PLUS THERAPEUTICS, Inc.

Good afternoon, ladies and gentlemen. Welcome to the PLUS Therapeutics third 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 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, 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. Good afternoon, everybody, 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 third quarter 2024 financial results. Joining me for 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 third quarter, and then turn the call over to Andrew for review of our financials, and then we'll both come back for Q&A. I'll begin this afternoon with an overview of our leptomeningeal metastases program in which we are investigating our lead radiotherapeutic, rhenium-186-obispo-meta, in the RESPECT-LM trial. As a note, going forward for this call, I'll refer to rinium-186-obispo-meta as RNL, which is its research name for the sake of brevity. Part one of our development program, our ongoing RESPECT-LN phase one single administration dose escalation trial, is perhaps closing in on a maximal tolerance in which we administer a very substantial dose of RNL for approximately 66 millicuries. Data Safety and Monitoring Board, the board recommended proceeding to a modified lesser cohort six dose of 75 millicuries, and the first patient has been treated. To date, 21 of those, including a subset of three patients who responded well to the initial dose and have received multiple doses under compassionate use. Part two of our integrated development plan is to expand the phase one respect LM trial to a multiple dose administration trial. Relatedly, in Q3, we reached agreement with the FDA to proceed under a multiple dose escalation protocol, and we are currently in site startup phase for that trial. I'll review that trial design more fully in a moment. In terms of clinical data from the RESPECT-LM single administration trial, we presented an interim update at the SNO-ASCO conference in August through cohorts one through four. Here are the key highlights from that presentation. Doses of RNL up to 44 millicuries were found to be safe and well-tolerated with no dose-limiting toxicities. Pharmacokinetic data demonstrated a very high therapeutic index specifically about a 50 to 100 target to off-target ratio. Through cohorts one through three, mean circulating tumor cells were reduced on average 53% at day 28 post-treatment, and median overall survival for cohorts one through four was 12 months, which is quite favorable compared to the historically reported consensus of approximately four months with treatment in breast and non-small cell lung cancer. The full presentation from that meeting is available on our website. Later this month at the SNO, Society for Neuro-Oncology annual meeting, which is going to be November 21st to the 24th in Houston, we will provide a comprehensive update on the phase one single administration dose escalation trial through cohort five with important new data including PK, PD response and survival data. We will also host a luncheon symposium to discuss the data in greater detail with leading subject matter experts, Dr. Priya Kumtekar, Dr. Jonathan Yang, and Dr. Andrew Brenner. As I mentioned before, we have reached agreement with the FDA to initiate enrollment in a phase one trial of multiple dose administrations of RNL for treating patients with LM. Favorable outcomes observed in compassionate use patients receiving multiple doses of RNL from our single-administration dose escalation trial reinforced the safety and potential value of multiple-dose administration regime to obtain long-tail survival in patients with LM. More specifically, the Phase I RespectLM multiple-dose administration trial is an open-label, two-part study aimed at evaluating the safety, dosing intervals, and efficacy of administering multiple doses of RNL to patients with LM. Primary objectives are to assess safety and tolerability and to identify both the maximum tolerated and the maximum feasible doses at various dosing intervals and frequencies. The secondary objectives include evaluating response and survival. The first part of the study will treat up to 24 patients administering at minimum three doses of RNL at 13.2 millicuries at progressively shorter intervals, starting at 56 days and then every 28 days and finally every 14 days, and then potentially up to six doses in a subsequent cohort. The trial is expected to begin enrollment in Q1 2025 with the aim to utilize current seven active U.S. trial sites being enrolling patients in our RESPECT-LN phase one single administration dose escalation trial. We plan to provide further details on the integrated development plan and path to approval for leptomeningeal cancer at the 2024 Snow Annual Conference in Houston. Now, for discussion around our diagnostic. Increasingly, we are recognizing the importance of our CNSIDE cerebral spinal fluid assay platform in both the investigation of RNL for LM and the assay's commercial value as a standalone diagnostic product in the broader group of patients at risk for LM or other CNS malignancies. The CNSIDE cerebral spinal fluid assay platform consists of four lab-developed tests, or LDTs, and may be used by neuro-oncologists, neuroimmunologists, medical oncologists, or other practitioners for the diagnosis treatment selection, and monitoring of patients with or at risk for LM, as well as other CNS malignancies. In terms of market access activities related to the planned CNSide launch in January, as you may recall, step one was tech transfer and initiating lab testing, which was completed earlier this year. Step two, at our wholly owned sub based in Houston, Texas, we obtained a CLIA certificate of registration in Q3, and we intend to obtain a CLIA certificate of compliance in Q1 2025, following inspection by CMS. This quarter, we will apply for expanded reimbursement with a Z code to the Diagnostics Exchange, which helps ensure that both healthcare providers and payers understand which test is being and it also allows payers to automate the preauthorization or adjudication of claims. Specifically, the Z code is required by well-known payers such as Medicare, UnitedHealthcare, Humana, Blue Cross Blue Shield, and so forth. Next quarter, following receipt of the CLIA certificate of compliance, we intend to apply for a CPT proprietary laboratory analysis code or PLA code with the American Medical Associations. This code is required by Medicare and certifies labs for complex testing, ensuring they meet federal standards for quality, accuracy, and safety. And the PLA code further specifically identifies the test. In parallel to these activities mentioned above, we are negotiating with a number of commercial payers which previously had agreements in place for the C&Side assay. Specifically, we're informing them that we acquired the assets of C&Side from the previous owner and plan to make the test platform commercially available again, and new agreements will be put in place. Also, we are focused on pairs that cover regions containing the highest number of LM patients. Currently, the see-inside tumor cell enumeration, LDT, continues to be used in the RESPECT-LM clinical trial. We are on track to commercially reintroduce the test as part of a limited market release in the U.S. in January of 2025. At the same time, we are expanding the CNSI test menu on a rolling basis to include specific cellular biomarker assays and molecular assays, and we'll talk more about that in 2025. Aggregate 2024 investment in the test will remain limited as test costs are offset in a meaningful way by our current CPIRT grant. In 2025, post-expanded market access, We will guide more specifically toward forecasted diagnostic growth ramp and related economics. Now shifting gears to our Respect GBM trial, which evaluates a single dose of RNL in patients with recurrent glioblastoma. Enrollment in the Phase I portion for patients with recurrent glioblastoma tumors greater than 20 mLs has been completed successfully. and we will be evaluating that data into 2025 and completing the final Phase 1 clinical study report. Enrollment continues for the RESPECT-GBM Phase 2 trial, limited to patients with tumors less than or equal to 20 mLs. The last RESPECT-GBM trial update was at the Congress for Neurological Surgeons annual meeting in October of this year. As a reminder, key highlights include a total of 42 patients had been enrolled across three sites at that time. In phase two, most adverse events were mild or moderate with over half deemed unrelated to the study drug. Only two of the nine severe adverse events were related to the study drug, and systemic radiation exposure remains low. Moreover, the average absorbed radiation dose to tumors in phase two was 300 gray, well above the 100-grade threshold observed preclinically and in phase one that is highly correlative with increased overall survival. Furthermore, approximately 90% of patients achieve critical drug delivery parameters also correlating with improved survival. Finally, objective tumor response analysis using both cerebral bud volume and volumetric analyses showed a statistically significant relationship between tumor control and absorbed dose. Specifically, patients receiving doses above 100 gray showed effective tumor control within the treated areas. The RESPECT-GBM trial continues to benefit from substantial NIH support, and we are pleased to announce we have added two new large-volume clinical trial sites to support Phase II enrollment and potentially a pivotal trial. We've added Ohio State University, which provides us coverage in the upper Midwest, and North Shore Hospital, part of the Northwell and Lenox Hill Network in the greater New York metropolitan area. With these two new additional sites activated and screening patients for enrollment, we expect phase two completion with 34 total patients by mid-year 2025 in a data readout in the second half of 2025. Additionally, we would like to announce that we recently entered into a research and collaboration agreement with BrainLab, a software-driven medical technology company, to develop and implement optimized case planning software for convection-enhanced delivery of R&L for brain cancers. BrainLab's software, married to their CED device ecosystem, will enhance treatment planning, procedure execution, and more precise drug delivery for GBM patients anticipated to further improve patient outcomes. Now, just a bit about our pediatric brain cancer program. Recall we previously announced that we have received a U.S. Department of Defense award of a $3 million grant to substantially support a Phase I trial for children with pediatric high-grade glioma and ependymoma. Approximately 900,000 payment was received in September of 2024 as part of this award. We anticipate obtaining IND approval in the first half of 2025 at Lurie Children's Hospital in Chicago, serving as the initial clinical trial site.

And moving on to drug production and manufacturing.

We are expanding our GMP manufacturing capabilities and building redundancy in terms of materials and intermediates to support registrational trials and future commercial demand projections. To ensure a reliable supply of RNL, we recently announced our second GMP manufacturing partnership, this time with Spectrin Rx. Through this partnership, we have completed process qualification to transition from single dose single-batch production to a pilot-scale process capable of producing multiple doses per batch with a potential opportunity for scale-up at capacity of approximately 15,000 doses per year around the time of anticipated FDA approval.

So, Andrew, can I turn it over to you for discussion about 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 third quarter ended September 2024. The cash and investments balance was $4.8 million at September 24 compared to $8.6 million at December 23. In addition, we received the first advance from the DoD grant in October 24 of $0.9 million and are on track to receive the next separate advance of $3.9 million within 90 days of today. The company recognized 4.4 million in grant revenue year-to-date 24 compared to 3.6 million in the same period of 23. This represents separate shares of the cost incurred for our R&L development for the treatment of patients with LM. We expect 2024 grant revenue to be in the range of 6 to 7 million. The total operating loss year-to-date 2024 was 10.8 million compared to $9.5 million in the same period of 2023. The increase is primarily due to increased spend related to the Respect LM trial. Net loss year-to-date 2024 was $9.1 million, or $1.46 per share, compared to a net loss of $9.5 million, or $3.54 per share, for the same period in the prior year. I'd also like to provide an update on our runway and cash position based on the previously announced private placement and provide guidance on our grant funding for the remainder of 2024 and into 2025. There are three additional sources of cash that PLUS has access to beyond the balance disclosed in cash on hand at liquid investments on our Q3 2024 balance sheet. First, 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, with up to $12 million remaining available under this financing. The second source of cash remains our continued funding through now three announced grants. Firstly, the CIPRIT grant to support the Respect LM trial. As reported, we received $3.3 million from CIPRIT in Q2. At this time, $7.8 million remains due on the grant, and we remain on track to receive the next advance from CBRIT of $3.9 million within the next 90 days from today. An additional $3.9 million is expected from CBRIT in Q3 2025. Secondly, 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. The first advance was received in October for just under $1 million. PLUS also continues to benefit from the NIH grant to support the RESPECT-GBM Phase 1-2 trial. Although expected to be complete in the next six months, it currently covers approximately 90% of the overall trial costs. We also continue to source other non-diluted sources of grant capital with the target of applying for at least $10 million per year. We will continue to only report on individual grants when they're awarded. Taken in total, there's cash on hand, financing, warrants are fully exercised, and committed and contractual grant revenue is approximately $27 million. And now I'll turn it back to you, Mark.

Great. Thank you, Andrew. Appreciate it. Before we move on to Q&A, I'll take a moment to provide a specific summary of guidance for anticipated key events and milestones taking us through the remainder of 2024. First, in terms of conferences, we'll have a substantial presence at the SNO, the Society for Neuro-Oncology Annual Meeting, from November 21st to the 24th this year. There, we will present three abstracts, host an educational symposium on LM and GBM, conduct our annual investigator meeting, and showcase our CNSide cerebral spinal fluid assay platform in our booth, as we will showcase our investigational drug, RNL, for LM, GBM, and pediatric brain cancer. More specifically, in terms of the three abstracts. As mentioned for our LM therapeutic program, we will present data on the safety and feasibility of RESPECT-LM Phase 1 Single Administration Dose Escalation Trial through Cohort 5, including important PK, PD response, and survival data. We'll also provide an update on our integrated development plan for both single dose and multiple dose respect LN programs, and linking them to an FDA approval plan and timeline. For our See Inside assay platform, we will present data on, first, the 4C clinical trial data on CSF tumor cell detection, including its clinical utility in accurately diagnosing LN patients with high sensitivity and specificity compared to the gold standard cytology. and also its clinical utility in enhancing clinical management of patients with LM. Second, we will show the results of a retrospective analysis of C-INSIDE's real-world ability to detect a variety of gene mutations in CSF tumor cells, offering insights into potential treatment strategies and also ways LM patients may benefit from complementary regional therapies such as R&L and other treatments. As mentioned, the company will host an educational symposium featuring three subject matter experts, Drs. Kuntekar, Yang, and Brenner, who will provide updates on our LM and GBM programs in our CNSide platform. Lastly, we will showcase our investigational therapies as well as the CNSide diagnostic at our booth. Later in the year, in December, we will also attend the San Antonio Breast Cancer Symposium in San Antonio, Texas, where we will present the data on the safety feasibility of the RESPECT-LM phase one single administration trial through cohort five with a focus on the breast cancer patients and related data. That happens to be the primary cancer with the highest incidence of patients with LM. In addition to those upcoming events and conferences mentioned above, the company also anticipates completing our RESPECT-LM single administration dose escalation trial by year end initiating enrollment in our RESPECT-LM multiple administration dose trial in Q1 of 2025, and launching a limited commercial release of our CNSide platform as an LDT in early 2025. Completing enrollment in our RESPECT-QBM phase 2 trial by mid-2025, and for our pediatric brain cancer trial, obtaining IND acceptance, initiating enrollment for our RESPECT trial for pediatric ependymoma and high-grade glioma in patients in 2025. So, Sherry, with that, I'll turn it back over to you for any questions.

Thank you. If you would like 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. Congrats on all the progress. I'm wondering how you view the opportunities for C-Inside and R&L in LM as complementary products versus on their own?

Hi, Justin. Great question. You know what? We continue to see more and more synergies. And you may recall when we first considered this acquisition, it made sense solely on one factor, and that is it could potentially increase the total addressable market for LM by two to four times just by improving diagnostic sensitivity. But since then, there's more and more data that shows that Using circulating tumor cells can be a proxy for survival and for disease monitoring. And we see more and more papers coming out related to that. And then we're now increasingly relying on it as an exploratory endpoint in the phase one. And we're going to be providing more insight into that data next week. I think it's highly relevant in supporting the other signals we've seen in terms of response and efficacy. And I think there's a recent publication by actually one of the key opinion-leading doctors in our symposium, Dr. Yang, who treated patients with targeted radiation, in that case from a proton beam craniospinal irradiation, but showed in that trial targeted radiation therapy, it correlated very highly. The C-inside assay, actually our assay, correlated very highly with survival and progression. So I think over time, we'll see more and more reliance on that. Is it ready to be used as a primary endpoint in a pivotal trial? I don't think so. But I think as a secondary endpoint, it provides substantial collaborative data to other progression data and survival.

Great. Thanks for taking the question. Looking forward to the presentation.

Thanks, Justin.

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 the progress. I was just wondering, what does the landscape look for grants? Has it changed in terms of the opportunities that are available? And do you anticipate any change with, I guess, the change in the incoming government? Thank you.

Hi, Ed.

To answer your latter question, I don't know. It's hard to tell. I think we're in a pretty good spot through the next year as it relates to grants. We think being in Texas insulates us a bit from what's going on at the federal level. We've been very successful in uh it's secret as i think you know we have a almost 18 million dollar active grant from them in an aggregate 25 million dollars total in active grants what we're what we're hearing no guarantees but what we're hearing from secret is that they're from time to time there's additional capital that they can deploy and they tend to reach out to companies who are executing, and we're executing precisely to our proposed and planned timeline. So we're kind of hoping there might be some opportunities there, but also we'll continue, as Andrew said, to talk about grants as they come in, but we think there's continued opportunity in Texas if things change at the federal level.

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

Thank you.

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. Hi.

Good afternoon, guys, and thanks for taking my questions. I just have two quick ones. One is, first is on the LM multi-dose study. So how did you guys come up with the 13-millicurie dose to be used in that study, and how does that compare to what patients have received so far through the Compassionate Use Program?

Hey, Sean. Thanks for the question. It's a good one. So as we were, we're increasingly taking a Bayesian approach clinical development, and we'll talk more about that in our integrated development plan, both next week and in an ongoing manner. But we found, as we were getting into cohort four, which is approximately 44 millicuries, that we were seeing excellent safety and also strong response in cohort. And so as we began our negotiations with FDA on the multiple-dose approach, we felt like we could support taking that cohort four dose and then fractionating it. And that follows approaches that FDA is very comfortable with. So we were able to get them to go along with that. I think that because of, based on what we're seeing clinically, that earlier compression of doses will be very important in getting that long tail survival that I mentioned. In terms of the compassionate use, I've had, I think, two patients that have received three aggregate doses. We're actually giving them whatever dose is currently enrolling. So they're getting actually in the neighborhood of 40 or more higher dose, but their dose frequency is much longer. They're being treated when they come back with symptoms. In other words, patients seem to are responding to the initial dose And then they're doing well for an extended period of time, maybe up to a year or so. They're coming back with symptoms or progression and asking to be retreated. And so we treat them with that dose that's available. So back to my original point, I think increasingly we recognize the Bayesian design is appropriate. We're modeling that right now. That's integrated into the multiple dose trial. And then as we'll talk about over time, how do we leverage that and get to approval?

Great. Thanks. That's very helpful. My second question is on the CNS side, I'd say. So, in the prepared remarks, you mentioned that you needed to get the CLIA compliance followed by a CNS inspection, as well as getting the Z code and PLA codes. So, do you have a rough guideline for the possible timeline for these steps?

I'm sorry, Sean, just to clarify the timeline for getting most additional reimbursement.

Yeah. So getting the inspection done as well as having getting the reimbursements online. So like, you know, when can we expect the United States to start selling commercially and getting reimbursed?

Yeah. So I think we're on track to being able to, to, commercialize the test in Q4 of this year. I think the issue is going to be that we need to, we're more likely to get reimbursed if we have a see inside CLIA compliance and that inspection is not, it's not been scheduled, but it's going to be Q1 and we're pushing to make that as early in Q1 as possible because we want to try to accelerate that timeline. And then number two, I think some of these, some of the laboratory services agreements, which were, I think there were approximately 10, is that right, Andrew? 10 in place with Bioscept. We've hired a market access team that is actively negotiating with those 10 institutions on a regionally focused basis, based on my comments, you know, where are the patients and where the highest level of reimbursement is. So we're prioritizing those areas, just being practical, obviously. I think we're going to have some more things to talk about in Q1 as it relates to reimbursement. And I think once those reimbursement dominoes fall, then I think we'll feel more comfortable talking about pricing, ramp, margins and so forth. And I think right now it's just a bit premature until we get those things in place. We want to be really cautious in terms of guiding in the early phases until we get comfortable that we can stand behind that guidance. I can tell you that at the time that BICEP quit offering the test, they had 200 unique customers. They were growing at about a 30% per year CAGR. and that was with no data, no NCCN guidelines, no specific reimbursement, no 4C clinical trial data. So we have all those elements behind us, you know, at this point today, and that's only going to grow. There are only more papers coming out and so forth. So I think the environment continues to look really positive for that as a standalone product.

Got it. Thank you for that. That makes it a lot more clear. That's all the questions I have.

Thanks a lot, Sean. Appreciate it.

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call over to Mr. Andrew Sims.

Thanks, Sheree. We have two written questions. The first is, can you elaborate on the therapeutic ratio you are seeing in your trials and safety data profile?

Yes, so that's a good question. We'll talk probably more in detail. We will talk more in detail about that next week at Snow. But I think it's a key point that the therapeutic ratio that we're seeing going out to cohort four is very high in particular for LM. We're seeing about a ratio of about 50 plus in cohort four in terms of therapeutic to target versus off-target. I can give you a preview in cohort five. I think we're seeing that as greater than 100 to one ratio. So we're continuing to see a linear, as we dose escalate, a higher and higher absorbed dose, and the spinal subarachnoid space, and really relatively flat, absorption in the key critical organs. Bone marrow is starting to tick up a bit in cohort five, and we'll talk about that. And that was part of the rationale for the DSMB to cut back the cohort six dose. And I think we're increasingly becoming more comfortable that the cohort four dose will be the recommended phase two dose and the maximum tolerated dose will be cohort five. But the FDA has been very insistent about us continuing to dose escalate to failure, hence the cohort six dose. In terms of GBM, I think the therapeutic ratio is really hard to calculate because we're seeing essentially very minimal systemic absorption and very high delivery of radiation to the region of interest tumor in the infiltrated margin. So, yeah, I think what we're seeing is very favorable, much higher than other companies are reporting with their systemically delivered technology. So I think that's really a really strong part of the technology.

And the second question is, can you provide details on your integrated development plan for LM?

Yeah, I think... I've mentioned some of the details and I think we'll present more at Snow and roll that out over the first part of 2025. I think right now, I think there's, based on the data we're seeing in single dose, there is clearly activity and there is a strong potential for advancing the single dose in an expansion cohort. specifically focused on breast and lung cancer, non-small cell lung cancer. If that data continues to look strong, we can use that data to help de-risk a pivotal phase 2, 3 trial thereafter. And I anticipate getting that into the clinic pretty soon next year, but we'll talk more about that. In terms of multiple dose, I think we could follow a similar pattern where we pick As we complete each cohort, promising dose, cohort expanded, confirm that there's an efficacy signal there as well as a safety signal, and then move that forward. And I could potentially see taking two different doses to market, a high single dose and a lesser multiple dose regime. And then some more on that next week and then first half of next year. Are there any other questions? Okay. Thank you, Andrew. Well, just to conclude, thank you, Cherie, and thank you, everyone. I appreciate you being on the call. On behalf of the board, I'd just like to thank our employees and team members and the physicians we work with, and very much thank you to the patients who continually trust us to enter into these trials. Thank you for your participation. Have a good evening.

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