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spk02: fourth quarter and full year 2023 results conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during a session, you will need to press star 1-1 on your telephone. You then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. Please be advised that today's conference is being recorded. 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 Plus Therapeutics' annual report on Form 10-K and quarterly reports on Form 10-Q, followed with the Securities and Exchange Commission from time to time. Plus Therapeutics advises you to review these risk factors in considering such statements. Plus Therapeutics assumes no responsibility to update or revise any forward-looking statements, reflect events, trends, or circumstances after the date they are made. It is now my pleasure to turn the floor over to Dr. Mark Hedrick, Plus Therapeutics President and Chief Executive Officer. Sir, you may begin.
spk01: Thank you, Victor. Good afternoon, everyone, and thank you once again for taking the time to join us today as we provide an overview of recent business highlights and discuss our 2023 full-year financial results. And right up front, apologies for the hoarseness in my voice as I come back from the flu. Joining me for the call today are Mr. Andrew Sims, our Chief Financial Officer, and Dr. Norman LaFrance, our Chief Medical Officer. I'll begin the call this afternoon by reviewing our recent clinical and regulatory progress with a focus on the fourth quarter, and then turn the call over to Andrew to review our financials and Dr. LaFrance, then will be joining us for Q&A. Let me begin with the updates on our two lead CNS cancer programs. I think we're in an enviable position in the development of our rinium-obispamated drug in that with recent progress we have made in LM, This effectively means we have two promising lead clinical programs for LM and recurrent GBM. Our RESPECT-LM Phase 1-2 dose escalation trial of a single administration of rhenium-obispo-meta for LM continues to show positive safety and efficacy signals and is making very good progress. In November 2023, at the Society for Neuro-Oncology meeting, or SNO, we presented results from the RESPECT we showed that 13 patients with LM received a single interventricular dose of rinium obispo-meta between 6.6 escalating up to 44 millicuries through an indwelling Omaya reservoir. No DLTs were observed and the maximum tolerated dose mean, maximum feasible dose was not reached. The majority of adverse events were mild, 64% grade one or moderate 27% grade two and overall critical organ radiation doses were low. Rhenium abysmata circulated throughout the CSF space by one hour following administration and persisted in the CSF for up to seven days, again, with a single administration. CSF administration decreased by up to 91% following Rhenium abysmata treatment, and the mean reduction was 53%. Seven of 13 treated patients remained alive at the time of reporting with a median overall survival of 10 months for patients in the first three cohorts. That's cohorts one through three. Excuse me. Enrollment is on track to finish the phase one single administration dose escalation trial by year end 2024 and also along the way to determine a recommended phase two dose for a single administration phase two, three, This assumes complete enrollment through Cohort 7, and currently we anticipate that Cohort 7 is likely the max dose. Cohort 4, just completed, was the fastest enrollment of all the cohorts to date, and Cohort 5 is now enrolling. I can tell you that from both the neuro-oncology community and at sites, enthusiasm remains very high for this trial, and we have recently onboarded five new clinical trial sites. Later this year, our plan is to meet with the FDA and discuss a potential phase 2, 3 pivotal trial design, assuming the data set remains positive and continues to develop an accelerated development approach, focusing on metastatic breast cancer, for which we have orphan designation. This would be for a single administration of rinium obispo meta. The trial size, endpoints, and other key trial elements will be discussed later on in the year, but we anticipate substantial financial support for this trial through our CPRIID award. In terms of LM data, we anticipate presenting interim safety and feasibility data from the RESPECT-LM trial at the SNO-ASCO CNS Cancer Conference in August of 2024, and likely updating that for the full Phase 1 at the SNO Annual Meeting in November 2024. We are also currently working to expand the LM trial to accommodate multiple doses to maximize disease impact in the long term. As an aside, patients are requesting additional treatments of rinium-obispo-meta following their first administration in our current trial, so we are increasingly treating more patients with additional doses under compassionate use protocol which anecdotally seems to be going well from both a safety perspective and a clinical impact, both of which are being closely followed. We have developed a proposed approach for a multiple-dose expansion and anticipate meeting with the FDA in 2024 with the goal of enrollment beginning for dosing expansion in early 2025, if not before. Now, I've switched gears a bit, but still within the... the LLM discussion, please recall that we acquired rights to a highly specific sensitive cerebrospinal fluid tumor cell testing technology in September of 2023. We remain exceptionally encouraged by this test, but as you may recall, the prior company had very significant financial and operating issues. Our rationale for acquiring this was that because it could, A, double the market size for our LM therapeutic because of its significant diagnostic sensitivity improvement over standard of care, but also it allows for longitudinal disease assessment that is otherwise very difficult or impossible to do with the current standard of care in testing. The update on this test is that we have successfully implemented the test back into our Respect LM trial losing only a few patients in cohort four as of February 2024. The diagnostic work is being conducted in conjunction with our partner, K2 Bio in Houston. The assay uses proprietary technology and a broad panel of 18 monoclonal antibodies, largely geared towards various adenocarcinomas and melanoma. Working with K2, we can perform the test in a cost-effective manner for our trials and leverage existing grant funding for support. We are in the process of assessing whether broadening the test commercially beyond our trials and our current partnership with K2 is indeed viable. But overall, we continue to think this potential exciting new upside opportunity is great for the company. Now, finally, the Respect LM Phase 1 program continues to be funded in part through CPRIT, the state of Texas, through a three-year $17.6 million product development research award. That continues to go very well, and in September, we received a planned $1.9 million payment, followed by a $3.3 million payment this past December as part of the grant contract. To date, we have received approximately $7 million from CPREIT, and we anticipate receiving an additional $6.9 million throughout 2024. And I think Andrew will provide more detail on the CPRIT grant revenue in a moment. Now, an update on our RESPECT-GBM trial of a single dose of rinium-obispumate given via convection-enhanced delivery to patients with recurrent glioblastoma, or GBM. RESPECT-GBM continues to enroll patients, and we are actively adding new clinical trial sites. Until recently, we have been limited in terms of trial sites based on the NCI NIH Grant Funding Award, which has substantially supported this trial through the principal investigator, Dr. Andrew Brenner, and the University of Texas. Going forward in 2024, we will expand trial sites, more efficiently interface with sites, and provide broader and more direct corporate support for the trial. We are incredibly grateful for the five-year support from the NCI, University of Texas, and the trial PI up to this point as we take the ball to move the trial from phase two to a pivotal trial. We anticipate adding a total of five to eight new sites this year, which is currently ongoing, and we think that's going to provide a strong starting basis for a pivotal trial commencing in 2025. The impact of those sites on enrollment will be felt in the latter part of 2024 and we hope to complete Phase II enrollment in late 2024 or early 2025. Last November, we presented initial positive safety and feasibility data from the Phase II Respect DBM trial at the SNO meeting last November. As a reminder, the primary endpoint of that Phase II is to assess overall survival following a single dose of rinium-O-bispumatea in recurrent GBM and compare that to standard of care. In summary, that data showed median overall survival in the 15 patients from the phase two study treated at that time was 13 months, median overall survival 13 months versus approximately eight months for the standard of care. And nine of the 15 patients remained alive at the time of the analysis. Median progression-free survival was 11 months compared to Bevucizumab, which is 3.4 months. Rhenium abysmata continues to demonstrate a very favorable safety profile despite delivering up to 20 times the dose of radiation that is typically delivered by external beam radiation therapy for GBM, and that's typically around 35 gray, and we've gone up to 740 gray. And the mean dose we're giving now is about 300 to 350 gray. In 13 of 15 patients, or 86% of patients have thus far met the empirically derived rhenium-obespa made a dosing target threshold that we've established in Phase 1 and in preclinical studies of greater than 100 gray average absorbed dose to the tumor and greater than 70% tumor coverage. The Phase 2 trial performance in terms of median overall survival will be controlled in the Phase 2 using real-world data generated in conjunction with our partner metadata who has a sizable database in GBM and a history of using that successfully in GBM trials with the FDA. In the phase one with metadata, we conducted two real-world data trials in our GBM, one versus bevucizumab monotherapy and another versus other convection-enhanced delivery trials that were propensity matched to our phase one data. In those two trials, in terms of median overall survival, that was aligned with a recent meta-analysis showing current standard of care in recurrent GBM in terms of median overall survival is approximately eight months. And so currently we view that as an effective clinical hurdle rate, if you will, in a phase two and in a pivotal. So comparing our phase two data as it stands as of November of last year versus real-world data, that's the last time we reported data, A median overall survival, as a reminder, was 13 months, which is 63% better than current standard of care, which is bevusizumab monotherapy, for example, that carries an overall survival of approximately eight months. Also, I'd like to highlight another presentation of our imaging data that was also presented at the same meeting in November by the trial PI. is an important secondary endpoint in the trial supporting the overall survival signal and has until recently been difficult to assess because pseudoprogression has been commonly noted in patients that are receiving such a high dose of radiation, namely 10 to 20 times over EBRT. It was a very technical presentation and can be found on our website, but the bottom line is that using advanced imaging techniques beyond standard MRI and T1, T2-weighted images, using things such as relative cerebral broad volume, treatment response assessment maps, and flipbooks, we can increasingly, if not reliably, delineate pseudoprogression from progression, as well as better understand patterns of recurrence. And we think this is going to help ensure that we are able to more rapidly develop and improve upon this novel new therapy for GBM therapy but also adapted for primary GBM and other brain cancers in children and adults. And related to that point above, I thought it might be useful for me to take a couple of minutes and do a little bit of a forward-looking reframe of this GBM development program that we've been working on and look at it in sort of a unique way based on what we've learned over the last, over three years of development. In my view, what we've developed is not ideal to think about this as sort of a pure play GBM drug therapeutic per se, but rather I think it's more accurate to think about this as a novel targeted radiotherapeutic delivery ecosystem that can overcome not just the limitations of external beam radiation therapy, which is the mainstay of GBM therapy. In other words, we've increased by 10 to 20 times the amount of absorbed radiation dose over EBRT. But when you couple that with the state-of-the-art imaging, the custom treatment planning with specific software that's now available, the neuro-navigational technology and convection-enhanced delivery catheters that are optimized, we can also overcome the limitations of the blood-brain barrier that makes drugging GBM a very challenging matter. and also overcome the limitations of the aggressive local invasiveness that is well known with GBM, which makes complete surgical resection almost impossible. So given the safety margins that we have seen thus far with only a single administration of the radiotherapeutic drug and using the convection delivery modality, we see tremendous opportunity and potential in both improving upon the standard of care and radiation delivery for GBM, which is EBRT in general, but also improve upon current standard approaches for recurrent GBM, such as surgery and chemotherapeutics, and then expanding into other CNS tumor types of the brain parenchyma. And I'm happy to discuss this more in the Q&A session. Now, in terms of data, we anticipate an update at SNOW in November 2024. We also intend to meet with the FDA in 2024, both on the GBM pivotal trial design and to obtain FDA IND approval to begin enrollment of the respect pediatric brain cancer trial for children with high-grade glioma and ependymoma. To meet our clinical goal of being in pivotal trials in 2025 with our rhenium-obespamated drug, we are focused in 2024 to expand our GMP manufacturing relationships, such that we have two fully validated manufacturers that can support primary drug supply, backup drug supply, scale-up activities, and all foreseeable commercial demand forecasts. So, relatedly, we are working to build in redundancy in all supply chain intermediaries, including radioisotope target and radiation services. We think rhenium is an exciting new clinically relevant radioisotope, and interest in that is very high. We are currently on track to meet both of these important drug production supply objectives. In terms of building out the pipeline, we are focusing on two discrete areas. Our new radiotherapeutic, which is rhenium nanoliposome biodegradable alginate microsphere, a long-term, but we call it RNL-BAM, and building on our organizational expertise and success in obtaining non-diluted grant funding. First, as it relates to RNL-BAM, as a reminder, this is a next-generation radioembolic device, as it's now designated by the FDA as of last year, which is designed to treat a variety of solid organ tumors. As the FDA path is now resolved, analyzing key device design attributes that we think will ensure this is an attractive product for both liver cancer and other cancers. And we'll provide more updates as that develops over the year. Second, as to the issue of grants, we currently have over 20 million in active awarded funding for our two lead programs in LM and GBM. In 2024, we filed for, excuse me, in 2023, we filed for approximately 7 million in grant funding and plan to increase that to at least 10 million in 2024. As per our practice, we report on specific grant funding only when awarded. Now, with that update, I'll turn the call over to our CFO, Andrew Sims, who will review the financials. Andrew?
spk03: Thank you, Mark. Good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the fourth quarter and year ended December 31, 2023. As of December 31, 2023, cash and cash equivalents were $8.6 million compared to $18.1 million as of December 31, 2022. We projected to receive an additional $6.9 million in grant funding from CPRED in 2024, with $3.3 million in the first half of 2024 and a balance of $3.6 million by the end of the year. In addition, as Mark mentioned, the company continues to benefit from grant awards of $3 million from the NIH to support the GBM trial through phase two. Based on the cash in hand and committed grant funding, our current balance sheet provides runway into the second half of 2025. The company recognized 4.9 million of grant revenue during the year ended December 31, 2023, compared to 0.2 million in 2022, reflecting the progress made on the LM indication in 2023. We expect grant revenue will continue to increase during 2024 and the remaining term of the CPRIG grant through August 2025. As we plan to expand the LN clinical trial to add clinical sites and enroll additional patients. Total operating expenses for the year ended December 31, 2023, 18.2 million compared to 19.7 million in the same period, 2022. The decrease due to lower professional and legal expenses Other income increased from $147,000 in 2022 to $400,000 in 2023 and fully offset interest expense. As a result of these changes, the net loss decreased by $6.9 million from $20.3 million in the year ended December 31, 2022 to $13.3 million in the year ended December 31, 2023. And now I'll turn it back to you, Mark. Great.
spk01: Thank you, Andrew. Before we move on to Q&A, I'll take a moment to provide guidance on selected key milestones anticipated over the next 12 months. First, safety and efficacy data from the phase one respect LM trial at the SNOW-ASCO CNS meeting in August of 2024 and likely further update at the full-on SNOW meeting in October 2024. We anticipate completing the phase one trial in LM by the end of 2024, and we're on track to develop a phase two, three pivotal trial design for breast cancer patients with LM in conjunction with the FDA. We will also be working with the FDA in 2024 to develop a multiple dosing approach to potentially further extend tumor impact of the rhenium-obispo-meta in leptomeningeal patients. In our GBM program, we intend to expand trial sites, as mentioned, and complete enrollment in the Phase II trial by late 2024 or early 2025, and in parallel, finalize pivotal trial design planning with the FDA. That's partially done at this point. Pending IND clearance from the FDA, we intend to initiate the Phase I pediatric brain cancer trial for pediatric brain cancer patients. And we also plan to bolster our iridium-obesifamate supply chain for commercial readiness in 2024, as well as complete device development optimization milestones for our next generation radioembolic device, RNL-BAM. Now, with those key milestones, I'll turn the call back over to Victor to introduce any questions we might have. Victor?
spk02: Thank you. As a reminder, to ask a question, you will need to press Star 1-1 on your telephone and wait for a name to be announced. To withdraw your question, please press Star 1-1 again. Please stand by. We compile the Q&A roster.
spk13: One moment for our first question. Our first question comes from the line of Justin Walsh from Jones Trading. The line is open.
spk09: Hi. Thanks for taking the questions. You alluded to this, but I was wondering if you could provide some more color on the current availability of rhenium-186 and what it'll take to scale up and meet potential clinical and then commercial demand.
spk01: Hi, Justin. It's Mark. So, if you kind of model out, I think, you know, in the near term, near to intermediate term, 2024, 2025, 2026, being in a pivotal trials and having commercial quality phase three quality drug, we can essentially scale from our current providers. So, you know, we're talking about, you know, maybe somewhere between five to eight doses a week throughout the year that can be further scaled up by adding more days to the week. So what we're really doing is kind of looking at commercial assumptions based on GBM, which is a much smaller indication. As you know, it's about 15,000 patients in the US every year versus LM, which is a much bigger number of patients. So that's going to require, as mentioned, an additional GMP manufacturer. So we'll have at least two GMP manufacturers that can meet the GMP manufacturing goals that we've set for ourselves from a commercial perspective. We're talking about now having five to ten years of GMP supply from a manufacturing perspective. We are also looking at increasing the radiation services provider to a second provider as well. to make sure that radioisotopic services is not limiting in the overall supply chain. It's not limiting now. We have plenty of upside and ability to increase specific activity with our current provider. But kind of looking downstream, three to five years, we'd have to bring on additional radiation services. And then in terms of the other supply intermediates, We really have those pretty well in place. It's really about building up backup supply agreements and then risk mitigation through increasing shelf life and improving inventory.
spk09: Got it. Thanks. One more question for me. You'd mentioned that you're still evaluating the long-term commercial potential of the CN side assay. I was just wondering if you'd share any initial thoughts about potential clinical utility of the assay outside of or in addition to rhenium abyssinata?
spk01: Yeah, thanks, Justin. So, you know, from looking at a few different levels, so first just from our trial, we see a step function improvement in diagnosis and also in disease management potential just in our patients, our small number of trials in our LM trial thus far. So we see it firsthand, the value there. Kind of a second level, when we talk to clinical trial sites, which are the NCCN sites primarily in the U.S., and we talk to those principal investigators that are interested in our trial, this assay was off the market for a few months, there was really a big hole from their perspective in their therapeutic and diagnostic armamentarium not having that test. So we, from their side too, from physicians and centers that weren't even in our trial. And then as we look at the magnitude of the under diagnosis of LM. We think I under LM is probably two to four times under diagnosed based on autopsy studies. We sort of lump all those, all those things together. Um, it impacts us therapeutically by significantly increasing the, the, uh, the size of the market. And I, I know Justin, you know this, but that's, that's a very significant potential, uh, increase in our ability to treat patients and create value for shareholders. And then, um, there's also the opportunity to follow patients. So if you're following patients over months or years, you're improving survival, this assay could be used as a potential surrogate biomarker to determine when it's appropriate to retreat patients. And that sort of further magnifies the commercial opportunity. So even though it's a diagnostic opportunity, it impacts us by expanding the therapeutic market, but also as a standalone opportunity diagnostic opportunity, it's actually very meaningful. We're not interested really long-term in being in the diagnostic business per se, but it's so closely aligned with what we do therapeutically, and it's a very unique opportunity in an unmet medical area that we think it's well worth going for it from a commercial perspective, and that's our goal.
spk09: Great. Thanks for taking the question.
spk00: Thanks, Justin.
spk13: Thank you. One moment for our next question. Our next question comes from Sean Lee from AC Wainwright.
spk02: Your line is open.
spk10: Good afternoon, guys, and thanks for taking my questions. I just have two quick ones. First, for the CNS side, I say, Is it, you mentioned that it's starting to be used starting in the first quarter. So, will we start to see more results based on that from, I guess, cohort four of the LM study?
spk01: Hi, Sean. Yeah, I think, yeah, I want to be clear. So, yeah, the test is actually up and running. We have all 18 monoclonals up and running. We have the microfluidics, the transplants up and running. We missed, more or less, we missed cohort four when the test was unavailable. We're in cohort five, and so you'll start seeing additional data from cohort five on. That's our goal. So absolutely, we're looking forward to having that data again, as are the investigators, quite frankly.
spk10: Great. Thanks for the clarification. And as a follow-up on that, for the potential future pivotal study that's coming next year, do you see CNS side serving as a primary endpoint for that study, or will it be more used alongside more standard measures such as OS and response rate?
spk01: Yeah, good question. I'm going to let Dr. LaFrance take the brunt of that question, but I can... I think most likely this will be used as an exploratory endpoint in our LM pivotal, phase 2, 3 pivotal trial. We just don't have enough data to know how we might incorporate that as a primary endpoint. But, you know, I think long-term it could be in LM. Another reason why we think it's a valuable test for these patients. But, Dr. LaFrance, would you like to talk a little bit about primary endpoint selection in LM?
spk11: Sure, Mark, and thanks. And Sean, great question. And for LM, I think it's important to look at what our options are. So mentioning on the CN side, given the study and where FDA typically feels about surrogate endpoints, probably the most realistic, as Mark mentioned, is a secondary or exploratory endpoint and will be we'll be positioning that and getting some of those data as we progress the current phase one monotherapy. And as Mark mentioned in his remarks, there are several additional LM programs that will be starting later this year or early next year. We would expect all of those to have the see inside assay in some regard as a secondary or exploratory endpoint. Those data will really drive what makes sense in terms of generating the best pivotal database. But I think it's important to underline how the investigators feel about this test. And they've been using it before the prior company's difficulties in a lot of standard of care applications and very successfully. In terms of trial endpoints, although we have reported OS, and of course we know the agency likes an OS primary endpoint, I think we all need to remember LM is a very tragic and difficult to treat complication of a primary tumor. We would anticipate focusing on breast cancer with the leptomeningeal complications. for several reasons. First of all, that's one of the main contributors to a leptomeningeal complication. And as we all know, FDA is very specific on wanting disease-specific indications. And we've already accomplished their preliminary agreement by having orphan drug designation for that indication. In terms of endpoint, OS would certainly be one of the endpoints. I would anticipate that likely to be a secondary endpoint, despite some of our very provocative and promising preliminary information, only because we know that what drives these patients' survival is their primary tumor. In our current database, we have seen that the patients that although have gotten some benefit both some clinical benefit and certainly the benefits of CSF tumor reduction that Mark mentioned in his remarks. The patients that unfortunately have expired have all expired from the primary tumor. So the important thing with this indication will be the control of the leptomeningeal complications so their medical oncologists can focus on the treatment of the primary tumor, giving them more runway for that. All of this needs to be reviewed with FDA, and that's the plan. I'll stop here and see if that satisfied your question, and happy to give you more feedback if you'd like.
spk10: Thank you, Norman. That's very helpful. And my last question is for Andrew. Could you provide us with an overview of how much of the SIPR grants are still left? And what stakes, how much do you expect to recognize over the next year?
spk03: Hey, Sean. Thanks for the question. so at this point we have um an additional fund funding expected from separate of just over 10 million dollars through kind of as allocated from now through um august 2025 which would be the end of the three-year period um so so how that how we expect and how we forecast that to break down is really into three additional payments to be received The first payment should be received late in the first half of this year, and it will be about $3.3 million approximately. We then expect the next incremental advance in separate to be $3.6 million to be received on or about the end of this year. And then the final piece in the balance will be received in probably early to mid-2025.
spk06: Great. Thank you for that. That's all the questions I have.
spk13: Thank you. Thank you. One moment for our next question. Our next question comes from the line of Edward Wu from Ascendant Capital.
spk02: The line is open.
spk08: Congratulations on all the progress. You mentioned that you guys were going to look for $10 million of grant proposals this year on top of $7 million last year. What are you seeing in terms of the landscape for grant opportunities out there? Is the pot getting bigger? Is the pot getting smaller? Is the pot about the same? And what about the competitive landscape competing with other people looking for grants?
spk07: How is that impacting your ability to get these grants?
spk01: Hey, Ed. Thank you. You know, I don't see a big change over the last few years. Grants are hard to get. And, you know, the yield is low, which means you need to put a lot of them out there to get, you know, one or two. So, you know, we are at an advantage, not only because we have unmet medical needs but also we're a Texas-based company, and that opens up what is still the second largest funder of cancer research in the world, which is the state of Texas and CPRIT. And we've had success. In fact, we have one of the biggest CPRIT grants ever given, which is for LM. So I think we have a pretty good, we have a great working relationship with CPRIT. We have a very good understanding of of how to get those grants. We know that there are companies that have up to three of those grants, and we know the process for that. So, you know, I think we'll continue to look not only at the more traditional U.S. governmental grants, but also look at CPRED as well. And development, that non-dilutive funding allows us to, you know, really to manage our our balance sheet in a materially different way than we would otherwise have to. And so it really makes a lot of sense leveraging, you know, very experienced team in terms of getting grants to continue to seek those for the, you know, foreseeable, you know, couple of years or so as we hopefully bridge to approved product and revenue.
spk08: Great. Well, congratulations again, and I wish you guys good luck. Thank you.
spk13: Thank you. Thank you. And now I'll turn it over to Andrew for written-in questions.
spk03: Thanks, Victor. So we have one question, and it's for Dr. LaFrance. What is the status of the pediatric trial, and when do you expect to start treating patients?
spk11: Thanks, Andrew. Great question. As everyone heard, Mark touched on that briefly at the end of his remarks that we, you know, we have been to FDA and we'll be following up with them for submitting the final IND for approval. I would add that FDA has embraced and are very pleased that, you know, with PLUS and are pursuing the pediatric indications for high-grade glioma and ependymoma. So, you know, we have, we already have basically an agreement with FDA for the pediatric protocol. They had some final minor questions, not so much on the pediatric protocol conduct, which like I said, we have their preliminary agreement, but some additional, some GBM data that we've generated in adults around dosimetry, all of which is very straightforward. We committed to get that information back to them as we've enrolled more phase two adult patients. We will be getting that data to FDA in the first half of this year, which we hope means we will be getting and be able to enroll by second half of 2024 our first patients. Importantly, we have our pediatric site, first pediatric site identified, and preparation at that site is well underway, and the principal investigators at that site are already well engaged and partnering with us for that. So PEDS is on track and it's been very well embraced by the agency.
spk04: All right.
spk01: Andrew, any other email questions?
spk04: That is it tonight.
spk01: Okay. Thank you. All right. I want to thank everybody for joining us. Again, thank you to the investigators and patients and employees who work so hard. And we're obviously very excited about where the company is right now. And this is a great road ahead of us in 2024. So we appreciate your time and your interest. And we'll look forward to talking to you next time. Thank you, Victor.
spk02: Thank you. Thank you for your participation in today's conference. This does include the program. You may now disconnect.
spk13: Everyone, have a great day. Thank you.
spk05: Thank you.
spk02: Good afternoon, ladies and gentlemen. Welcome to the Plus Therapeutics fourth quarter and full year 2023 results conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during a session, you will need to press star 11 on your telephone. You then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. 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 Plus Therapeutics' annual report, on Form 10-K and quarterly reports on Form 10-Q, followed with the Securities and Exchange Commission from time to time. PLUS Therapeutics advises you to review these risk factors in considering such statements. PLUS Therapeutics assumes no responsibility to update or revise any forward-looking statements, reflect events, trends, or circumstances after the date they are made. It is now my pleasure to turn the floor over to Dr. Mark Hedrick, Plus Therapeutics President and Chief Executive Officer. Sir, you may begin.
spk01: Thank you, Victor. Good afternoon, everyone, and thank you once again for taking the time to join us today as we provide an overview of recent business highlights and discuss our 2023 full-year financial results. And right up front, apologies for the hoarseness in my voice as I come back from the flu. Joining me for the call today are Mr. Andrew Sims, our Chief Financial Officer, and Dr. Norman LaFrance, our Chief Medical Officer. I'll begin the call this afternoon by reviewing our recent clinical and regulatory progress with a focus on the fourth quarter, and then turn the call over to Andrew to review our financials and Dr. LaFrance, then will be joining us for Q&A. Let me begin with the updates on our two lead CNS cancer programs. I think we're in an enviable position in the development of our rhenium-obispo-meta drug in that with recent progress we have made in LM, this effectively means we have two promising lead clinical programs for LM and recurrent GBM. Our RESPECT-LM Phase 1-2 dose escalation trial of a single administration of rhenium-obispo-meta for LM continues to show positive safety and efficacy signals. and is making very good progress. In November 2023, at the Society for Neuro-Oncology meeting, or SNOW, we presented results from the respect. We showed that 13 patients with LM received a single intraventricular dose of rinium obispo-meta between 6.6, escalating up to 44 millicuries through an indwelling omia reservoir. No DLTs were observed, and the maximum tolerated dose mean, maximum feasible dose was not reached. The majority of adverse events were mild, 64% grade one, or moderate, 27% grade two, and overall critical organ radiation doses were low. Rhenium abyspamate circulated throughout the CSF space by one hour following administration and persisted in the CSF for up to seven days, again, with a single administration. CSI depression decreased by up to 91% following a rinium abysmata treatment, and the mean reduction was 53%. Seven of 13 treated patients remained alive at the time of reporting, with a median overall survival of 10 months for patients in the first three cohorts. That's cohorts one through three. Excuse me. Enrollment is on track to finish the phase one single administration dose escalation trial by year end 2024 and also along the way to determine a recommended phase two dose for a single administration phase two, three trial. This assumes complete enrollment through cohort seven and currently we anticipate that cohort seven is likely the max dose. Cohort four just completed was the fastest enrollment of all the cohorts to date. and cohort five is now enrolling. I can tell you that for both the neuro-oncology community and at sites, enthusiasm remains very high for this trial, and we have recently onboarded five new clinical trial sites. Later this year, our plan is to meet with the FDA and discuss a potential phase two, three pivotal trial design, assuming the data set remains positive and continue the accelerated development approach focusing on metastatic breast cancer for which we have orphan designation. This would be for a single administration of rinium obispo-meta. The trial size, endpoints, and other key trial elements will be discussed later on in the year, but we anticipate substantial financial support for this trial through our CPRIID award. In terms of LM data, we anticipate presenting interim safety and feasibility data from the RESPECT-LM trial at the SNO-ASCO CNS Cancer Conference in August of 2024, and likely updating that for the full Phase 1 at the SNO Annual Meeting in November 2024. We are also currently working to expand the LM trial to accommodate multiple doses to maximize disease impact in the long term. As an aside, patients are requesting additional treatments of rinium-obispo-meta following their first administration in our current trial, so we are increasingly treating more patients with additional doses under compassionate use protocol, which anecdotally seems to be going well from both a safety perspective and a clinical impact, both of which are being closely followed. We have developed a proposed approach for a multiple dose expansion and anticipate meeting with the FDA in 2024 with the goal of enrollment beginning for dosing expansion in early 2025, if not before. Now, to switch gears a bit, but still within the LLM discussion, please recall that we acquired rights to a highly specific sensitive cerebrospinal fluid tumor cell testing technology in September of 2023. We remain exceptionally encouraged by this test, But as you may recall, the prior company had very significant financial and operating issues. Our rationale for acquiring this was that because it could, A, double the market size for our LM therapeutic because of its significant diagnostic sensitivity improvement over standard of care, but also it allows for longitudinal disease assessment that is otherwise very difficult or impossible to do with the current standard of care in testing. The update on this test is that we have successfully implemented the test back into our RESPECT-LM trial, losing only a few patients in cohort four as of February 2024. The diagnostic work is being conducted in conjunction with our partner, K2Bio in Houston. The assay uses proprietary technology and a broad panel of 18 monoclonal antibodies largely geared towards various adenocarcinomas and melanoma. Working with K2, we can perform the test in a cost-effective manner for our trials and leverage existing grant funding for support. We are in the process of assessing whether broadening the test commercially beyond our trials And our current partnership with K2 is indeed viable. But overall, we continue to think this potential exciting new upside opportunity is great for the company. Now, finally, the Respect LM Phase 1 program continues to be funded in part through CPRIT, the state of Texas, through a three-year $17.6 million product development research award. That continues to go very well. And in September, we received a planned $1.9 million payment, followed by a $3.3 million payment this past December as part of the grant contract. To date, we have received approximately $7 million from CPREIT, and we anticipate receiving an additional $6.9 million throughout 2024. And I think Andrew will provide more detail on the CPREIT grant revenue in a moment. Now an update on our RESPECT-GBM trial of a single dose of rinium abyspamida given via convection-enhanced delivery to patients with recurrent glioblastoma, or GBM. RESPECT-GBM continues to enroll patients, and we are actively adding new clinical trial sites. Until recently, we have been limited in terms of trial sites based on the NCI NIH grant funding award, which has substantially supported this trial through the principal investigator, Dr. Andrew Brenner, and the University of Texas. Going forward in 2024, we will expand trial sites, more efficiently interface with sites, and provide broader and more direct corporate support for the trial. We're incredibly grateful for the five-year support from the NCI, University of Texas, and the trial PI up to this point as we take the ball to move the trial from phase two to a pivotal trial. We anticipate adding a total of five to eight new sites this year, which is currently ongoing, and we think that's going to provide a strong starting basis for a pivotal trial commencing in 2025. The impact of those sites on enrollment will be felt in the latter part of 2024, and we hope to complete phase two enrollment in late 2024 or early 2025. Last November, we presented initial positive safety and feasibility data from the Phase II Respect GBM trial at the SNO meeting last November. As a reminder, the primary endpoint of that Phase II is to assess overall survival following a single dose of rinium obispumata in recurrent GBM and compare that to standard of care. In summary, that data showed median overall survival in the 15 patients from the Phase II study treated at that time was 13 months, median overall survival 13 months versus approximately eight months for the standard of care. And nine of the 15 patients remained alive at the time of the analysis. Median progression-free survival was 11 months compared to Bevucizumab, which is 3.4 months. Rhenium abysmata continues to demonstrate a very favorable safety profile despite delivering up to 20 times the dose of radiation that is typically delivered by external beam radiation therapy for GBM, and that's typically around 35 gray, and we've gone up to 740 gray. And the mean dose we're giving now is about 300 to 350 gray. In 13 of 15 patients, or 86% of patients, have thus far met the empirically derived radium ovispamate dosing target threshold that we've established in Phase I and in preclinical studies of greater than 100 gray average absorbed dose to the tumor and greater than 70% tumor coverage. The phase two trial performance in terms of median overall survival will be controlled in the phase two using real-world data generated in conjunction with our partner, Metadata, who has a sizable database in GBM and a history of using that successfully in GBM trials with the FDA. In the phase one with Metadata, we conducted two real-world data trials in our GBM one versus bevucizumab monotherapy and another versus other convection enhanced delivery trials that were propensity matched to our phase one data. In those two trials, in terms of median overall survival, that was aligned with a recent meta-analysis showing current standard of care in recurrent GBM in terms of median overall survival is approximately eight months. And so currently we view that as an effective measure clinical hurdle rate, if you will, in a phase two and in a pivotal. So comparing our phase two data as it stands as of November of last year versus real-world data, that's the last time we reported data, a median overall survival, as a reminder, was 13 months, which is 63% better than current standard of care, which is bevucizumab monotherapy, for example, that carries an overall survival of approximately eight months. Also, I'd like to highlight another presentation of our imaging data that was also presented at the same meeting in November by the trial PI. Imaging is an important secondary endpoint in the trial supporting the overall survival signal and has until recently been difficult to assess because pseudoprogression has been commonly noted in patients that are receiving such a high dose of radiation, namely 10 to 20 times over. It was a very technical presentation and can be found on our website, but the bottom line is that using advanced imaging techniques beyond standard MRI and T1, T2-weighted images, using things such as relative cerebral broad volume, treatment response assessment maps, and flipbooks, we can increasingly, if not reliably, delineate pseudoprogression from progression, as well as better understand patterns of recurrence And we think this is going to help ensure that we are able to more rapidly develop and improve upon this novel new therapy for GBM, but also adapt it for primary GBM and other brain cancers in children and adults. And to get her related to that point above, I thought it might be useful for me to take a couple of minutes and do a little bit of a forward-looking reframe of this GBM development program that we've been working on. and look at it in sort of a unique way based on what we've learned over the last, over three years of development. And in my view, what we've developed is not, it's not ideal to think about this as sort of a pure play GBM drug therapeutic per se, but rather I think it's more accurate to think about this as a novel targeted radiotherapeutic delivery ecosystem that can overcome not just the limitations of of external beam radiation therapy, which is the mainstay of GBM therapy. In other words, we've increased by 10 to 20 times the amount of absorbed radiation dose over EBRT. But when you couple that with the state-of-the-art imaging, the custom treatment planning with specific software that's now available, the neuro-navigational technology and convection-enhanced delivery catheters that are optimized, we can also overcome the limitations of the blood-brain barrier that makes drugging GBM a very challenging matter, and also overcome the limitations of the aggressive local invasiveness that is well known with GBM, which makes complete surgical resection almost impossible. So given the safety margins that we have seen thus far, with only a single administration of the radiotherapeutic drug, And using the convection delivery modality, we see tremendous opportunity and potential in both improving upon the standard of care in radiation delivery for GBM, which is EBRT in general, but also improve upon current standard approaches for recurrent GBM, such as surgery and chemotherapeutics, and then expanding into other CNS tumor types of the brain parenchyma. And I'm happy to discuss this more in the Q&A session. Now, in terms of data, we anticipate an update at Snow in November 2024. We also intend to meet with the FDA in 2024, both on the GBM pivotal trial design and to obtain FDA IND approval to begin enrollment of the respect pediatric brain cancer trial for children with high-grade glioma and ependymoma. To meet our clinical goal of being in pivotal trials in 2025 with our rhenium-obespamated drug, we are focused in 2024 to expand our GMP manufacturing relationships such that we have two fully validated manufacturers that can support primary drug supply, backup drug supply, scale-up activities, and all foreseeable commercial demand forecasts. So relatedly, we are working to build in redundancy in all supply chain intermediaries, including radioisotope target and radiation services. We think rhenium is an exciting new clinically relevant radioisotope, and interest in that is very high. We are currently on track to meet both of these important drug production supply objectives. In terms of building out the pipeline, we are focusing on two discrete areas. our new radiotherapeutic, which is rhenium nanoliposome biodegradable alginate microsphere, a long-term, but we call it RNL-BAM, and building on our organizational expertise and success in obtaining non-diluted grant funding. First, as it relates to RNL-BAM, as a reminder, this is a next-generation radioembolic device, as it's now designated by the FDA as of last year. which is designed to treat a variety of solid organ tumors. As the FDA path is now resolved, analyzing key device design attributes that we think will ensure this is an attractive product for both liver cancer and other cancers, and we'll provide more updates as that develops over the year. Second, as to the issue of grants, we currently have over 20 million in active awarded funding for our two lead programs in LM and GBM. In 2024, we filed for, excuse me, in 2023, we filed for approximately $7 million in grant funding and plan to increase that to at least $10 million in 2024. As per our practice, we report on specific grant funding only when awarded. Now, with that update, I'll turn the call over to our CFO, Andrew Sims, who will review the financials. Andrew?
spk03: Thank you, Mark. Good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the fourth quarter and year ended December 31, 2023. As of December 31, 2023, cash and cash equivalents were $8.6 million compared to $18.1 million as of December 31, 2022. We projected to receive an additional $6.9 million in grant funding from CPREIT in 2024, with $3.3 million in the first half of 2024 and a balance of $3.6 million by the end of the year. In addition, as Mark mentioned, the company continues to benefit from grant awards of $3 million from the NIH to support the GBM trial through phase two. Based on the cash in hand and committed grant funding, our current balance sheet provides runway into the second half of 2025. The company recognized $4.9 million of grant revenue during the year ended December 31, 2023, compared to $0.2 million in 2022, reflecting the progress made on the LM indication in 2023. We expect grant revenue will continue to increase during 2024 and the remaining term of the CPREC grant through August 2025. as we plan to expand the LN clinical trial to add clinical sites and enroll additional patients. Total operating expenses for the year ended December 31, 2023, 18.2 million compared to 19.7 million in the same period, 2022. The decrease due to lower professional and legal expenses. Other income increased from 147,000 in 2022 to 400,000 in 2023, and fully offset interest expense. As a result of these changes, the net loss decreased by 6.9 million from 20.3 million in the year ended December 31, 2022 to 13.3 million in the year ended December 31, 2023. And now I'll turn it back to you, Mark.
spk01: Great. Thank you, Andrew. Before we move on to Q&A, I'll take a moment to provide guidance on selective selected key milestones anticipated over the next 12 months. First, safety and efficacy data from the phase one RESPECT-LM trial at the SNOW-ASCO CNS meeting in August of 2024, and likely further update at the full-on SNOW meeting in October 2024. We anticipate completing the phase one trial in LM by the end of 2024, and we're on track for develop a Phase 2-3 pivotal trial design for breast cancer patients with LM in conjunction with the FDA. We will also be working with the FDA in 2024 to develop a multiple dosing approach to potentially further extend tumor impact of the rhenium-obispo-meta in leptomeningeal patients. In our GBM program, we intend to expand trial sites, as mentioned, and complete enrollment in the Phase 2 trial by late 2024 or early 2025, and in parallel, finalize pivotal trial design planning with the FDA. That's partially done at this point. Pending IND clearance from the FDA, we intend to initiate the phase one pediatric brain cancer trial for pediatric brain cancer patients. And we also plan to bolster our Iridium Obesifumate supply chain for commercial readiness in 2024, as well as complete device development optimization milestones for our next generation radioembolic device, RNL-BAM. Now, with those key milestones, I'll turn the call back over to Victor to introduce any questions we might have. Victor?
spk02: Thank you. As a reminder, to ask a question, you will need to press star 11 on your telephone. and wait for a name to be announced. To withdraw your question, please press star 1-1 again. Please stand by. We compile the Q&A roster.
spk13: One moment for our first question. Our first question comes from the line of Justin Walsh from Jones Trading.
spk02: Your line is open.
spk09: Hi. Thanks for taking the questions. You alluded to this, but I was wondering if you could provide some more color on the current availability of rhenium-186 and what it'll take to scale up and meet potential clinical and then commercial demand.
spk01: Hi, Justin. It's Mark. So if you kind of model out, I think, you know, in the near term, near to intermediate term, 2024, 2025, 2026, being in a pivotal trials and having commercial quality phase three quality drug, we can essentially scale from our current providers. So, you know, we're talking about, you know, maybe somewhere between five to eight doses a week throughout the year that can be further scaled up by adding more days to the week. So what we're really doing is kind of looking at commercial assumptions based on GBM, which is a much smaller indication. As you know, it's about 15,000 patients in the US every year versus LM, which is a much bigger number of patients. So that's going to require, as mentioned, an additional GMP manufacturer. So we'll have at least two GMP manufacturers that can meet the GMP manufacturing goals that we've set for ourselves from a commercial perspective. We're talking about now having five to ten years of GMP supply from a manufacturing perspective. We are also looking at increasing the radiation services provider to a second provider as well. to make sure that radioisotopic services is not limiting in the overall supply chain. It's not limiting now. We have plenty of upside and ability to increase specific activity with our current provider. But kind of looking downstream, three to five years, we'd have to bring on additional radiation services. And then in terms of the other supply intermediates, we really have those pretty well in place. It's really about building up backup supply agreements and then risk mitigation through increasing shelf life and improving inventory.
spk09: Got it. Thanks. One more question for me. You'd mentioned that you're still evaluating the long-term commercial potential of the CN side assay. I was just wondering if you'd share any initial thoughts about potential clinical utility of the assay outside of or in addition to rhenium abyssinata?
spk01: Yeah, thanks, Justin. So, you know, from looking at a few different levels, so first just from our trial, we see a step function improvement in diagnosis and also in disease management potential just in our patients, our small number of trials in our LM trial thus far. So we see it firsthand, the value there. Kind of a second level, when we talk to clinical trial sites, which are the NCCN sites primarily in the US, and we talk to those principal investigators that are interested in our trial, this assay was off the market for a few months, there was really a big hole from their perspective in their therapeutic and diagnostic armamentarium not having that test. So we, from their side too, from physicians and centers that weren't even in our trial. And then as we look at the magnitude of the under-diagnosis of LM. We think LM is probably two to four times under-diagnosed based on autopsy studies. When you sort of lump all those things together, it impacts us therapeutically by significantly increasing the size of the market. And I know, Justin, you know this, but that's a very significant potential increase in our ability to treat patients and create value for shareholders. And then... There's also the opportunity to follow patients. So if you're following patients over months or years, you're improving survival, this assay could be used as a potential surrogate biomarker to determine when it's appropriate to retreat patients. And that sort of further magnifies the commercial opportunity. So even though it's a diagnostic opportunity, it impacts us by expanding the therapeutic market, but also as a standalone opportunity diagnostic opportunity, it's actually very meaningful. We're not interested really long-term in being in the diagnostic business per se, but it's so closely aligned with what we do therapeutically, and it's a very unique opportunity in an unmet medical area that we think it's well worth going for it from a commercial perspective, and that's our goal.
spk09: Great.
spk13: Thanks for taking the question.
spk00: Thanks, Justin.
spk13: Thank you. One moment for our next question. Our next question comes from Sean Lee from HC Wainwright.
spk02: Your line is open.
spk10: Good afternoon, guys, and thanks for taking my questions. I just have two quick ones. First, for the CNS side, I say, Is it, you mentioned that it's starting to be used starting in the first quarter. So, will we start to see more results based on that from, I guess, cohort four of the LM study?
spk01: Hi, Sean. Yeah, I think, yeah, I want to be clear. So, yeah, the test is actually up and running. We have all 18 monoclonals up and running. We have the microfluidics, the transplants up and running. We missed, more or less, we missed cohort four when the test was unavailable. We're in cohort five, and so you'll start seeing additional data from cohort five on. That's our goal. So absolutely, we're looking forward to having that data again, as are the investigators, quite frankly. Great, thanks for the clarification.
spk10: And as a follow-up on that, for the potential future pivotal study that's coming next year, do you see CNS side serving as a primary endpoint for that study, or will it be more used alongside more standard measures such as OS and response rate?
spk01: Yeah, good question. I'm going to let Dr. LaFrance take the brunt of that question, but I can I think most likely this will be used as an exploratory endpoint in our LM pivotal, phase two, three pivotal trial. We just don't have enough data to know how we might incorporate that as a primary endpoint. But I think long-term, it could be in LM. Another reason why we think it's a valuable test for these patients. But Dr. LaFrance, would you like to talk a little bit about primary endpoint selection in LM?
spk11: Sure, Mark, and thanks. And Sean, great question. And for LM, I think it's important to look at what our options are. So mentioning on the CN side, given the study and where FDA typically feels about surrogate endpoints, probably the most realistic, as Mark mentioned, is a secondary or exploratory endpoint and will be we'll be positioning that and getting some of those data as we progress the current phase one monotherapy. And as Mark mentioned in his remarks, there are several additional LLM programs that will be starting later this year or early next year. We would expect all of those to have the see inside assay in some regard as a secondary or exploratory endpoint. Those data will really drive what makes sense in terms of generating the best pivotal database. But I think it's important to underline how the investigators feel about this test. And they've been using it before the current, you know, the prior company's difficulties in a lot of standard of care applications and very successfully. In terms of trial endpoints, although we have reported OS, and of course we know the agency likes an OS primary endpoint, I think we all need to remember LM is a very tragic and difficult to treat complication of a primary tumor. We would anticipate focusing on breast cancer with the leptomeningeal complications. for several reasons. First of all, that's one of the main contributors to a leptomeningeal complication. And as we all know, FDA is very specific on wanting disease-specific indications. And we've already accomplished their preliminary agreement by having orphan drug designation for that indication. In terms of endpoint, OS would certainly be one of the endpoints. I would anticipate that likely to be a secondary endpoint, despite some of our very provocative and promising preliminary information, only because we know that what drives these patients' survival is their primary tumor. In our current database, we have seen that the patients that although have gotten some benefit, both some clinical benefit and certainly the benefits CSF tumor reduction that Mark mentioned in his remarks. The patients that unfortunately have expired have all expired from the primary tumor. So the important thing with this indication will be the control of the leptomeningeal complications so their medical oncologists can focus on the treatment of the primary tumor, giving them more runway for that. All of this needs to be reviewed with FDA, and that's the plan. I'll stop here and see if that satisfied your question, and happy to give you more feedback if you'd like.
spk10: Thank you, Norman. That's very helpful. And my last question is for Andrew. Could you provide us with an overview of how much of the SIPRC grants are still left, and how much do you expect to recognize over the next year?
spk03: Hey, Sean, thanks for the question. So at this point, we have additional funding expected from SIPR of just over $10 million through, kind of as I look at it from now through August 2025, which would be the end of the three-year period. So how we expect and how we forecast that to break down is really into three additional payments to be received. The first payment should be received late in the first half of this year, and it will be about $3.3 million approximately. We then expect the next incremental advance in separate to be $3.6 million to be received on or about the end of this year. And then the final piece in the balance will be received in probably early to mid-2025. Great. Thank you for that.
spk06: That's all the questions I have.
spk13: Thank you. Thank you. One moment for our next question. Our next question comes from the line of Edward Wu from Ascendant Capital.
spk02: The line is open.
spk08: Congratulations on all the progress. You mentioned that you guys were going to look for $10 million of grant proposals this year on top of $7 million last year. What are you seeing in terms of the landscape for grant opportunities out there? Is the pot getting bigger? Is the pot getting smaller? Is the pot about the same? What about the competitive landscape competing with other people looking for grants?
spk07: How is that impacting your ability to get these grants?
spk01: Thank you. You know, I don't see a big change over the last few years. Grants are hard to get, and the yield is low, which means you need to put a lot of them out there to get one or two. So we are at an advantage, not only because we have unmet medical needs, but also we're a Texas-based company, and that opens up what is still the second largest funder of cancer research in the world, which is the state of Texas and CPRIT. And we've had success. In fact, we have one of the biggest CPRIT grants ever given, which is for LM. So I think we have a pretty good, we have a great working relationship with CPRIT. We have a very good understanding of of how to get those grants. We know that there are companies that have up to three of those grants, and we know the process for that. So, you know, I think we'll continue to look not only at the more traditional U.S. governmental grants, but also look at CPRED as well. And development, that non-dilutive funding allows us to, you know, really to manage our our balance sheet in a materially different way than we would otherwise have to. And so it really makes a lot of sense leveraging a very experienced team in terms of getting grants to continue to seek those for the foreseeable couple of years or so as we hopefully bridge to approved product and revenue.
spk08: Great. Well, congratulations again, and I wish you guys good luck. Thank you.
spk13: Thank you. Thank you. And now I'll turn it over to Andrew for written-in questions.
spk03: Thanks, Victor. So we have one question, and it's for Dr. LaFrance. What is the status of the pediatric trial, and when do you expect to start treating patients?
spk11: Thanks, Andrew. Great question. As everyone heard, Mark touched on that briefly at the end of his remarks that we, you know, we have been to FDA and we'll be following up with them for submitting the final IND for approval. I would add that FDA has embraced and are very pleased that, you know, with PLUS and are pursuing the pediatric indications for high-grade glioma and ependymoma. So, you know, we have, we already have basically an agreement with FDA for the pediatric protocol. They had some final minor questions, not so much on the pediatric protocol conduct, which like I said, we have their preliminary agreement, but some additional, some GBM data that we've generated in adults around dosimetry, all of which is very straightforward. We committed to get that information back to them as we've enrolled more phase two adult patients. We will be getting that data to FDA in the first half of this year, which we hope means we will be getting and be able to enroll by second half of 2024 our first patients. Importantly, we have our pediatric site, first pediatric site identified, and preparation at that site is well underway, and the principal investigators at that site are already well engaged and partnering with us for that. So PEDS is on track and it's been very well embraced by the agency.
spk04: All right.
spk01: Andrew, any other email questions?
spk04: That is it tonight. Okay.
spk01: Thank you. All right. I want to thank everybody for joining us. Again, thank you to the investigators and patients and employees who work so hard. And we're obviously very excited about where the company is right now. And this is a great, great road ahead of us in 2024. So we appreciate your time and your interest. And we'll look forward to talking to you next time. Thank you, Victor. Thank you. Thank you for your participation in today's conference.
spk02: This does include the program. You may now disconnect. Everyone, have a great day.
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