PLUS THERAPEUTICS, Inc.

Good afternoon, ladies and gentlemen. Welcome to PLUS Therapeutics' second quarter 2024 results conference call. Before we begin, we want to advise you that over the course of the call, including any 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 positions. 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, filed 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 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, Cherie, and good afternoon, everyone. Thank you once again for taking the time to join us today as we provide an overview of of recent business highlights and discuss our second quarter 2024 financial results. Joining me on the call today is Mr. Andrew Sims, our Chief Financial Officer. I'll begin the call by reviewing our recent clinical and corporate progress in the second quarter, then turn the call over to Andrew to review our financials, and then we'll both come back on for Q&A. So let me begin with updates from the 2024 Society for Neuro-Oncology and Combined American Society for Clinical Oncology CNS Metastases Conference, which met last week in Denver. At SNOW-ASCO, PLUS was quite busy. We had four presentations, sponsored a symposium on novel emerging diagnostics and therapeutics for leptomeningeal metastases, and participated in a panel discussion on the opportunity for emerging therapies for brain metastases alongside senior executives from Novartis and Pfizer. Two of our four presentations warrant highlighting on our call this afternoon, and the full data from those presentations and from the symposium will be available soon on our website. First of all, Dr. Andrew Brinner, the Respect LM Trial Principal principal investigator, presented an interim update on the trial through cohort four, and that's N equals 16 patients. This is the most significant update that we provided since the SNOW 2023 presentation. His presentation showed that through cohort four, which is an administered dose of 44 millicuries, rhenium obispumata was safe and well-tolerated with no dose-limiting toxicities and the maximum tolerated dose had not been reached. Furthermore, supporting the relative safety of the drug thus far, the PK data demonstrated a high therapeutic window. Specifically, the mean absorbed radiation dose to the ventricles and cranial subarachnoid space was approximately 160 gray compared to only about one gray to the spleen. a linear increase in absorbed dose to the regions of interest, specifically the craniosubarachnoid space and cerebrospinal fluid, was noted from cohort one to cohort four to increase, but there was no increase noted in the spleen, which was the critical organ. In terms of response data, circulating tumor cell data was not available through cohort temporarily available unavailable at that time, but it's now available, and we are back up and using the test currently in cohort five. But recall that we observed a mean 53% reduction in CTCs, circulating tumor cells, in the CSF for the first three treated cohorts. It was observed out to 28 days post-treatment, but the CTC number came back up by 56 days post-treatment. Additional and significant response data through cohort five is currently being reviewed and will be presented in detail at SNO in November, and I'll talk more about that in a moment. In terms of the median overall survival signal, again, with 16 evaluable patients through cohort four, median overall survival was 12 months, with half the cohorts, that's eight out of the 16 treated patients, remaining alive at the time of analysis. This is an increase from that that was reported after cohort three last November, which showed a median overall survival of 10 months. To put that data in perspective, LM is a devastating disease, I think, as most of you know, from both the morbidity and mortality perspective, with typical survival rates ranging from two to six months after diagnosis, depending on primary tumor type. So this emerging efficacy signal, though early, is very encouraging vis-a-vis the standard of care. There was also a second presentation at Snow ASCO. I'd like to thank Dr. Priya Kumtekar, who reported the top-line clinical results from our 4C trial. 4C evaluated the clinical utility of C-INSIDE, our newly acquired novel CNS diagnostics, on leptomeningeal metastases treatment decision-making by physicians in 40 patients. The trial used a well-described trial design that's used commonly in the diagnostic space. Specifically, she reported that 4C met its primary endpoint with C-inside influencing treatment decisions in over 90% of clinical decisions. That's 50 clinical decision points evaluated. And that substantially exceeded the 20% level, which was the target for the primary endpoint to show effectiveness. Moreover, the study also showed that C-INSIDE helped identify actionable mutations in the CSF, such as HER2 amplification, that influenced 24% of therapeutic selection decisions. That's 14 out of 55 clinical decision points evaluated. Importantly, and related to the current state-of-the-art diagnostically that's found in major hospitals around the country, C-INSIDE demonstrated more than twice the sensitivity in detecting tumor cells in the CSF compared to what is now the gold standard, which is cytology. Specifically, it showed a detection rate of tumor cells of 80% versus 29% for cytology. Also important, C-INSIDE demonstrated exhibited a very high specificity in that no tumor cells were detected in patients without leptomeningeal metastases. We were pleased to see this data and present it formally, and these four C results highlight and validate our previous high conviction that C-INSIDE as a diagnostic and therapeutic selection and diagnostic therapeutic monitoring tool fulfills a critical clinical need in brain metastases that now has been shown to improve patient management and we believe will lead to better patient outcomes in the near future. Finally, in addition to our presentations at SNO-ASCO, we also reported important data at the 2024 Society for Nuclear Medicine and Molecular Imaging, known as SNMI Annual Meeting in June 2024. The reported study used dosimetry data from the RespectLM clinical trial to evaluate the safety and potential for spinal cord toxicity of beta emitters or beta emission radioisotopes in the related physics and found that lower beta energy radionuclides, such as rhenium-186, largely spare the spinal cord versus other beta radionucleotides that we studied. These findings further support the thesis that rinium-186 is an ideal radionuclide for CNS cancers, hitting the therapeutic window, delivering high therapeutic doses to the region of interest while minimizing toxicity. Now, kind of moving on in terms of our leptomeningeal program, broadly speaking. First of all, therapeutically, the current phase one single administration respect LM dose escalation trial We'll continue dosing until the next DSMB meeting, and at that time, we will determine if progressing to cohort six is advisable. But thus far, as mentioned, a maximum tolerated dose has not been reached, despite delivering up to a maximum of 66 millicuries to the CSF. In terms of upcoming data releases, a definitive trial update is planned for Society for Neuro-Oncology 2024 that will be held in Houston this November. To date, we have dosed a total of 25 patients and also treated a subset of patients with multiple doses of rhenium-obispo-meta under compassionate use, and those patients have done really well. Also, the company has filed a new protocol under its open FDA IND to treat individual patients with a multiple dosing regime. This submission follows a positive FDA type C meeting in Q2. Once formally approved with final agreement with the FDA, the company will share the details of that trial protocol. That trial is anticipated to begin enrolling later in 2024 at the current seven trial sites with a number of new sites to be added in the interim. The LeptomNinja program continues to be significantly supported by an approximately $18 million product development award from CPREIT that covers approximately two-thirds of programmatic expenditures. Also, the company continues to be involved in active dialogue with CPREIT regarding program advancement and are actively seeking expanded ways to work with CPREIT that are mutually advantageous. In terms of our diagnostic LM program, we are in the process of expanding our C&Side diagnostic capabilities at our facility in Houston, Texas, in specific, targeted, but strategic ways. First of all, we hired Dr. Greg Fuller, former chief of neuropathology at MD Anderson Cancer Center in Houston, and an LM expert to be the full-time medical director of the C&Side lab and oversee lab operations and also help support our LM therapeutic objectives. We have also improved the lab quality assurance systems and our capabilities to steadily increase testing capabilities as anticipated for growing research use, both from PLUS's growing trial number in LM, but also other trials that have contacted us with similar interest. In addition, we have applied for CLIA certification for a see-inside as a laboratory-developed test, and approval under CLIA is anticipated later in 2024. We anticipate providing further business updates on the see-inside diagnostic program later this year as developments warrant. Now I'd like to shift gears to our RESPECT-CBM trial. As most of you know, this trial evaluates a single dose of rhenium obispumata in patients with recurrent glioblastoma and is funded mostly through the NIH. We continue to enroll both Phase II patients with recurrent GBM, and that's for tumors that are less than or equal to 20 cc's, and also enrolling patients in our Phase I, now at Cohort 8, for patients with larger tumors. We anticipate three new active GBM convection enhanced delivery sites will be enrolling soon, and these should be able to transition to pivotal trial sites when the time warrants. Those are Ohio State University, providing us a site in the upper Midwest, and North Shore Hospital, part of the Northwell Lenox Hill Network in the greater New York region. We are also evaluating other additional sites with the intention of adding at least one site in the greater Southern California region. These sites, specifically OSU and North Shore Hospital Lenox Hill, are on track to enroll patients in 2024. Additional sites beyond those mentioned are also being investigated for activation to support a potential pivotal trial. We are working to complete enrollment by the end of 2024, but more likely to wind up completing enrollment in the first half of 2025. A faster timeline will be influenced to a significant degree by participation of these new sites. Our plan is to provide a substantial update on the phase one and phase two data this fall at the CNS, or Congress for Neurologic Surgeons, annual meeting, which is in late September, early October in Houston, Texas. And this will be our first time to be on the podium presenting this data to the neurosurgical community. In addition, I'd like to briefly update you on our pediatric brain cancer program. We've previously announced that we received a U.S. Department of Defense award for $3 million to substantially support the phase one trial for children with pediatric brain cancer, specifically pediatric high-grade glioma and ependymoma. That award is in an administrative phase and is anticipated to begin funding this September 2024. We are also on track to obtain IND approval for this trial, and Lurie Children's Hospital will be the initial clinical trial site. Finally, we are making good progress behind the scenes on a number of important business items, specifically building in redundancy and commercial readiness in our supply chain and enhancing our drug delivery capabilities, and we plan to make material public updates on those in the near future. And with that, I'll now turn the call over to our Chief Financial Officer, Mr. 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 second quarter ended June 30, 2024. The cash and investments balance was $8.4 million at June 30, 2024, compared to $8.6 million at December 31, 2023. The company recognized $2.9 million in grant revenue in the first half of 2024, compared to $2.3 million in the same period of 23. This represents a separate share of the cost incurred for our rhenium abysmometer development for the treatment of patients with LM. We expect 2024 grant revenue to be in the range of $6 to $7 million. Total operating loss for the first half of 2024 was $7 million, compared to $6.2 million in the same period of 2023. The increase is primarily due to increased spend related to the Respect LM trial. Net loss for the first half of 2024 was $6.2 million or $1.15 per share of $6.3 million or $2.06 per share for the same period the prior year. an update on our runaway in cash position and provide guidance on our grant funding for the remainder of 2024. There are two additional sources of cash to which PLUS has access beyond the balance disclosed in cash on hand and liquid investments on our Q2 2024 balance sheet. First, and as a reminder, we announced in May that we closed a private placement financing of up to $19.25 million from new healthcare-focused institutional investors and company insiders, with a total of $7.25 million received at closing. In addition, there are up to $12 million of cash on exercise of the one- and five-year warrants. As a side note, at June 30, 2024, the warrants issued as part of this private placement were recorded as a liability on the balance sheet, and as outlined in the subsequent events footnote 14, The warrant form was amended, eliminating the liability, and henceforth, these warrants will be accounted for under the equity accounting method. The second source of cash remains our anticipated ongoing funding through now three awarded grants. First, the CPRIG grant to support the Respect LM trial. As reported, we received the first of two expected amounts from CPRIG in 2024, the first in Q2 of $3.3 million. We remain on track to receive the next advance from CPRIID of 3.7 million in mid to late Q4 2024. An additional 3.7 million is expected from CPRIID in 2025. Second, as reported on April 22nd, PLUS has received an award recommendation from the United States Department of Defense for 3 million to support the upcoming RESPECT pediatric brain cancer trial. This funding is expected to commence in September 2024 and materially cover the cost of the planned Phase 1 trial. Funding is received annually in advance and covers a three-year period, i.e. approximately $1 million will be received under this grant in 2024. Third, PLUS also continues to benefit from the NIH grant to support the RESPECT-GBM Phase 1-2 trial. Although expected to be complete in 2024, It currently covers approximately 90% of the overall trial costs. We also continue to source other non-dilutive sources of grant capital and have applied for approximately $13 million in additional grant funding year to date. We will continue to only report on individual grants when they are awarded. In summary, this provides incremental access to cash of $22 million. $10 million from CPRIID and DOD, and $12 million from the exercise of A&B warrants from the May private placement. And now I'll turn it back to you, Mark.

Great. Thanks a lot, Andrew. Before we move to Q&A, just let me take a moment to provide some specific guidance for key events and milestones that we're looking towards through the remainder of 2024. As mentioned during the Congress from Neurological Surgeons, CNS, and that's in late September, early October. Dr. John Floyd, who's the chief of neurosurgery at UTESCA, University of Texas Health Science Center in San Antonio, will be presenting an update on the current GBM phase one and phase two trial and most recent results. At the Society for Neuro-Oncology annual conference, which will be held in Houston, November 22nd through 26th of this year, We'll have three presentations. The first is a substantial update, as I mentioned earlier, on the RESPECT-LM trial. In addition, we have two see-inside diagnostic abstracts. The first is entitled CSF Tumor Cell Detection, Quantification and Biomarker Assessment and How It Helps in the Clinical Management of Breast Cancer and Non-Small Cell Lung Cancer in patients with leptomeningeal disease. The second, which actually deals with a very important emerging issue of genetic drift in LM patients, that is where patients have a certain genetic component to their cancer that flips from their primary tumor to a metastasis, for example, in the CSF. And the title of that is the oncogenic flip in patients with leptomeningeal metastases, specifically the longitudinal detection in cerebral spinal fluid tumor cell counts and what it reveals in terms of implications for the differential treatment of the LND tumor. And so all three of those will be on again for SNOW in the November timeframe this year. We also anticipate FDA approval on the RESPECT-LM phase one multiple dose trial So the IND for the Phase I-II study of rhenium obispumata for pediatric ependymoma in high-grade glioma patients is anticipated also later this year. So with those, Cherie, I'll turn it back over to you, and we can have our Q&A session.

Thank you. To ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, press star 1-1 again. One moment while we compile the Q&A roster. And our first question will come from the line of Justin Walsh with Jones Trading. Your line is open.

Hi, thanks for taking the question. I was wondering if you could provide some more context around the types of treatment decisions that are likely to be informed by CNSide. Obviously, therapy selection is one, but the 24% that informed therapy selection is lower than the 90% total decisions that were impacted.

Yeah, that's a good question, Justin. So one of the key decisions is, A, does the patient have the disease or not? And having a highly sensitive test like the circulating tumor cells, and we showed the comparative data with cytology from the 4C trial, informs whether or not the patient requires treatment for LMD. And there have been a number of reports that we've received where patients have indeterminate clinical signs, indeterminate imaging, or maybe even supportive imaging consistent with LM disease, but their spinal fluid is negative. that's probably the most important decision, quite frankly, do they have the disease or not. And even with the combination of clinical evaluation, MRI, and CTCs in cytology, that can often be a difficult decision to make. And generally what physicians are using now is they look to get two repeat CTC cell determinations and then make the decision if the patient does not have and doesn't require treatment. So that's kind of number one. Number two is an assessment of the genetic drift issue. And we think that goes beyond just the HER2 issue, but into other actionable biomarkers that will dictate whether certain type of drug checkpoint inhibitor might be utilized in one kind of tumor versus the other. And that genetic drift goes both ways. from positive to negative in the leptomeningeal space or the opposite. The other issue is whether it's potentially advantageous to stop treatment. For example, there are some case reports, certainly not significant series, but case reports where therapy can drive the number of circulating tumor cells down to zero. And then one can theoretically stop treatment, monitor patients that are doing well, and then reevaluate based on the ongoing CTC count going forward. So we're just beginning to open the envelope on what the data means, but there are at least, I think, three solid ways where decision-making can be impacted by the clinicians.

Got it, thanks. Quick follow-up. It might be a little early, but I'm curious if you have any expectations with respect to timing once you get into the multi-dose LM portion of the trial.

Timing in terms of when it gets started?

Yeah, and if you think there'll be relatively rapid enrollment or if it'll maybe be along the same pace as the single dose version. Just curious about your thoughts on that.

Yeah, yeah, yeah. So thank you, Justin. So a couple of things. So the IND is open. I think we're optimistic that what we've currently negotiated with FDA will ultimately go through. So we'll hear back in less than 30 days. And assuming that's the case, and in fact, we're already talking to sites and doing the activities you would do for site startup, there'll be a different protocol that's got to go through IRB review and budget and so forth. But because we have an open IND that's very similar, I think it ought to go pretty quickly. Our plan is to go back to the current seven sites that we're working with, where that should also go more quickly. But we've also got a number of of leading sites that want to participate. So that'll be an important part of the plan. So I think, as mentioned, we'll get the trial up and running later this year. Some sites will be before other sites, obviously. So that's number one. In terms of how long it'll take to enroll, the phase one single administration was plagued by a couple of things. Number one, it had a part A and a part B. The FDA was very... the amounts in terms of the administered dose of radiation that we were giving and wanted a formal stopping point. And we had to go back, as you'll recall, to move forward to the second half of that trial, which we're now in. Plus, we had intra-cohort DSMB decisions that we could roll very quickly, but then we had to wait for 90 days from the first patient and 30 days from the last patient before we go back to DSMB. So bottom line is, I think we'll be getting data a lot more quickly from this. What's currently contemplated is we're dialing in multiple doses for these patients without going back to the FDA. So I think the data will accumulate quickly. both in terms of number of patients and longitudinal data on a variety of endpoints within four individuals. My preference is to wait until once we have the final feedback from the FDA, which we anticipate shortly, and then we'll make all that public and then put out some guidance about timing.

Great. Thanks for taking the question.

Thanks, Justin.

Thank you. One moment for our next question. And that will come from the line of Sean Lee with HC Wainwright. Your line is open.

Good afternoon, guys, and congrats on the clinical progress this quarter. My first question is on the CS side, I say. So my understanding is that, correct me if I'm wrong, but all the tech transfer has been completed and you're now just setting up the has to be manufactured and marketed. So I was wondering, what are the next steps that you have to do before you can start selling the tests to the market or at least to the clinical sites?

Hey, Sean. Thanks for the question. Yeah, let me kind of review where we are and the plan going forward. So what we've done is we've... We've acquired all the IP, hard assets, know-how, SOPs, and technology-related information plus customer information. Remember, this test was commercial for a couple of years and was growing at about a 30% year-over-year rate with about 200 individual customers at the time the test became unavailable prior to our acquiring it. We transferred the technology, I think, back in Q1 of this year, got the test up and running, re-implemented it in our cohort five, as mentioned, and we're now performing the test within our trial. In the background, what we've done is we've hired a medical director. We are actually manufacturing ourselves some of the chips that the test has done on, the microfluidic chips, we're now manufacturing those. Those were a gating item in terms of expanding the testing. We're now manufacturing those. So those are no longer a critical supply element. And so now it's really... scaling the test. Now we can scale the test effectively for our multiple dose trial. We're going to be testing many more tests on patients longitudinally because they're getting multiple doses and that's going to require a pretty significant ramp up in testing throughput. And so now we're kind of positioned well to accommodate that from a QA perspective. And as I mentioned, Dr. Fuller's on board, will be the medical director. So in the background, we are doing a significant amount of commercial evaluation to determine what the magnitude of the commercial opportunity for this test and then what's the required investment. That analysis is going well. Thus far, it looks very positive. But I think before we kind of commit, we want to have a full and well thought through plan and be ready to execute on that before we say too much more. But I will say that's going well, and we'll be talking about that relatively soon as we finalize that plan.

Great. Thanks for that. My second question is on the LM studies. Now that you have a multi-dose study in the works, does it still make much sense to continue the single-dose study, especially to a higher dose cohort, or would you be switching your focus mainly to the multi-dose study going forward?

It's a really good question, and here's how I would respond to that. The FDA, both in our GBM trial and related to this LM trial, they're very interested to getting to a maximum tolerated dose. They've made that very clear. So I think we're committed to understand where the level of toxicity lies. And I think we're close, quite honestly. I think kind of what we see from the safety signals in cohort five kind of lead us to believe that we're probably pretty close, if not there, but close. As I mentioned, we have not officially reached an MTD at this point, but we'll continue that until we get to the formal stopping point or we get to a maximal feasible dose. We're not there yet. Secondly, I think we think long-term, based on what we see in the single administration trial and specifically that small group of patients that have had multiple doses, they're doing quite well. we believe we can get with this disease, but it likely will require multiple doses. So we wanted to get that multiple-dose trial going quickly at our cohort two dose, and that data thus far from a single administration perspective has looked very promising, and you've seen that data, and we've now presented that multiple times. So that's up and running. So the next step really, I know it's a long answer, but look at the phase one data, understand it, look at the response data, discuss with FDA, get the multiple dose study up and running, and then we'll make a decision about whether or not we want to take a single administration dose into a phase two, three pivotal, as envisioned in our CPRIG grant, for example. That was the initial clinical plan. That may still be the right thing to do. That may accelerate things, but provide a bit more risk. or we might wait for the data related to multiple doses. But if we look like it's potentially safe and effective with a single administration, then we have to really seriously consider whether or not we want to take that to a pill or not. It'll be an interesting discussion, but that'll be a good problem to have.

Thanks for that. That's very helpful. My last question is on the GBM study. I think in the prepared remarks, You mentioned that the grant for the GBM studies will be coming to an end towards the end of this year. I was wondering whether we can expect any more data updates from that later this year as well. Thanks.

Yeah, so with respect to the GBM trial, so as mentioned, we'll do a meaningful update on the Phase I progress and the Phase II progress at the CNS, the Congress for neurosurgeons, which will be in late September and into early October in Houston this year. So that'll be the next update. And the goal is to get enrollment completed this year. As mentioned, I think that's going to be difficult. We've got two new sites that are in the final stages of onboarding right now. If those can contribute substantially, we've got a chance at getting that trial enrolled by the end of the year. If not, we think it'll be in the first half of next year. And then at that point, we'll evaluate the data. We've continued to have good safety signals and very interesting efficacy signals related to standard of care. If we continue to see that, then I think based on our previous discussions with the FDA, we have a pretty good idea what a pivotal trial design would look like. and we'll be ready to pull the trigger on that.

Great, that's all I have. Thanks again for taking my questions. Thank you, Sean.

Thank you. One moment for our next question. And that will come from the line of Edward Wu with Ascendant Capital. Your line is open.

Yeah, congratulations on all the progress and congratulations on lining up additional potential grant funding. I was wondering, is there any seasonality to the grant funding? Are they issued all in certain times of the year? And have you noticed any change in the funding that's out there? Has it been more or less, or has it been about the same? Thank you.

Hey, Ed. Yeah, thanks for the question. It's definitely seasonal in this regard. And I'll take CPRIT for example. CPRIT has historically had two times of the year where they accept grants. And so it takes about six months to go through that funding cycle. So if you submit a proposal and let's say July or August in that timeframe. It takes about six months to go through the review process to get a decision for funding and then get the administrative award mechanics finalized so you can receive funding. So it's seasonal in that we're responding to their granting calendar. And our experience with the NIH is similar, but oftentimes it's more sporadic where they have requests for proposals. specifically our DoD proposal that we responded to in RFP, as I recall. And that's more of a one-off situation. So there's some peculiarities that can be seasonal, but also can be sporadic in affecting the timing. As mentioned, I think we've developed a really good relationship working with CPRET. We know of companies that have up to at least three grants per company. And we also know that CPRIT will fund up to $20 million through phase two. So I think there's, you know, that's been a nice relationship and that capital has been very important to us. And so I think that's what we'll continue to try to work with them closely as well as look at some of these more sporadic alternatives to continue to to leverage that non-dilutive capital and minimize the dilution to shareholders.

Great. Well, thanks for answering my questions, and I wish you guys good luck.

Thank you.

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Dr. Mark Hedrick for any closing remarks.

Thank you, Cherie. And we thank everyone, our analysts and shareholders and for listening to this call and also want to thank our patients. We'll be talking to two of them next week in Texas who trust us to give them this investigational treatment and thank you to all our employees who work so hard to make it happen. We wish everyone a nice evening. Thank you.

This concludes today's program. Thank you all for participating. You may now disconnect.