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

Good afternoon. My name is Katrina, and I will be your conference operator today. At this time, I would like to welcome everyone to Plus Therapeutics Key Opinion Leader Roundtable on the ReSPECT-GBM Trial Conference Call. [Operator Instructions] Thank you. Before we begin, we want to advise you that over the course of the call and question-and-answer session, forward-looking statements will be made regarding events, trends, business prospects and financial performance, which may affect Plus Therapeutics' future operating results and financial position. All such statements are subject to risks and uncertainties, including the risks and uncertainties described under the Risk Factors section included in the Plus Therapeutics' annual reports on Form 10-K and quarterly reports on Form 10-Q filed with the Securities and Exchange Commission from time to time. Plus Therapeutics advises you to review these risks and factors in considering such statements. Plus Therapeutics assumes no responsibility to update or revise any forward-looking statements to reflect events, trends or circumstances after the date that they are made. It is now my pleasure to turn the floor over to Dr. Marc Hedrick, Plus Therapeutics' President and Chief Executive Officer. Sir, you may begin.

Great. Thank you, Katrina, and thank you, everyone, for joining us. My name is Marc Hedrick. I'm the President and CEO of Plus Therapeutics. And I'm glad to be here in Boston at Day 1 of this 2021 Society for Neuro-Oncology Meeting. And with me to my left is Dr. Andrew Brenner, and on the phone with us from Dallas is Dr. Toral Patel. And I'd like to begin by just giving everyone a little bit of a game plan for what we plan to talk about today. So as you may know, we released data interim update from the Phase I ReSPECT trial. The data was presented in poster form today. And the purpose of the call this evening is to have 2 of the investigators with us to talk a little bit about the data, what it means and potentially next steps for the technology as it relates to the treatment of patients with recurrent glioblastoma. So joining me, as I said, is Dr. Andrew Brenner, who is a neuro-oncologist at the University of Texas Health Science Center at San Antonia; and Dr. Toral Patel, Associate Professor and neurosurgeon and actually my alma mater at University of Texas Southwestern Medical Center in Dallas. So let me just provide you a little bit of overview of the company. Those of you that are familiar with the company know that we're focused on this space called targeted radiotherapeutics, and many of you may have heard me say, I just fell in love with this space. There's so much potential for innovation and clinical advancement in bringing targeted radiotherapeutics to the market. I think this is an incredibly hot and fascinating space to be in. And we can see a little bit later on in terms of the data as to why we think that. Radiation therapy has been around for 100 years. And in fact, about 40% of cancer patients get some sort of radiation therapy. As I have heard Dr. Brenner say, potentially any cancer can be cured if you can get enough radiation to the tumor. And that's where the precision targeted delivery strategies come in. If we can target the radiation to the tumor, we can mitigate the safety concerns and potentially improve outcomes. That's the idea. We're not the only people that think this. If you look at a variety of different market reports, here is one, are predicting very significant year-on-year growth in this market from 2021 to 2027, about 20% annual growth per year. And if you look at the amount of investment and the deals that are going into the targeted radiotherapeutic space, it's really indicative of a renaissance in the radiotherapeutic market. So also if you're familiar with the company, our lead drug is a drug called Rhenium NanoLiposomes or RNL, and we use the 186 radio isotope in the current configuration of the investigational drug. That's a proprietary nanoscale compound. And Dr. Brenner will talk a little bit about the technology because he is one of the ones that brought it from [ recruitment ] into the clinical stage. But currently, we have a disease pipeline that's focused on 3 different indications. Recurrent glioblastoma, which we're going to talk about today. We have approved IND for leptomeningeal disease and a pediatric brain cancer IND that is on the horizon. So what's allowed us to develop this therapy is in part the drug, but it's also the marriage of a number of developments across multiple specialties, including advances in imaging, nuclear medicine, drug formulation and neurosurgery. And we're fortunate to have Dr. Patel who is going to talk a little bit about one of the key advancements, which is convection enhanced delivery, which allows us to precisely place the drug directly in and about the tumor. And Dr. Patel, can I turn it over to you?

Wonderful. Thank you very much. It's an honor to speak to each of you today about something that I'm passionate about, and this is drug delivery improvements for neurosurgical disease. And so specifically today, I'm going to give you an overview on convection enhanced delivery, something that I've been working on for better part of a decade. So what is the problem? Why do we even talk about things like convection enhanced delivery? What does drug delivery to the CNS involve? This schematic briefly highlights the problem in getting therapeutics to the brain. When you try to deliver therapeutic to other parts of the body, you can inject it intravenously and you can get high concentrations of that drug, let's say, to the liver or lungs. And that's wonderful for those disease states. But when you similarly inject the drug intravenously and try to get it into the brain, there are tight junctions that rest between the cells that line blood vessels, and they prevent the drugs from getting into the brain space. And in terms of a broad picture, that's good so that every time a human gets the common cold, they don't end up with meningitis. But when you're trying to treat brain cancer, it's hard to get drugs to pass through the blood vessel. It's hard to get drugs through the blood vessel and into the brain space. And so 2 ways to try to achieve that are getting drugs into the brain through receptor-mediated transcytosis or something called absorptive-mediated transcytosis. But it turns out that both of those processes are relatively inefficient. And so you still don't get high concentrations of drug into the brain. And so convection-enhanced delivery is an idea to bypass the traditional blood-brain barrier that prohibits efficient delivery of intravenous compounds. And the way that convection-enhanced delivery works is that a catheter is placed into the brain directly. And through that catheter, you infuse a therapeutic, and you infuse that therapeutic with a pressure gradient. And so when that therapeutic is into the brain parenchyma, it diffuses and moves via not passive diffusion, but via a chemical engineering principle called bulk flow. And when you infuse things, convect things and use bulk flow properties, then you get an area of distribution that looks square-shaped with high levels of concentration at some distance from the infusion catheter, because again, the molecules are moving via bulk flow as opposed to simple diffusion-mediated transport in which the concentration rapidly falls off as the chemical gradiant is lost. And so this is convection enhanced delivery. Insert a catheter into the brain, deliver a therapeutic via pressure gradient and get a square-shaped distribution over quite a distance. And if you look into the physics of this, the ideal volume of distribution to volume of infusion ratio for something in the brain is approximately 5. And we're getting closer and closer to approaching that with modern techniques. In addition to convection-enhanced delivery of free drug, there's a second advance that's really improved drug delivery via CED, and that's the idea of encapsulating a therapeutic in a nanoparticle. And so if you just have CED of a free drug, you get this very fabulous region of distribution, volume of distribution during the infusion. But at some relatively short time after the infusion is done, that drug will be metabolized and disappear. And so although you get a good distribution upfront, it's not long-lasting. But if you then encapsulate your therapeutic, your free drug into a nanoparticle, something that can protect it from standard degradation pathways, then you can convect those nanoparticles over that same large distance, that same big volume of distribution. And then the nanoparticles will slowly release the therapeutic based on the half-life of the nanoparticle so that you get sustained large-volume drug delivery. And that is a technology that's employed by the Rhenium-186 NanoLiposome. In terms of the history of this technology, 10 years ago, when I was still in training, there is this paper that was published in neuro-oncology, the PRECISE trial, where people did try to convect a therapeutic, a pseudomonas exotoxin that was conjugated to IL-13 into the parenchyma of recurrent glioblastomas. And they did this in an upfront manner versus GLIADEL Wafers, and the trial had parity between the 2 approaches. And so people were a little concerned about CED after this trial. But this trial importantly showed us why CED failed in that design. And it was because the catheters that were used for the PRECISE trial were just simple tubular silastic catheters without any real physical modifications, the same kind of catheters that we use to drain spinal fluid out of the nervous system. And because of that catheter design, there was a lack of targeting of the convection infusate and a lot of backflow up the catheters. And people went back to the lab after this and tried to think about how we could improve catheter design to improve convection-enhanced delivery. And when I was studying this in the lab 10, 12, 15 years ago, we made these catheters ourselves with sort of raw materials, but then Brainlab became a good partner and has created this on a mass scale. And so the Brainlab company has a catheter that is perfect for convection enhanced delivery, and it has a very important feature that you see on this screen, which is a step-down design of the catheter tip. And although that seems like a simple modification, it took many years of research to understand this and that step-down design, where you go from a larger bore catheter to a smaller bore catheter, helps you to improve the convection enhanced delivery by a log fold really compared to what was done in the [ PRECISE trial ]. So you can get very large volumes of distribution without backflow issues. And so this is what something like that might look like. In blue in the solid area is the tumor volume, and you can convect your infusate over something that is a purple volume, and this is 116th of this solid area, and this is 1/8 of that, and this is 1/4 of that. And this sort of follows physical principles. But you can now convect over a very large distance in a very targeted manner with these step-down catheters. And from a practical standpoint, as a neurosurgeon, these catheters need to be implanted stereotactically and precisely so that we are putting them in just the area of interest, the high-risk area in the brain. And Brainlab has also developed a kit that easily allows a neurosurgeon to accomplish this. It's a pretty standard drill kit that you might use for various applications, biopsies, insertion of catheters for draining cerebrospinal fluid. But this drill is quite flexible and so it can also be used to insert these catheters for drug delivery. And so I've used these many times. And for the average neurosurgeon, this would be a very simple procedure to do. And once you drill a hole through a very small minimally invasive incision, you anchor the catheter via skull bolts, and then the patient can comfortably have these catheters in their head and resting in a regular floor bed following the procedure. And then if you look at what the protocol looks like in terms of infusing these particles, and Dr. Brenner will go into this in more detail, there's -- we're now on cohort 7, and each of these cohorts have had an increasing amount of volume infused. And again, we expect an ideal volume of distribution over volume of infusion to approach a ratio of 5. And with these increasing volumes with each subsequent cohort, the radiotherapeutic activity has increased, and all this is pretty doable from a neurosurgical perspective without too much difficulty. And then this is a snapshot of a clinical experience. This is a patient of mine who I enrolled in the trial and outlined in yellow and what shows up as bright white on the MRI images is the recurrent glioblastoma. And then the circles following the yellow outline show you the different dosimetric deliveries of the radiotherapeutic. And so quite a good volume of distribution for the size of the lesion. And this kind of volume of distribution allows you to get very high dose to the enhancing portion of the tumor, but also a relatively therapeutic dose to the at-risk zone, which we define as 2 centimeters from the area of contrast enhancement. Now I'll turn it over to Dr. Brenner.

Great. Dr. Patel, thank you very much. And can you hang with us for another 30 minutes or so for Q&A.

Sure thing.

Great. Thank you. Thank you very much. We really appreciate you being able to join us. And now I'd like to turn it over to Dr. Brenner. We actually put data out, as I mentioned, this morning in poster form. We're very excited about the data. It's very unusual in a Phase I to have over 5 years of data, including the type of overall survival data that we have in this trial. There are some nuances to understand the data. And I'm going to turn it over to Dr. Brenner to let him walk you through the data as it stands now, and then we can answer questions and talk about next steps. Dr. Brenner?

Great. Thanks, Marc. That was a great introduction, Toral, and I appreciate you setting me up perfectly. So when we talk about the therapeutic that we're delivering, it's Rhenium NanoLiposomes, or RNL, RNL-186. And it involves a radiotherapeutic, Rhenium-186, that has a very short path length, but it needs to be held in the tissue. And in order to achieve that, we've developed a method of encapsulation or use BMEDA as a chelator. And BMEDA, once it gets within the liposome, it's really trapped there, so it can't go anywhere. The liposomes themselves are about 100 nanometers, which is 1/100th of a cell diameter. But the particle length is about 2 millimeters. So it can travel about 1,000 cell widths. So it can go pretty good distance from that cell that it gets encapsulated in or trapped in once it's encapsulated. And so we can have basically a system where we have a dual energy emitter. We emit betas, which are cytotoxic; and then gammas, which allow us to see where those particles are located. And it has a very short average path length. While think of it as 1,000 cell width, that seems far from a cell perspective, but it actually allows us a very high degree of precision. So it really stays where we put it. And on top of that, it's a very low dose rate that allows for increased safety for the normal tissues. And then it has a very high radiation density, which ultimately should overwhelm DNA repair mechanisms of the tumor cells. So this highlights again what Dr. Patel was referring to earlier about the need to retain the therapeutic. If you look at the graph on top, you'll see that under the triangles, the red and the green, if you inject BMEDA nonencapsulated Rhenium or the Rhenium directly itself into tissues, it rapidly clears from the tissue. You don't have really anything left by 10 hours. So inadequate timing could really affect the tumor. Once it's encapsulated, however, it's retained very well within tumors, not for hours, but indeed for days. And if you look at the activity over time, it's really a factor not of clearance, but of decay. And on top of that, when you look at the distribution of the therapeutic, if you inject the radiotherapeutic unencapsulated, naked by itself into the tissue, it really doesn't spread very far. But if it's encapsulated because of the larger size of the particle, you get better distribution, more dispersion of those liposomes, so better coverage. And so when we looked at this in animal models, we were actually kind of surprised, and let me explain. We were expecting what you would consider a bimodal survival distribution. We were expecting, when we get very low doses, not to see much improvement. When we get to moderate doses, to see improved survival. When we get the high doses, maybe we'd expect to see some toxicity from those high doses because this is relatively new to us. But we didn't see that at all. Matter of fact, what we saw is, is that no matter how much we gave, when we gave the maximum dose, and we even had animals that had doses up to 1,845 gray, which by comparison is 30-fold what we use in patients when they're newly diagnosed. They tolerated it well without any significant weight loss or neurological deficits. On top of that, when we looked at doses and survival, we saw that once you got above 100 gray, we started to see really good separation in terms of animal survival. And it was independent of which model we looked at, whether U87 model or U251 model, we saw improvement in survival, statistically significant and really limited by the end of the experiment. And when the neuropathologists went back and looked at the brains of the animals that we treated, there was no residual tumor in those animals. And when we looked at it by a number of different techniques, whether we look by MRI, which is what we're showing here in these figures; or by bioluminescence, which is not shown. We saw that the tumor was well eradicated. On the left, you see the control animal where day minus 1, you see the enhancing tumor there in the brain. And by 2 weeks later, it's filled up most of the hemisphere. On the treated animals, day minus 1's equivalent size of tumor, by 14 days post-treatment, not a significant change. By day 70, it has regressed, the tumor is gone. And we saw the same thing with the bioluminescence where the tumor was no longer luminescing and there was a not significant amount of tumor left. So we moved on to do a single-arm prospective Phase I/II study. This is being done through funding through the National Institute of Health, through the National Cancer Institute and done together with our colleagues at UT Health San Antonio as well as Dr. Patel and her team at UT Southwestern; Dr. Weinberg and his team at MD Anderson Cancer Center. And it uses a modified Fibonacci dose escalation scheme, where we're initially doubling the dose and then going by incremental increases thereafter. And the goal is to get to a recommended Phase II dose and then to expand at that recommended Phase II dose with the plan of up to 55 subjects. And the NCI grant [ dose-supported ] all the way through the Phase II study. And this shows the dose escalation scheme. So each cohort is an increase, but it's not always an increase in concentration of drug. We increased the activity, the total amount of radiation we're giving. But for the first 4 cohorts, as you see there, the concentration remains stable. And we increased the volume to get -- to show that as we increase the volume, we get better coverage and more tissue is exposed with safety. And then as we got to cohort 5, we doubled the concentration keeping the volume steady. And we are now in Cohort 7 with a total amount of radioactivity of 31.2 millicuries being administered and a total volume of 12.3 mLs. And something to note there, as you can see, in our most recent cohorts, we're getting very good absorbed doses, with the average absorbed dose in the most recent cohort 6 is 584. And we have a feeling that we're going to be in similar lines with this current cohort. In terms of patient demographics of the 22 patients treated to date, the majority were male. The tumor volume was about 8.3 milliliters. And obviously, it ranged in size, because as we start up with the smaller volumes that we're administering where we use smaller tumors and, as we got to bigger treatment volumes, using larger -- enrolling patients with larger tumors. Patients had an average 1.7 treatments, and 5 of those patients had previously received bevacizumab. The vast majority of these patients were wild type. In other words, those are the ones that tend to do worse, whereas the patients who are mutated tend to do better. The majority, 75%, were unmethylated. Again, those are patients who tend to do worse. The typical is about 50% methylated ,50% unmethylated. Ours was heavily leaning towards unmethylated population. We did have a couple of patients with Grade III, these one in the earlier cohorts, and then we only enrolled glioblastoma for the subsequent cohorts. And in terms of results, I discussed the escalation scheme earlier, and you can see we had 7 cohorts and are up to 31.2 millicuries in a volume of 12.3 milliliters. The maximum rate is now at 20 microliters per minute, and the maximum of catheters we've used is so far 4. So as we've increased the volume, we've also increased our rate, increased the number of catheters, which achieves 2 things. Number one, it increases how quickly we could administer this. We shortened the duration of treatment significantly for patient comfort. And on top of that, we seemed to be getting better delivery with the higher rates [ and more ] catheters. When we look at the average absorbed radiation to the tumor, the AARD, it was 273 gray across all cohorts, and the exposure outside of the brain was really negligible. When you look specifically through the first 4 cohorts, first 12 patients, the AARD was greater than 100 gray in 5 out of 12 patients versus 8 out of 10 patients treated in the most recent cohorts, cohorts 5 through 7. So we have increased our coverage as we've gone up on dose, volume as well as rate and number of catheters. When you look at the tumor coverage or percent tumor volume coverage, TuV, in the treated volume, so that's a ratio of how much of the tumor has been covered, it was 71% across the cohorts. And the 5 out of 22 patients who received prior bevacizumab, the AARD was 149 gray, and the amount of coverage was about 47.9%. And that wasn't great. We have not really been treating patients with bevacizumab resistance based on this because we believe that bevacizumab affects the delivery. And the 17 patients, importantly, that had not received prior bevacizumab, the dose was 302 gray and the percent tumor volume and the treatment volume was about 78%. So very good coverage, very good radiation exposure in those patients that did not receive prior bevacizumab. In terms of safety, just to highlight, of the 22 patients so far, we have not seen any dose-limiting toxicities. There were no adverse events with outcome of death that resulted in discontinuation. The AEs were mild or moderate in most cases, and the highest ones that we saw were fatigued at 50%, some muscular weakness and headaches in 1/3 of patients, and gait disturbance in 1/4 of patients. Most of these were deemed causally unrelated to RNL, except for 1 case of scalp discomfort, which can occur after placing a catheter. And then 1 case of cerebral edema. We did see some Grade 3 AEs of leukocytosis, hyperglycemia, muscle weakness, et cetera, but all were considered unrelated to 186 RNL. We did see serious adverse events in 2 subjects in Cohort 2, 1 subject in Cohort 4 and Cohort 5 and 2 subjects in Cohort 6. We observed no meaningful difference or patterns in the incidence of treatment emergent AEs across the different cohort groups. In terms of efficacy, we are leading what data we can. If you'll remember what we discussed before when I mentioned the animal data, we started seeing improvement in terms of animal survival when we got above 100 gray. But we see an interesting trend here as well. As we get up in the tumor volume that's covered by the treatment volume, when we get best -- better and 70% tumor coverage, we also seem to get better absorbed doses to the tumor, as you would expect. So those -- if you look at the size of the bubbles there, those relate to the patient survival. The patients who have the greatest survival are the ones with the best coverage and best absorbed doses, suggesting if we get good coverage, we can get better survival. And if you look in green, there are a number of these patients that are still alive. And so this data is not mature, but is already trending in the right direction as p of 0.065. So we're getting there, and we still have patients alive. So it will be interesting to see how that finalizes when we complete the Phase I portion of the study. And in terms of overall survival, again, leaning back on what we learned from the animal studies about less than or greater than 100 gray, if you look at all patients, the median survival, we're looking at 231 days. But when you -- and an average of 340 days. But if you look at those patients above 100 gray, we're seeing a median of 330 days and a mean of 450 days, which is encouraging. And to put this in perspective, people ask, well, what is the survival of patients with recurrent glioblastoma? We previously published a meta-analysis as part of another study that we did. And it was routinely around 8 months is the median expected survival for patients with recurrent glioblastoma. And here, we can look at our patients who we consider at subtherapeutic dosing. So if they got less than 100 gray, we consider that to be not sufficient. And you just look at their survival versus the patients where we got what we think to be a therapeutic dose of greater than 100 gray. And on that Kaplan Meier graph, it looks very promising with a highly statistically significant result. We'll need more patients, obviously, to be treated to confirm these results. But for a Phase I trial, this is very encouraging data. And I would like to share with you a couple of examples. This is a Subject 14. And you can see his baseline MRI on the top and his covered tumor coverage at 24 hours at day 5. Again, this goes to what we can achieve with liposomal encapsulation. If you look at 24 hours and day 5, you see excellent retention within tissue. And you look at coverage in the colored circles around the tumor there, you'll see we got very good coverage of this tumor. So the tumor volume was 6.5 mLs, and the coverage was better than 90%. When we got -- I'm sorry, to correct myself, when we achieve good coverage, we see good absorbed doses, and in this case, with greater than 90%. He had an absorbed dose of 419 gray, which is excellent. Now initially, this is something that we've seen with our patients with the RNL, and this is why we really need to use survival as an endpoint. And this is something that's been seen with conventional radiation and was particularly something noted when we started using the typical regiment we use today with temozolomide and radiation is that you can see an initial increase in size. And so if you look at day 28 versus day minus 5 on the same patient, you can see there's an increase in size somewhat, not really significant. But then when you get to day 118, it looks even more. But if you're patient and know what time, if you look at day 362, it decreased again and the edema resolved. And if you consider this patient survival, he remains alive more than 900 days out. Another way of looking at the same patient, and we see again an increase about 4 months out, but by 1 year, it is back down in size. And on the right, we're looking at something called cerebral blood volume. This looks at blood flow through the tumor. This is a common used technique in order to look at true tumor growth versus radiation change. And we do not see an increase in blood vessel supply, suggesting that this is not viable tissue, but rather this is pseudoprogression rather than true tumor progression. Another way of looking at this is volumetric assessment. We have independent volumetric assessment where we're not looking at it as investigators, but we have a separate volumetric assessment where we determine the actual volumes of the tumor in 3 dimension. And what we can see is, is, with this case, again, day 123, you see there's an increase. But over time, when you go out to 1 year and even beyond, looking at 1.5 years now, that the patient's tumor remains stable all the way out to day 487. So pseudoprogression is something we have to keep in mind. But ultimately, we're not treating images, we're treating patients and we want survival. This is another case, Patient 17, and you can see excellent coverage of the MRI above, with the tumor in white. SPECT at 24 hours, again, day 5, not loss of coverage, but a matter of fact, some increase in coverage with additional dispersion over time. Tumor was 18.8 mLs in this case, and tumor coverage was 87%. And the absorbed dose, again, 336 gray, so excellent absorbed doses. So what have we seen in this patient? Well, this is a good example of where you can see not only a loss of tumor, but also a loss of a perfusion associated with it, the enhancement treatment on the top on the MRI with the white representing the tumor. And you see below in the green is the blood vessel supply, and you see that area highly vascularized. And then by day 56, complete loss of perfusion, no blood vessel supply to that area that we treated and the tumor seems to be melting away. So our conclusions. We seem to have a good safety profile, well-tolerated, no dose-limiting toxicity so far in the therapeutic range. And we see some clear biological response and some signals of improved overall survival with -- especially with the therapeutic dose compared to what we see historically. And this is a heavily pretreated recurrent GBM population with what would we consider a negative or adverse attributes, including IDH wild type, MGMT unmethylated. We are not seeing any dosing failures. Single administration achieving up to 20x what would be utilized in the recurrent setting with external beam radiation. And SPECT/CT is able to show us real time of how we are able to deliver it and able to show us how much we are actually absorbing in the tumor. And then we do see tumor pseudoprogression, which is common. That can actually -- that is something that we have to consider as we do the assessment of response. But ultimately, what we're interested in is survival. And we see a statistically significant overall survival benefit in patients who received greater than 100 gray when we compare them to subtherapeutic doses. And in cohorts 5 through 7, we achieved therapeutic doses in 80% of our patients. And many of those patients remain alive and still under follow-up. And I think that's the end of my part. Thank you.

Great. Thank you, Dr. Brenner. I appreciate that. So we've got about 20 or so minutes, and I see there are a number of questions that have been texted in. Thank you, and we'll get to those. But first, let me ask Trina. Are there any call in questions for Dr. Brenner or Dr. Patel? You can ask me, but you should talk to the smart people while they're here. Trina?

[Operator Instructions] And we have our first question coming from the line of Robert LeBoyer with NOBLE Capital Markets.

Well, first, thank you, Dr. Patel and Dr. Brenner, for the presentations that illustrated a lot of the concepts and the data behind the therapy. The question I had was really on the survival and the comparison with what would be expected for these patients. And I understand this is an open-label trial. But just to put the survival data in perspective for these patients -- the number of days for overall and median survival was in the press release. But just to put this in perspective of what would be expected if this -- if they hadn't been given this therapy was one of the things I would hope that you can illustrate. And the other part of that question is that in the prior cohorts, there was a separation between the patients who were treated with bevacizumab and those who weren't, not only with the absorption, which you mentioned, but also with their overall survival. So could you just describe a little bit about the benefit of the therapy compared with what would be expected without it in both cases?

Yes, if Dr. Patel doesn't mind, I'll start off and then I'll shoot it off to her if she wants to elaborate further. So overall survival after failure for upfront therapy has not moved. We had the approval of bevacizumab in about, I think, 2008 or so. It's been a while now. And we continue using it. It received initially an approval that required confirmation, but was never able to be confirmed in terms of the survival benefit. It was given based on response rates, that was the approval. And we've had multiple, multiple studies trying to show that it makes a survival difference, and it doesn't. So theoretically, what you can do is you can take all those studies that we did with Avastin, and you can use those as a comparator. And what we did in our meta-analysis is we combined everything that had been done in terms of Avastin studies. And the median survival was about 8.3 months. So the median survival for a patient who is bevacizumab-naive, who hasn't received bevacizumab, is about 8.3 months. So for those patients that we're comparing to that haven't had bevacizumab, that's the market you really want to see. So ideally, if you get patients beyond the year, that is considered really [ statistically significant ] because they usually make it for about 8 months. For patients that failed bevacizumab, the median survival has been shown to be about 120 days. So they've already chewed up most of those 8 months. And then -- during the bevacizumab and then they have about 3 more months, 4 more months or so, and they don't live beyond that. So that's the historical control, and that's really what we need to be beating. Toral, I don't know if you have any further comments?

No, I agree with all those. That's the data and accurate.

And our next question is from Sean Lee with H.C. Wainwright.

Congratulations, guys, for the great results. My questions are for Dr. Patel. So for a neurosurgeon who has never used CED before, how easy is it for them to learn this procedure and be able to perform them consistently? And then as a follow-up, are there any parameters such as tumor size or tumor location that makes -- do you see would be particularly difficult or impossible?

Yes. Those are great questions. The actual surgical procedure is quite simple. And I would say that the average neurosurgeon who has gone through normal residency training should be able to easily do something like this. It requires the same level of technical skill that you would need to do a stereotactic biopsy, which is a routine neurosurgical procedure; or to place an ICP monitor, which happens all the time at bedside. And so the technical skill set is not extraordinary by any means. The most sort of sophisticated part of the procedure is really the planning. And so we use a software that's integrated in Brainlab to plan out what the expected volume of distribution is per catheter. And so that requires some background knowledge and, in our current workflow, that requires and uses conversations between myself and Dr. Brenner and the other PIs in terms of where do we think we want to focus the infusion and what are particularly high-risk areas in this particular patient's brain. And so that requires some judgment and sophistication, but it's pretty easy to pick up after 1 or 2 cases. And the physical, technical aspects of the surgery are very straightforward. In terms of size constraints and things to avoid, you need to be careful when you're convecting near ventricular surfaces, you need to be careful when you're convecting near cortical surfaces or close to pial surfaces. All of those are higher risk for backflow. But with the stereotactic catheter placement, which is something that they didn't do a good job of necessarily in the original CED trials, you can make some pretty slick trajectories to avoid said issues. And in terms of size, each catheter, if you sort of use the ideal Vd or for Vi of 5, can convect the volume that is directly related to how much infusate you're going to put in, and so you can make models and understand how much your volume of distribution is going to be per catheter and so for a given lesion size, and you would then just do the back calculation about how many catheters you need to implant.

Thank you, Dr. Patel. Sean, anything else?

No, no, I'm good.

[Operator Instructions] Our next question is from Ed Woo with Ascendiant Capital.

Yes. Congratulations on the data. Marc, you've been telling us data that's been pretty positive since the trial has started. Has this really changed your time line and view on how you're going to proceed with the FDA going forward?

Yes, we're very pleased with the data. That's an understatement. So we're going as fast as we can go. And there are a couple of text questions related to when are you going to get the next trial or what are the next steps. So the key gating item is really GMP drug. And we had an 18-month plan when we licensed the drug to begin to make it in GMP fashion and at scale. And we're still on track, knock on wood, have GMP drug available with 6-month stability testing in the mid-2022 time frame. So we're still on track there. So that being the gating item, what do we do in the interim? So our plan is to finish the current cohort. That's -- as I've said before, I think that probably is the last cohort. I'm looking at Dr. Brenner. I think he is shaking. I think he sort of has a sense that we're kind of here near the end. But we'll have to see kind of what the rest of the safety data looks like as we finish this cohort. And then also, we're planning on having 2 FDA meetings, 1 that's going to be CMC-focused and then 1 that's going to be clinically focused. It's very likely -- we'll see very likely -- it's likely that these patients will -- there are 7 still alive. They're going to live for a much longer, I hope, if the trend continues. So the plan will be, in the first part of 2022, we're already planning that to go to the FDA with the current data set and talk to them and discuss next clinical steps with the agency. And so GMP drug at scale, 2 FDA meetings, 1 for CMC, 1 for clinical. And we're going to -- our hope is to move this as carefully, but as fast as we can and hopefully see if we can get this drug approved.

There are no further questions over the phone at this time. Dr. Hedrick, I turn the call back over to you.

Great. Thank you, Trina. I've got a number of questions, and I'll try to sort through those. One is one of our analysts, it's related to the question regarding bevacizumab to both doctors, Brenner and Dr. Patel. Can you talk a little bit about why there's a difference in convection in the bevacizumab patients and whether kind of longer term, that's going to be an impediment to adoption? And how do you see this therapy may be integrating with bevacizumab? Dr. Brenner?

Yes, I'll lead that one off. So there's -- it was a little bit surprising. I think that one thing that is achieved by bevacizumab that is really good at is reversing vessel permeability. So the tissue becomes less swampy, less so -- less [indiscernible] when you use bevacizumab. When you have already, I think, a preloaded tissue, in other words, the tissue already kind of has a little bit of a high interstitial pressure from the leakiness, I think that actually helps the convection to some degree. In other words, you don't have to have this initial volume to kind of saturate the tissue for it to start convecting further. That's my guess. I don't think we completely know, and I'm interesting in Dr. Patel's thoughts as well. But clearly, there were some differences in how they convect. Another reason we really don't want to push forward with bev anymore is because we really see this as treating reasonable-sized tumors when patients are still doing well after having no prior therapy. And bev doesn't do anything for survival. And it just kind of [indiscernible] symptoms by relieving edema, but it doesn't make them live longer. So we're really looking to have this before bevacizumab. And I think that's the consensus really in the community these days is that really we need something better than bevacizumab. And so drug development really should be in advance of bevacizumab, not trying to extend off of bevacizumab because it's really not improving survival. It's really just a treatment to help with morbidity. So I guess those are my thoughts on it. And I'll give it over to Dr. Patel to see with she thinks.

I agree with the comments about the swampiness or lack thereof in the setting of bevacizumab. The initial work on convection enhanced delivery, dating back to the NIH several decades ago, really focused on the poor size of the interstitial space. And so if the poor size is clamped down by therapeutic like bevacizumab, which I do think it creates that, then you don't have sort of looser spaces for the particles to convect through. So I think that's the issue there.

Great. Thank you, Dr. Brenner, Dr. Patel. Another question is what trials are open now and is expanded access available? So the current trial is the ReSPECT-GBM trial, and that's specifically for patients who meet the inclusion-exclusion criteria that can be found at clinicaltrials.gov. We don't have expanded access yet. It's something that we can consider going forward. And kind of related to that question is -- and I'll turn this part of the question over to Drs. Brenner and Patel. What about the opportunity for re-treating these patients? This is a disease that patients succumb from the local spread of the disease, not so much from distant metastases. So local control is critical. Obviously, there's been some patients in the trial that have recurred or perhaps not been ideally treated. Dr. Brenner, what do you think about the opportunity to re-treat these patients?

Yes, I think Dr. Patel can comment on this as well because we've had cases where we get great coverage of everything, but like a little margin. And you're kind of wishing, gosh, we wish you got that better, and that ends up being the area that progresses. We get great control where we deliver it, but there's a little area out there that we kind of miss. And while we might still be improving patient survival, we'd like to get everything. And so you want to go back, but you know you can't under the current protocol. And then there's the other instance where maybe you get a good response at one place and something pops up somewhere else and in a completely untreated area that you didn't expect, and we've seen that happen, too. And then you have the patients that have had a good response, and then they start to progress down the road. And you're like, well, it would be really great -- and they ask, patients ask, can we do this again. And so right now, the answer is no, but we are working on a protocol for re-treatment. And so the hope is, is that we have a patient that if we missed something or they [ degrade ] and they really want to receive it again or if there's a good response in one spot, but there's something else that pops up, that we could go back and potentially treat those other lesions. Again, it shouldn't really interfere with anything in terms of scientific outcomes because we designed the Phase II as a survival study. And so the response won't matter. The survival is what really matters Dr. Patel, I'll refer to you.

Yes. No, I agree with that. The failures that I have seen have been local failures from the margin of really overall well-convected tumor, and then there's 5% of it that had an under-dosing relative to the remainder, and then that represents the site where the disease progresses. And so -- and I have had those patients certainly ask if they could have another round of CED of these nanoparticles and currently not part of the protocol. But I would be interested in that in the future. And from a surgeon's perspective, it would be straightforward to do. That would not be prohibitive at all.

Great. Thank you. Another question from an analyst, given the ability to achieve absorbed doses of 10x or more over EBRT, is there the potential to bring this into first-line therapy standard of care in place of EBRT? I'll let -- Dr. Brenner, I'll let you go first and then Dr. Patel.

Well, this is certainly one of the situations we think of when we think about the unresectable tumor. There's often patients who have a tumor that you just can't reach. And if we have a certain level of precision with this, it would be nice if we could kind of treat that area. You can even potentially go back with an external beam and treat a larger margin around it. We think that the combination of beta and photon, [ might we say ], There is work to do towards that, but certainly, that's something we're interested in. I think in terms of replacing for newly diagnosed external beam radiation, there is really a lot of work we'd have to do before we get there. We're still learning. We're learning very quickly, and this has been great, not just in terms of the therapeutic, but in terms of new data that is kind of revolutionary in terms of nanoparticle distribution by convection enhanced delivery that has not been out there before. So I think we have a lot to do. I think our sets are really on extending survival after initial failure, but those are good questions, things that we are thinking, but we'll have to kind of, I think, put off for now.

Dr. Patel?

I agree with those sentiments. I think that to get the kind of dose painting of the FLAIR abnormality and the margin beyond that, that you currently look for with EBRT with this type of technology is not apples-to-apples. But I do think that this technology has potential for the "unresectable glioma." So butterfly glioma that you might not want to resect or a thalamic lesion, things that people have explored indications for LiT4 most recently, this might be a different option to consider an interesting in a heads-up trial.

Great. Thank you, Dr. Patel. We're sort of right at time there. A handful more questions, but I'll -- we'll just pull one of them. The question is about other indications that we're working on are that are in -- have been recently researched that we're moving forward. I know leptomeningeal carcinoma is one that I mentioned. And I'll -- Dr. Brenner and Dr. Patel, I think, see those patients. So Dr. Brenner then Dr. Patel, just kind of comment on the potential utility for other indications and specifically leptomeningeal metastases.

So we actually have explored preclinically RNL for a number of different indications, including ovarian cancer, breast cancer. Most recently, we went back to leptomeningeal disease. And let me explain the rationale for that. A significant proportion of the patients with metastatic disease, independent of their type of metastatic disease, can develop leptomeningeal disease, which is dissemination of cancer cells within the spinal fluid. Once that happens, survival is really very poor. We have used, in the past, whole brain radiation -- craniospinal radiation. In other words, you're doing the entire brain and spine. That's fallen out of favor and for a good reason. It has a lot of toxicity. The path length of this therapeutic is really just perfect. And what I mean by that is, is toxicity is not so much from radiation. It's not so much to the neurons, which their bodies sit on the surface of the brain, but more so in the white matter, which is deeper. And the cortical thickness is usually around 2 to 3 millimeters. And they are known to have -- the neurons in the cortex have a little bit better tolerance of radiation than other places. So because of the path length of this, just imagine if you just can just push this into the spinal fluid, have it just treat all the spinal fluid and you spare the white matter of the brain, again, this therapeutic window that we've been talking about for glioma would be potentially even more significant for leptomeningeal disease to sterilize the spinal fluid, get rid of the cells out of the spinal fluid and leave the majority of the cord and the majority of the brain unaffected. And so we have done preclinical studies with that. We have presented those at meetings. And we have been able to show a very similar safety profile. We got -- I believe we did up to 1,500 gray more or less and directly into the ventricle of rats with really negligible symptoms. They had a little bit of decreased feeding for 1 week, and then they got [indiscernible] afterwards and went on to be normal. And -- but no toxicity, no neural toxicity that we could see and nothing on pathology. And then we treated those animals that had tumor growing in their spinal fluid space and saw improvements in survival. So I think it has great potential for leptomeningeal disease, which is really just a devastating disease. It makes sense from a scientific perspective that in order to sterilize that spinal fluid, you use a short path length radiotherapeutic like RNL.

I want to just say quickly -- yes, I agree with all of that. I am very excited about this upcoming clinical trial. We have a lot of enthusiasm for it at my institution. The prevalence of leptomeningeal disease that we're seeing in our own program is going up extraordinarily over the last 5 years because of advances in systemic therapy that are allowing cancer patients to live longer. So there's a [ lot more opportunities ] to develop this kind of carcinomatous dissemination in the CSF. And there are no good therapeutics for this really. And so I'm very hopeful for this strategy, and I certainly think it merits investigation.

Great. Thank you, Dr. Patel. So let me just conclude by thanking you, Dr. Patel, for taking the time to be with us. And Dr. Brenner, thank you for being here. Thank you to all of those that have asked questions. And thank you to those that have asked questions that we're unable to get to. Apologies, we weren't able to get to all of those. You're welcome to e-mail me, and we'll try to get those answered. Thank you very much for taking the time, those of you that are listening and haven't asked questions. I hope this has been informative. I always learn something when I listen to 2 smart doctors like Dr. Brenner and Dr. Patel and very appreciative for their time, and thank you. And we'll sign off and talk to you soon. Thank you.

Thank you, presenters. This concludes today's conference call. You may now disconnect.