we're still completing the cohort 8 now. We're still looking at what is the exact maximum tolerated dose. So we still are analyzing some of our data from cohort 7 and 8. During this time, we have increased the volume that we are injecting 25x. With increased volume, we are using more catheters. So at the beginning of the cohort, we started with 1 catheter injection and now it's not uncommon to utilize 4 catheters from different trajectories to ensure that we cover the entirety of the tumor. And the radiation dose has increased by 40x as well. On the right-hand side, you'll see a chart breaking down the demographics of our patients. We've had 28 patients that we have treated. Again, this is the first 28 patients in-human. And so we have 18 male, 10 female. The average volume of tumor is 11 ccs. Let's say, going from a very small volume of 0.88 ccs to 33 ccs being the largest volume treated so far. Some of the molecular status is shown there in the table. We can go through that later, but there's a variety of molecular alterations in our patients. And in the early part of the trial, we allowed a grade 3 malignant glioma to participate, that was in the first 3 cohorts. We also allowed Avastin failure patients to also enter the trial. This was changed after several cohorts and to where it's just pre-Avastin failure and grade-4 diagnosis. Next slide, please. So how do we [ identify ] patients and what is the workflow? Well, patients are seen in your multidisciplinary neuro-oncology clinics, they're screened to see if they are surgical candidates. We look through if there's any exclusion criteria. And if they're screened and consented and want to proceed with the trial. We obtain a presurgical MRI. Now this is a standard presurgical MRI. This is not -- we do have some research features in the trial, MRI scan, but it's a standard acquisition that any neurosurgeon would use across the country for stereotactic surgery. Within that MRI we're able to upload it into our planning software with Brainlab and plan the personalized treatment plan, which is a trajectory optimized to enter the tumor and deliver the nanoparticles into the tumor. This is an important part of the treatment planning. We have to avoid certain brain structures and it's something that we do centralized currently, but it's easily adaptable to stereotatic neurosurgeon's practice. The Brainlab Flexible CED catheter is we have been utilizing, as Dr. Patel mentioned, this has really been a breakthrough for us. I participated in some of the early trials utilizing a non-convection therapy catheter and those failed miserably. That was in the early 2000s. And so this really has revolutionalized the ability to deliver catheter-based infusions into the brain. So patients go to the -- we do a standard care biopsy. It's important that we have to confirm that there's recurrent tumor. Once we have confirmed that with a neuropathologist then the catheters are immediately then placed as Dr. Patel had mentioned. And patients go back to recovery to get a standard postoperative head CT scan, if everything looks good, they go back to the room and then the following day, the infusion is performed. Can you go the next slide, please? This was our very first patient that we ever treated. This was in 2016. This scan just shows our planning software, and there is an enhancing portion of the tumor that is outlined in orange, and then blue is the catheter planning that took place before the treatment. Now with our software, we can plan around certain structures such as resection cavities, CSF spaces, surface blood vessels, important eloquent brain. We can map out sensory motor portions of the brain, and we can plan a trajectory that optimizes placement of the nanoparticle in the tumor while avoiding critical structures of the brain. Next slide, please. And then this is just a 3D rendition of the planning, superimposed on the -- on the skin map. So we get to see exactly where the catheter will be placed. And all this is done, again, before we even go into the operating room. Again, on this one, the 3D rendition, the orange is the tumor, the blue catheter you can see entering the tumor. The dark blue around it is peritumoral edema around the tumor. And then that lighter blue beneath it is the resection cavity. So these are all visual representation of our procedure. Next slide, please. And this is what it looks like. So this is minimally invasive. We don't have to open up previous surgical incisions, we don't have to remove previous bone flaps. It's a single -- this was an early part of the trial. So this was a single catheter injection through a small 3-millimeter incision of the skin and the skull bolt holding the catheter in place, the patient is very comfortable during the infusion. As we treated larger volumes, instead of 1 catheter, there would be 2 or 3, sometimes 4 catheters, but it looks very similar to this, and they usually are relatively close together. You can see that there's -- a larger catheter you can see there is actually an outer shell, and the infusion catheter is inside of that one. Next slide, please. So on the Phase I summary, to date, we have had 28 patients in the dose escalation in 8 cohorts. We -- looking at the tolerability and safety of the Phase I. We saw that this was very well tolerated by patients. Most adverse events were just grade 1 or 2 grade, the most common being headache and fatigue. Most adverse events that we observed during the course of the Phase I study were actually unlikely to be related to the drug and most likely related to disease progression. We had no evidence at all of systemic radiation toxicity, and we really have not found the dose limiting maximum tolerated dose, and we're still looking to analyze our data from cohort 8, but during the interim analysis of our Phase I trial based on the data, we elected to proceed with the Phase II at the medium-sized tumors of -- limiting it to 20 ccs tumor with a dose of 22.3 millicuries in 8.8 ml volume. We're currently enrolling into that trial. And I'll turn it over to Dr. Brenner, who can walk us through the Phase II part.

Thanks, Dr. Floyd. Next slide, please. So in Phase 2, as mentioned, we moved forward with treating with our cohort 6 dose, which was 8.8 millicuries of RNL and in the volume of 22.3 mls. As of currently, we have a total of 15 patients at the Phase II dose that have been treated. You can see their distribution there on the right, slight male predominance. The tumor volume has been from approximately 1 ml all the way up to 23 mls and they represent the targeted patient population that we're looking for in Phase II, which is glioblastoma, which should all be IDH wild type. And then in terms of methylation status, almost evenly -- slightly more methylate then non-methylate but almost even in terms of 8 versus 7 patients. And then they should all be grade 4 as you see it there. Next slide. Here's an example of 1 of our patients enrolled in Phase II. You can see on the top image there on the right, the SPECT images. So that basically showing us our drug distribution, there's the various isodose lines, which kind of basically tell us where the different levels of radiation were administered. So basically, looking at the green line is our volume of distribution for the therapeutic in this particular case. Whereas below it, you see the -- on the second row, you see the pretreatment imaging and then at various times thereafter to see how we basically were able to cover the tumor in this case. In terms of this patient, again, since this is the Phase II as we administer 23.3 millicuries and 8.8 mls, the total tumor volume, in this case was 9.9 mls. And we got approximately 70% coverage, absorbed dose to the total tumor was about 353 gray, and this patient remains alive with all the enhancement changes within the treatment volume as well we might expect. Next slide. Here's another example of a patient that was treated. This tumor was slightly smaller. As you can see there, the top left corner, the pretreatment imaging and then the drug distribution. And then at the various time points below, you can also see the distribution lines. We tend to see enhancement develop within the treatment field, and I'm going to kind of go over this a little bit more later, but within that treatment field, we can see some increased enhancement for them first from the infusion itself, which tends to stabilize over a period of time. And in this case, the volume was 3.5 mls. We received -- were able to achieve 99% coverage. The total dose to the tumor was approximately 740 gray. So quite a bit of coverage to the tumor here in terms of dose. This patient remains alive with a survival of 946 days. Next slide. So we have treated 15 patients to date. We haven't seen any significant change in terms of safety signals during the Phase II, continues to be safe and well tolerated. There's no evidence of systemic radiation toxicity, and these patients were able to very closely determine dose to any outside organs because we had whole body planar imaging, and so we can see any radioactive distribution outside of the tumor, including to distant organs, and we don't see any significant signal of radiation activity out -- at external organs. 13 out of 15 patients or about 87% received are cut off our threshold of greater than 100 gray, that we have determined this to be kind of our cut off based on preclinical experiments as well as what we observed in Phase I as it continues enrolling. You can see there on the right, the average absorbed dose in this group of patients was about a little over 300 gray, and we're getting good coverage with about 87% coverage. Now, Important to keep in mind when we say 87% coverage, that means to the 100 gray isodose line that does not mean that areas outside of that are not still also receiving coverage. In terms of the adverse effects, you can see the distribution of them. They're almost all grade 1 with about 1/4 of them being grade 2, very few grade 3, the typical ones that we're seeing are headache and fatigue. This is identical to what we saw in Phase I. So no new safety signals there. Next slide. And then we look at these patients to try and get an idea of how they're doing in terms of survival. You can see their median progression free survival on the left and their overall survival on the right. This is from the Phase I, and you can see that on the right, when we look at the survival by the less than or 100 gray. You see that the patients who had greater than 100 gray had a significantly improved survival compared to the ones with less than 100 gray, the patients who had a greater than 100 gray had a significantly improved overall survival of approximately -- I'm sorry, we're still in progression free survival here, my apologies. So you see the median progression free survival was at 6 months versus the patients less than 100 gray at 2 months. Next slide. Here's the survival one. So all patients on the left here from cohort 1 through cohort 8, so you can see that the median overall survival was approximately 11 months, which is better than what is described for the patient population. Recurrent glioblastoma typically has a survival of around 8 to 9 months. And then the median overall survival, when we look by absorption level less than 100 gray or greater than 100 gray. You can see less of 100 gray there in blue and then greater than 100 gray in red, and we're seeing a median overall survival for those patients who had greater than 100 gray by approximately 17 months. So again, significantly better than you would expect for this patient population where the median overall survival is 8 to 9 months. Next slide. And here's the Phase II data of where we stand. It's still very early. It's important to note that a lot of these patients remain either progression free or alive. And so it's challenging to say what the median actually will be. But this is as censored for that at this time. You can see on the left the progression-free survival, and we are at about 11 months of progression-free survival for these patients and then the overall survival there on the right, again, heavily censored because we have a number of these patients still alive. And it is right now at 13 months. Next slide. And then we try to analyze the images to better predict what's happening and trying to understand where we were doing well or not doing well. And in this case, what we did is we took both the MRI images as well as the SPECT images, which show our radiation activity, and we combine it together into a single analysis. For the SPECT images, which you saw on the top for what I was showing you where you see the color maps, we took those and we extracted from them the areas of interest, which defined a dose of 100 gray or more. And we generate these volume areas and then we extract those and then on the MRI, we take the enhancing area, which we would think could be tumor and we take out those and subtract out from anything that's not enhancing to get a tumor map. And then we're able to look at blood flow to the tumor using something called dynamic susceptibility contrast imaging, or perfusion imaging. And we can look at what is the amount of blood flow to the area there. And we combine this all into 1 statistical analysis. Next slide, please. This is just an example of our treatment maps. So in this case, this is a patient who had very high level of tumor coverage. The area in red indicates everything that -- received a dose of 100 gray or more. So this patient had very good coverage and in fact did very well. So still alive almost 3 years later, as you can see on the left side. Next slide. And when we get over time, what we see is these values on the graph on the left. So to explain this graph, if we see increase in enhancement outside of our treatment area, then the curves go up. If we see increase in enhancement within our treatment area, then the graphs go down. So basically, this is asking the question, where is the increase in enhancement coming from in these patients. Or do you see an increase in enhancement. And so each individual patient is color labeled there and so these are paired tumor volume differences by day of untreated versus treated volumes. And what you see is you have some patients, as you see there at the day 28 time point which have an increase of enhancement within the tumor volume. That's not terribly unexpected, we often call that Pseudoprogression but then that stabilizes because it doesn't continue to go down. As a matter of fact, what you see is that any enhancement that occurs thereafter tends to be really outside of the treatment volume. And so when we ask statistically the question, what we -- the answer is that the untreated tumor volume was significantly increased compared to the treated tumor volume. So we're actually basically able to say statistically that in the area that we treat, we get good control and in the area where we miss, we get less than ideal control. The next slide. So in summary, Rhenium obisbemeda is generally safe and well tolerated with no evidence of systemic radiation toxicity in any treated patient. We're -- we have administered up to 41.5 millicuries and 16.3 milliliters. We're able to -- with better treatment planning and patient selection, we previously deliver drug levels that cover what we're looking for in terms of the 100 gray and other than 70% coverage with 80% of the patients in Phase II that are at or above that target. And likely, we'll be able to continue improving on that. Absorbed doses to the tumor greater than 100 gray and tumor treatment percentage of greater than 70% strongly correlate with increased overall survival and mid trial analysis Phase II data, including feasibility, safety and efficacy is consistent with the Phase I patients receiving greater than 100 gray. Next slide. At this point, I'll turn it back over to Tara and we'll -- I think the plan is to move forward with question and answers here.

Great. Thank you so much, Dr. Brenner. At this time, we'll be conducting a question-and-answer session with our speakers. [Operator Instructions]. So our first question comes from Justin Walsh from JonesTrading.

So maybe just from a broad perspective here for the physicians on, based on the results that we've seen so far, how likely you believe it is that the treatment is providing a clinically meaningful benefit to patients?

I'm happy to handle this, but maybe my colleagues can chime in. I think I think that our imaging analysis, we really have done -- tried to get as much information on these cases as possible to understand what's going on. And I think in a number of different ways that we've looked at it. So we've done modeling where we've asked the statisticians to look at all the different factors from these patients that we've treated so far in terms of their tumor size, the -- their demographics, their age and then the amount of coverage we have, the amount of dose we have, everything. And so in that modeling, 1 thing consistently comes out. Age is an important factor for survival. That's something we've always known. It's not a factor for progression. Tumor volume in our trial is really not -- does not statistically come out as an important factor and tumor size is a known factor. And so something is mitigating that aspect of it. But with the highest statistical degree of certainty, the absorbed dose and the percent coverage repetitively come out as a hazard factor for survival and progression as well. So what that's saying is, is that treatment is impacting survival and progression. So in these patients that have very good coverage, they have a longer survival and the patients who don't have good coverage to have a worse survival. And then on top of that, as I showed you in the imaging data, the imaging also says that if there's going to be some increase, it's going to come outside of the treatment field. And if there's going to be good control it is going to come within the treatment field. So I think I have no problem saying that in those patients who you get good coverage you get good survival, which means that is a -- that means that there is activity of the agent and should translate to clinical benefit. Ultimately, Phase III clinical trials are what's required to say with certainty that you are improving the standard of care for patients. We don't have Phase III data, so we have to lean on what we have. I think saying that this data is supportive that a pivotal trial needs to happen is there, but we have to complete the Phase II. So I don't know if I've answered your question, I think I've answered the best way I can. It's really hard while you're doing clinical trials to make definitive statements, but I think that's as close as I can get.

Great. Yes, that's perfect. So my next question, I'm wondering if you've seen any indications of or concern over dose to the healthy brain in the immediate area around the tumor? I know you've mentioned that the sort of the better tumor coverage you get the -- I guess, the better the outcome for the patient. But of course, it's a beta therapy. So I'm sure that there's at least some concern that you could have damage to surrounding tissue.

I can see Toral nodding her head, yes. So maybe I'll let her answer this in terms of what her experience has been.

Yes, it's an excellent question. And certainly, I have that same concern, our radiation oncologists have that same concern. And we have seen edema irritation of the surrounding brain, and I would expect that -- I think that if you're not seeing that, something's wrong with how the therapeutic is being delivered. In all cases, we've been able to rescue that with a short course of steroids or Avastin. And I think that, that will likely be a part of this treatment for recurrent GBM, if there's been a backbone of radiation previously, which would be the case in basically every patient but there is some inflammatory effects. They have been temporary transient, again, been able to be rescued and treated with medications, but they do require attention.

Great. So my next question here. I'm wondering if you can just remind us and provide some more color on the thinking that went into the selection of the recommended Phase II dose and the continued dose escalation and maybe how your -- the learnings from the Phase II might inform a potential dose and design for a pivotal trial?

I'm happy to start that off, and I'm sure anybody can contribute to this. So 1 thing that we saw was that the area that we were treating was adequately treated. And so we didn't really feel strongly that an increase in the concentration of the drug, in other words, packing more radiation into the same area was really going to push the envelope very much. We had already done increases in concentration. And so what we really were trying to do with the dose escalation was to get better coverage. So we were leaving the concentration static but administering a greater dose in the hopes of getting greater distribution. So giving -- so while the concentration was static, both the amount of dose administered and the volume it is administered in increased. When we got to cohort 6, we're seeing very good results, very good safety. And so the idea was, is that here we have some signs of efficacy. And if we know we're going to go up, we're just going to be covering larger tumors, but this doesn't preclude us from treating tumors that we know we can cover now in the Phase II. And then if we experience any toxicity that would be the dose-limiting, then we would, in subsequent cohorts, higher dose levels, we can always either just not pursue those or if we see larger coverage with higher doses be applicable, we can always add those in later. So given the excellent results through cohort 6, we thought it made sense to go ahead and begin accruing in the Phase II. We did present this to FDA and they did agree with us. But the FDA also did want us to look at higher volumes, higher dose levels and to continue to determine the MTD. So that was kind of the logic there. We could have waited and explore larger volumes and waited and just included all larger volumes in the Phase II. But -- we can all -- they didn't really seem to make a lot of sense since we knew that we had plenty of patients with these size tumors that we could still treat in the Phase II. And then we can always add in larger volumes later if we cleared them in the Phase I.

Got it. Last question for me. Maybe you could just comment and remind us if this treatment was not available, what trajectory would you expect for these patients? And what would their alternative therapies look like?

So does anybody else want to handle it? I don't want to hog all the questions.

Sure. I'll take a stab at that. Can you hear me okay? So in our -- most patients then would be screen for other potential clinical trials that your cancer institution locally may have available for the patients. There's other FDA-approved therapies for recurrences. There's tumor treatment fields with Optune, and there are second-line systemic therapies with bevacizumab and lomustine. But in general, the options are limited, but they would go down additional pathways for those secondary treatment plans.

I'll add a little bit to that. In terms of recurrent GBM, we have a number of challenges. First of all, even the drug that we use most commonly in the salvage setting is Avastin, bevacizumab. And that has not even shown a survival benefit. We mainly use that as a palliative drug. We're trying to delay the onset of symptoms, but we don't make people live longer. We might improve their quality of life initially, right? But even in those patients that have a response, which radiographically they 30% to 40% improve, the duration of that response is only about 4 or 5 months. So whether you use a Avastin or not, the survival in multiple -- multiple, we've done a lot of studies in this setting and none of them have pushed the needle and remains between 8 and 9 months. So we have nothing, 0, zip. As of right now, that improves survival in the second line setting after failure of conventional therapy.

Thanks. Justin, anything else from you? You said that was the last question. So I'm assuming it is and we will leave it at that for Justin. We'll now move to -- we've got a lot of incoming written questions. So thank you for those. And hopefully, we can get to everything. I'm going to start with a question about systemic toxicity. And the question is why haven't we seen any systemic toxicity given these very high levels of radiation? Dr. -- go ahead Dr. Floyd.

Well, any of us can chime in on this one. We know that from our pre-human FDA trial and also from our early experience in our cohort -- in our Phase I trial. When uranium nanoparticles are placed into the tumor, the retention is excellent. It is retained by the tumor. And we can see that over time with our SPECT imaging. And then when it does eventually get cleared from the CNS, it goes through rapidly and cleared through the urine and out of the body. And so through our preclinical and clinical trials, we have studied bone marrow toxicity, we studied liver, thyroid, kidney, bladder, all potential systemic toxicities. And there's just is a negligible amount of radiation that ever reaches in the other end or organ. I don't know if you wanted to add on to that, Dr. Brenner or Dr. Patel, but it's cleared pretty quickly.

Yes, I can say I totally agree with what Dr. Floyd said, that the main thing is that whatever is not retained rapidly clears out mainly through the urine. So there's not really anything left outside of what's trapped in the tumor in the brain to really cause any toxicity.

Great. All right, I think that covers that one. Next question gets to the PFS that you observed, the new data showing from this Phase II, a progression-free survival of 11 months and compared to the published overall survival in all previous studies that you kind of alluded to around 8 months, that looks really encouraging. The question is more how likely is that to hold up in a larger Phase III? Or is there something specific about your center that's driving that improved progression survival than what might be expected?

It's an excellent question. The real trick here is to, I think, make sure that what you're doing is easily transferable to other institutions. If it's a matter of just institutional expertise only, that is able to achieve this, then it's just not to be good for anybody. But I think Dr. Patel did a great job, so did Dr. Floyd, of kind of how we do it. And how we do it isn't some mystery voodoo magic. I mean it's really based in science and development of techniques that have really impacted the field. Having a local therapy that is highly efficacious, is only as good as being able to place it. And so we're continuing to work on that to make it as easy as possible. There's a number of different things that we are doing to do that. Number one, as we mentioned, the imaging that we're doing, we're going to try and make that available to the investigators early on so they can see how we did. And then there is the potential of going back. And if we have a case where we don't get good coverage about putting another catheter in there and treating an area that we missed. So this is going to be in development. I mean, there's absolutely -- there's never guarantees when you're doing clinical development. But certainly, we have to do everything we can to make this as easy as possible to expand to other institutions. So far, I don't see any major impediments in that. It seems to be, as Dr. Patel and Dr. Floyd both, I think, well, stated. I think it's really the techniques are within the capacity of most academic centers in the U.S.

I think that it's a good transition to the next question. And you kind of already answered it, but maybe have Dr. Floyd and Patel chime in, and that is the procedure seems simple from what you've presented, but how specialized is the convection-enhanced delivery procedure and how much learning would be required if the product were eventually approved and available more broadly in the U.S.?

Yes, it's a great question. It speaks to how generalizable this surgical technique is. I think that any neurosurgeon that knows how to do a stereotactic biopsy can put in 1 of these catheters. And that's certainly bread and butter neurosurgery and part of everybody's neurosurgical training. So there is a little bit of fiddle factor to understand how to put the bolt in the first time. But after you've done it 2, 3, 4 times, it's pretty straightforward.

Dr. Floyd, anything to add to that?

I agree with Dr. Patel. Our goal through the early Phase I trial was to not do -- get away from anything that was institutional, special. That we can only do at this institution and we're doing it here to make it work. Anything that we had started utilizing early in the trial, we got away from to more standardized neurosurgical technique, with being intentional about it, about being able to generalize this procedure across the country. And so I agree with Dr. Patel. It's -- the learning curve is relatively fast for this procedure.

Thanks. Next question has to do with the dose that's being used in Phase II. So I know you're using 22 millicuries in Phase II but if you still haven't found any MTD from Phase I, might it still be possible to go even higher in dose and any evidence from cohort 7 and 8 that you're getting any better coverage or efficacy yet?

Yes, I can start and others can chime in. So the specific intent of continuing dose escalation was to see if those could be added to the Phase II. So yes, there's the possibility that we could use higher doses to treat larger tumors, really, that's the goal to expand the number of patients that can benefit from this. But we still have to process that data. And I really don't want to comment on it because we're still gathering all the toxicity data and everything, and that really requires a formal analysis for us to comment on that. But yes, it's possible. And if cohort 8 doesn't work, but we go back and we see cohort 7 looks really good. We can always expand cohort 7 and say, "No, we're not going to do cohorts 8 dose we're going to do cohort 7 dose," for example. So yes, is the summary.

There's another question having to do with the population size of patients with recurrent GBM, and what percent of those patients are represented by these tumor sizes of 20 ccs or less in the Phase II? So 50%, 80%?

I can take a stab at this, and please, any of my colleagues jump in. We're looking at screening for our convection therapy trial there -- not all patients would be eligible for convection therapy. So it may depend on the overall shape of the recurrence and even to an extent the location of the recurrence, if it's progressing in an area that's what we call deep gray matter or portions of the brain that may not tolerate intervention or if it's potentially co-located around a large resection cavity or CSF space. So there are some constraints and it's -- there are patients who may not necessarily qualify, who go on to other therapies. But to have a stat number of patients who do go on, it's hard to answer that question. I don't have a percentage there. Dr. Patel do you have a feeling on that?

Yes. I think that is hard to quantify. I think if you're imaging often enough, every patient at some point will have a less than 20 cc recurrence before they have a greater than 20 cc recurrence. And so you could capture them all. But many times you -- in your q2-month surveillance imaging, you may not capture that interval. But if you were really aggressive about screening for trials like this, and you could image more often and find more patients. But I think that the bigger issue is not going to be volume but going to be 1 of size, shape and location of the recurrence next to [ cellside ] ventricles and big CSF spaces, are these physically appropriate lesions for convection.

All right. Next question is, I see you're getting almost 90% of patients treated at your target dose of greater than 70% and over 100 gray. That's much better than in the Phase I, right? So is that a function of just a higher administered volume and dose? Or is it more of improved technique and learning? Similar to the question we asked earlier.

I can comment a little bit about that. So first of all, when we started with this study, we didn't know our volume of distribution. We were working on a number of different things, convection rate, how fast we were administering it, and could we get better coverage, the number of catheters were -- we were using. Working with both bevacizumab-naive and treated patients, which we learned later that affected the flow. There were a lot of different things we were learning about the drug itself in terms of administering it. So there was a learning curve, right? We started off never having given this to a human before, not knowing if we gave 1 ml, would it go to 1 ml, would it go to 3 ml, would it go to 5 ml? What shape would the convection look like. Lots of different things here. How close can we get to the ventricle, how far, cases of leakage, things like that, okay? So once you know those things, then you can do a better job going forward. So that's number one. The other thing is, we also learned how much we could cover. So when we say tumors less than 20 milliliters for Phase II, the reason is because we know we can get an approximately 30-ml convection volume. So that means that when you do that, as long as you place the catheters in the right spot, that you should be able to cover a tumor. So I think it's really those factors that went into it. And Dr. Patel and Floyd were there so they can comment further, I believe.

No, I agree completely with what you said.

Next one is an interesting question. A little bit of a different topic. And would this be useful for brain metastases maybe after patients have failed stereotactic radiosurgery or SRS? And are there any clinical trials being contemplated in this setting? Anything new coming out of the SNO Conference on this front?

That's a great question. One of our peers who's a leader in exactly that in terms of radiosurgery, actually, was at our investigators meeting and made the point like, "Why aren't you going after brain metastases after SRS?" And so yes, there's been some contemplation in that regard. So we are contemplating that, but there is no formal study planned right now. But I certainly see that, that could be a patient population that could benefit. If SRS isn't working and they have recurrence at the same site, you have limited things that you can do. You can go back and re-resect, you can go back and re-radiate but when you re-radiate there's a high chance for necrosis, symptomatic necrosis. So this might do a lot better than that.

Anything else on that? If not, this one looks like it's for Dr. Brenner asking to elaborate more on what was meant by pseudoprogression that you mentioned in prepared remarks and how obisbemeda plays into that?

Yes. So this is something that we've been working or trying to understand the concept of pseudoprogression for almost 2 decades now. So when you give radiation, you can have patients that have an increase in enhancement. And it's sometimes indistinguishable from the tumor itself. When we did studies with temozolomide, the alkylator that we currently use, we saw that actually increase. And those patients who had this increased enhancement that can look like the tumor growing. They actually do better overall than their peers. So what happens is they get increased enhancement, but then it doesn't go anywhere. It just stays there and then it starts to get better or gets no worse. And those patients they tend to exhibit better outcomes than their peers. So it's been a real challenge over the years to define that. What is pseudoprogression? What is truly cancer growth? And what is the effects of radiation or immunotherapy or numerous other things that can make things look worse when in actuality what you're looking at isn't necessarily a tumor. So we try and do a lot of different techniques to do that. We use -- I showed you perfusion as an example or the blood volume there. If something is dead, it shouldn't need blood vessel supply, right? Whereas if it's actively growing, it should have a blood vessel supply. So looking at perfusion is 1 way of doing it. There's another other things like using PET agents like radioactive amino acids, and then we have something called delayed contrast, where we play -- where we go back and do the scan about 1.5 hours after the initial contrast was administered. And in that case, dead tissue tends to hold on to the contrast whereas live tissue because of the blood vessels, it just speeds right through. So we're trying to do a good job of assessing for that. There we did see, as you saw there, in the first -- at day 28 that within the treatment field, we did see increased enhancement, but it doesn't tend to go anywhere, okay? So it all stays within that treatment field, and then it just kind of either stabilizes or improves. So there is evidence that we're seeing some pseudoprogression or treatment effect within the treatment field, which is important to distinguish from tumor growth and sometimes challenging to do so.

Next question, what is the reliability and reproducibility of the procedure, i.e., radiation delivery, speak to things like case planning, catheter placement, drug delivery technique, et cetera? Who wants to tackle that one?

Dr. Patel, you want to...

Yes. I think I can maybe speak to that as I started the trial at UT Southwestern but was not the home site and so I can speak to some of the changes or differences that might exist from being at the parent site to a satellite location. The first treatment or to Dr. Floyd, came down or came up to Dallas, and was in the OR to sort of offer some in-person guidance. I think that, that would be critical to most sites starting up similar to other surgical technologies that are new in the OR. Dr. Brenner and I always have a short call before the cases to discuss catheter plans, and what we think the volume of coverage will be, what good trajectories are, and pick that together. And I think that, that kind of workflow is essential to get a high-quality treatment. I think the -- not putting that 10 or 15 minutes of effort in, which is not a lot, but is something could result in a lack of reproducibility. But I think it doesn't require more than that. And so each time you do a treatment, you need to plan it like any other surgical case. And in the first couple of cases, you may need a surgeon who has previously put in these bolts to come teach you the small nuances of how not cross thread something or small things that make a difference. But every time you should be working with the oncologist on catheter plans and making sure that we're getting adequate volume. And that takes on the order of 10 to 15 minutes per case.

Okay. Next question. There's a couple of questions just about heterogeneity in the general population for rGBM. And how heterogene -- other than tumor size, are there other factors that play into how you may be able to predict a priority, which types of patients may respond better to obisbemeda within the recurrent population? Dr. Brenner?

So the question is, can we, within the GBM population, try and decide who's going to be -- who's going to be able to do well and who's not, I guess.

Yes. And [ we need response ] for this drug, right. Not just overall.

Yes. So you know what, that's really difficult to say. I think, really, where this goes, this works. I don't think any of us really doubt that. I don't think that whether you're MGMT methylated or IDH mutated or anything else like that really makes a huge difference. I think really, it's the anatomical features of the tumor more than it is actually the molecular features, right? And so specifically as it relates to this drug, I don't think there's a lot. Now we are investigating though as we capture that data, and we are always looking at it. As a matter of fact, in the leptomeningeal studies, we're actually capturing the cells after treatment, and we're actually performing RNA sequencing on those cells to look and see what is happening biologically in these cells that are exposed to Rhenium obisbemeda. But as of now, I don't think we have any specific features or anything. I think it's all anatomic honestly.

Okay. Last question that I can see here comes from Sean Lee of H.C. Wainwright. What are some of the challenges preventing this treatment from reaching an even higher tumor coverage in all the patients, would centralized planning of the catheter placements help? That was kind of already addressed, but Dr. Floyd, do you want to elaborate on that one?

Sure. Well, we do have centralized planning, and it's a collaborative effort with our whole team with Dr. Brenner and myself, Dr. Patel and through a centralized planning software. So that's -- we are doing that. I think I think that the, again, the limitations really would be the anatomical structure of the tumor, the shape, the irregularity. There is a limit on how many catheters we should be -- we put in. We talked about to some degree by placing multiple catheters. If you have 3 to 4 catheters and we're more likely to be able to cover a larger area better. And should 1 catheter fail for 1 reason or another, we have a backup catheters. So we believe that having additional catheters has helped better coverage. But there still will be constraints of -- if it's very irregular shaped and being able to cover that full volume to 100 gray. And that's something that we are looking at. And with our planning software, we do have some simulation, where we can run some simulations on the software and we can change the catheter trajectory to optimize coverage. And I think that's very helpful to take the time to run those simulations and maybe try -- we try 2 or 3 different placements and 2 or 3 different versions of catheter placement to get the best possible coverage in utilizing our simulation software before surgery. I don't know if anybody else wants to add into that, too.

Anyone else? Anything to add? All right, I'll ask 1 more question and then turn it back to Marc for some closing remarks, and this is probably best addressed by Dr. Brenner because it asks about the overall survival that you showed here and was presented at SNO. Can you just confirm how the median OS was calculated for these 15 patients, it seems to exceed the length of time for the -- that the trial has been in progress. And I think you alluded to that there are a number of patients still alive and you're using censoring, but any comments on to the Kaplan-Meier curve and how it was calculated and where it's likely to go as more time progresses?

Yes. So for the Phase II, we did include cohort 6 Phase I patients, okay? Because they are being treated at exactly the same dose and everything is the same between the cohort 6 patients and the expanded -- the addition of the additional patients that accrued on Phase II. So you will see a range that is significantly longer because it includes the cohort 6 patients. So that partially answers it. But yes, there is a lot of censoring there and it's standard Kaplan-Meier methods. And so I cannot -- I don't think there's any really fancy about the way we're doing it with standard Kaplan-Meier methods and logrank for statistical significance.

Okay. Great. Those are all the written and other questions we have coming in right now. So thanks, everybody, for asking those. We'll be available for follow-up. On behalf of LifeSci, I'd like to thank our 3 KOLs, but turn it over to Marc for some more closing remarks.

Yes. What a great panel. Thanks, you guys. Dr. Floyd, Dr. Patel and Dr. Brenner. Thank you for being here, but also I say it with a very big smile. I know how much work you guys have put in this program kind of behind the scenes. Going back many years in some cases. So it is really excited to see the safety and feasibility and potential efficacy here with this. And I ran in a -- I ran in a 5k with 1 of Dr. Patel's patients a few months back. And that was sort of transformative not only just to be out there with them, but kind of -- he walked through kind of how the procedure was from a patient perspective. So we're super excited and we thank you guys and you represent your staffs that have done so much work in the nuclear medicine suite and in the OR and in the clinic. And we're really thankful for them and thankful for the patients that trust us implementing these kind of very innovative therapies. So thanks, you guys, very much, and thanks to you that are on the call that asked the questions and are listening. We really appreciate that. Thanks so much. That's all I had to say, Corey.