PLUS THERAPEUTICS, Inc.

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. PLOS Therapeutics advises you to review these risk factors in considering such statements. PLOS Therapeutics assumes no responsibility to update or revise any forward-looking statements to 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.

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 SNO, we presented results from the respect. We showed that 13 patients with LM received a single interventricular dose of rinium obispumata between 6.6, escalating up to 44 millicuries through an indwelling amaya 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 1, or moderate, 27% grade 2, and overall critical organ radiation doses were low. Rhenium abysmumate 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 decreased by up to 91% following 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 rhenium 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-obespamated 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?

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 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.