Good evening, everyone, and welcome to the Twenty-Sixth Annual H.C. Wainwright Global Investment Conference. My name is Sean Lee, and I'm an Equity Research Analyst at the bank. We look to provide value to you at this conference, with over six hundred companies presenting across a variety of sectors, including Biotechnology and Clean Energy, Fintech, Metals and Mining, and Medical Devices. With that said, we hope you have a wonderful and productive day. For our next presentation, I'd like to welcome Dr. Marc Hedrick, who is the CEO of Plus Therapeutics. Plus is a specialist in the development of novel radiotherapeutics against CNS tumors, and is one of my top stock picks for this year. Thank you, Sean. Good afternoon, everyone. Thanks for joining us for our corporate update. My name is Marc Hedrick. I'm the President and CEO of Plus Therapeutics. Plus is a targeted radiotherapeutic company that's going after novel CNS targets. We make nanoparticle formulations incorporating radionuclides of rhenium that are ideally suited to the CNS. This drug formulation strategy, married to unique delivery methodologies, allows us to overcome essentially all the biologic and anatomic limitations typically encountered in the treatment of CNS cancers. Our supply chain is mature, and I'll discuss that more in a moment, and then recently we added a novel CNS cancer biomarker technology and clinical diagnostic to the portfolio that potentially more than doubles the total addressable market for our lead drug, rhenium obisbemeda, and opens up new near-term partnering opportunities. From a macro level, partnering interest in the targeted radiotherapeutic space has been substantial, and the market has seen growing big pharmaceutical interest. So that's the context. So now drilling down on what we're doing in terms of CNS cancer, and talking about some of the general issues related to that. Successful CNS cancer treatments have been elusive. There are multiple biologic and anatomic factors that underlie this that are unique to therapeutic approaches with CNS cancers. Things like the mutational load of the tumor, the immunosuppressive environment, the blood-brain barrier is well-known. The tumors can be heterogeneous and can be resistant to typical chemotherapeutic approaches, and that plagues really any therapeutic approach to CNS cancers, no matter what kind of pharmaceutical agent one is using. On the flip side, external beam radiation therapy has been shown to be the most effective incremental treatment for CNS cancers. It gives us the most survival benefit of any of the other treatment modalities. The problem, practically speaking, is it has a very narrow therapeutic index or window, so you just can't get enough radiation to the tumor to get meaningful long-term benefit without getting normal tissue toxicity to the normal tissue. So this slide is a summary of our technology, how we use it, and then the why it works. What is the ultimate outcome that the drug produces in the patient? So the left panel illustrates our lead drug, rhenium obisbemeda, which is a liposomal encapsulation of novel radioisotope of rhenium, Rhenium-186, incorporated in 100 nanometer liposomes that can be delivered via multiple modalities. But in the CNS, there are basically two categories of tumors. There are tumors of the cerebrospinal fluid space called leptomeningeal metastases, and Ommaya reservoirs allow two-way access to the CNS and allow you to bypass the blood-brain barrier, get the drug to the region of interest where the tumor is residing. And then for parenchymal lesions or solid tumors of the CNS, glioblastoma, brain mets being the two most common of those, there's a very mature commercial-ready technology called convection- enhanced delivery, which allows you, again, to go past the blood-brain barrier and get your drug to the tumor. And what each of those delivery technologies, when married to our drug, accomplish is represented on the right panel, and that is getting a very high therapeutic index. In that, the more dose of radiation you deliver the tumor, you get an incremental linear increase in the amount of tumor. in the amount of radiation that gets to the tumor or your region of interest that you're targeting, but essentially no systemic exposure, and that's essentially the therapeutic window. And what we're seeing in our lead indications is somewhere between a five and twenty times the amount of radiation measured in gray that we could deliver with our drug versus standard EBRT. So why are we using rhenium? There are a number of commercially used radioisotopes, actinium, lead, iodine, lutetium, and so forth, but Rhenium-186 has the ideal mix of properties from a physical perspective to target CNS indications. It has a gamma particle, so we can measure absorbed dose, and then track it with typical SPECT imaging at any point in time, and know exactly where it is. It's got a long path length, so we can treat the tumor, not just the individual cell with a radioisotope. And then it has an optimal mix of keV, the energy level, the half-life, and the chemistry to allow us to use it in our drug formulation construct. Rhenium's not a new radioisotope to us. It's been used commercially in Europe successfully, but we're the first to adapt it to the CNS. One of the key issues that comes about when considering developing a targeted radiotherapeutic is, can you have a commercially viable and scalable supply chain? And the issue is that radioisotopes have a short shelf life, because the active pharmaceutical ingredient is decaying and decays relatively quickly. So the way we've solved the supply chain issue is we make our target, the target for the radiation, and all of the GMP intermediates beforehand. Those are actually long shelf life items. We store them. When the drug is ordered, we simply send target for irradiation, and then it's overnighted for GMP manufacturing, and then overnighted once again to the institution. It goes through standard radiologic shipping and receiving, and goes to the clinic or to nuclear medicine for delivery to the patient. It's a straightforward and highly scalable supply chain, and we're actually well ahead of where we should be. Now, we're in mid-phase 2, but we're essentially commercial ready or will be very soon. So the company with its lead drug, Rhenium-186 obisbemeda, has three active clinical programs. One for leptomeningeal cancer, and that's for cancer of the cerebrospinal fluid and the leptomeninges. One for recurrent glioblastoma, which is in kinda mid to late stage phase 2, and then an emerging pediatric brain cancer trial that should be starting this year. One unique aspect for these three programs is that all of them have substantial external funding. We have a total of about $25 million in external funding divided between these three programs. I'll talk about the milestones related to each program in a moment. Let me start off with leptomeningeal cancer or cancer of the cerebrospinal fluid. It's a cancer that has a significant addressable population, but incredibly poor prognosis, and one of the reasons the prognosis is so poor is because the diagnostics are so poor. A very insensitive diagnostic, and then there's nothing approved for these patients. When the patients are diagnosed, if it's late in diagnosis, generally, these patients live a few weeks before they expire, whether they have treatment or not. If it's earlier in the disease progression, they can live a few months with treatment, but as I mentioned, nothing's approved. The incidence is thought to be approximately 150,000 patients per year in the U.S., but if you look at large meta-analysis or studies of the particular tumor types that cause leptomeningeal cancer or autopsy studies, the general thinking is this is likely about 2-4 times underdiagnosed, and it occurs when relatively common primary tumors, such as melanoma, breast cancer, lung cancer, break through a blood vessel. Even though the tumor might be controlled locally at the breast or lung level, get into the cerebrospinal fluid and into that dead space, and at that point, it's incredibly difficult to eradicate and is beyond the blood-brain barrier, and typical drugs are blocked by that biologic limitation. So in approaching this, we developed a clinical trial strategy that includes a single-arm or single administration dose escalation trial, where we're right around phase cohort five in that dose escalation, which includes 66 millicuries of radiation administered to those tumors. We're likely very, very close to the end of the dose escalation phase. We haven't reached a maximum tolerated dose yet, but we're delivering very high doses of radiation to the region of interest. That includes the tumor, and the CSF, and so forth. And so, as I mentioned, while we haven't reached the maximum tolerated dose, we have a very good understanding of the pharmacokinetics of the drug, and that as when you use the Ommaya reservoir, you deliver the drug directly into the cerebrospinal fluid. It circulates very rapidly, and then we can image it and show that it stays there for at least seven days. The dosage of radiation to the critical organs that would cause systemic toxicity remains very low, even with dose escalation. Mirroring that cartoon, I showed you in one of the earlier slides when I showed an overview of our Rhenium obisbemeda drug. But you get very high doses in a linear increase based on cohort to the key therapeutic area or the region of interest, which is the cranial, the subarachnoid space, the ventricles, and the spinal fluid. And what we've seen is this is generally safe and well-tolerated. We haven't reached a dose-limiting toxicity. There's been no evidence of systemic radiation toxicity through cohort four despite the fact that we're giving over five times the amount of radiation that you can give with the most conformal emerging techniques, such as proton craniospinal irradiation. So very safe thus far, thus far. No DLTs through cohort four. And then kinda looking at the overall survival waterfall of the patients treated through cohort four. Most of the patients have been breast or lung cancer patients. Each patient is represented in the table to the left on the Y-axis. The bar going across represents the total overall survival. If it's a hatched line, it means the patient is still alive. If it's a solid line, it means the patient's expired. The farther to the right the line goes, the farther the patient median or overall survival is. And what we can see here from this graph is, you look at the bottom, where the breast cancer median overall survival and the lung cancer median overall survival in the case of leptomeningeal is about 100 to 150 days. You see a number of patients that are well beyond the median overall survival for lung and breast cancer, and this graph showing a very interesting potential survival signal. What can we say from that based on response? The NCCN recommends circulating tumor cells for the diagnosis and disease monitoring in LM. We evaluated this through the first three cohorts. The test was unavailable for cohort four, now back available again for cohort five. And we showed, on average, a reduction of 53% of the amount of circulating tumor cells, or the concentration of circulating tumor cells, in the CSF, with up to a 90% reduction in tumor cells. A significant improvement in circulating tumor cells at one month after treatment with a single administration that came back at 56 days. Furthermore, if you look at survival, the median overall survival through cohort four is 12 months. That's substantially longer than what's been observed in standard of care. This was reported at SNO/ ASCO last month, and in this Kaplan-Meier curve, eight patients of the 16 remain alive, so a promising overall survival signal. So what we can say thus far is that we can reliably deliver this investigational drug, rhenium obisbemeda, to the region of interest. It stays there for at least seven days, exhibits minimal evidence of systemic toxicity, despite giving very high doses of radiation to the region of interest, and we're coming to the end of the single administration basket dose escalation trial, but thus far, it shows safety, feasibility, and response. The next steps are to complete the single administration trial. We're actually funded to move that trial into a phase two/three registrational trial through our CPRIT grant. We plan a complete data readout at Society for Neuro-Oncology in Q4 of 2024, and then we have a multiple administration dose interval compression trial that's in front of FDA, and we anticipate hearing back on that soon. As soon as that's clarified and the issue's resolved with FDA, we'll be starting that as soon as we can at our current sites. Moving on to our glioblastoma program. Glioblastoma is the most common primary tumor of the brain and central nervous system. It affects about 15,000 patients per year. It typically doesn't kill from distant metastases, but it's very difficult to eradicate, and patients, after they're diagnosed and receive primary treatment, it typically always recurs or doesn't respond to primary treatment, and they go into secondary treatment. Generally speaking, clinical trials are recommended. There's no commonly understood standard of care in the recurrent setting, and we've started the development program for recurrent glioblastoma. Now, why is this so difficult to eradicate? And on the panel on the left, it shows this concept of the infiltrative margin, that you can image the tumor, but, you know, probabilistically, unless you take out about two centimeters of what appears to be normal brain around the imaged tumor, that which is the location of recurrences, you really won't get a long-term improvement, and that's called the infiltrative margin. And practically, surgery can't obtain those margins. Most drugs see an intact blood-brain barrier, and those tumors, particularly going out to the infiltrative margin, and they can't get into the tumor to treat it adequately. And as I mentioned, the problem with external beam radiation is its therapeutic index. You can't get enough radiation to the tumor and to the infiltrative margin without getting off-target toxicity. So on the panel on the right really describes what we're trying to do with our therapy, and that is get a very high dose of radiation, not only to the tumor and to the infiltrated margin, but without getting systemic toxicity, and I'll show you how we're doing that. Here's a couple of patients, a standard EBRT patient on the left. The tumor's in green. The isodose of radiation go out through the brain. This patient had a treatment plan of getting just under 30 gray maximum dose to the tumor with a relatively big space between the isodose lines showing radiation going out into the brain. That's pretty typical in the recurrent setting, about 30 gray maximum dose to the tumor using photon beam radiation. On the right is one of our patients, fairly standard patient. This patient got, and we can measure it, 250 gray, to the tumor itself, and you can see the isodose lines are very compressed, and you can see a lot of radiation is not only getting to the tumor, but to the infiltrative margin. That's what we're trying to do in every case. As we've gone through the phase 1 and now into phase 2, what we've learned is that we can get very high doses of radiation directly to the tumor site and the infiltrative margin. We can do it in a single visit, unlike external beam radiation. We can eliminate those challenges of EBRT. We can see the drug on the tumor, we can quantify the absorbed dose, and we can get up to 20 times the amount of radiation to the tumor. We think this is a step function improvement over EBRT, and could supplant EBRT for a number of CNS indications, including GBM. Now, how does it work from a treatment workflow perspective? It's very similar to brain biopsy. The patient's imaged, they have a worrisome lesion, they're scheduled for a brain biopsy, they come in and get a brain biopsy. All that sort of happens except for in the prior, pre-treatment timeframe, we actually do a case plan, similar to what you do for radiation oncology, and external beam radiation. But that we plan the navigation of a number of catheters, up to five catheters, into the tumor, assuming the brain biopsy is positive. The biopsy catheter is removed, the catheters are placed, up to five catheters, they're secured in place. The patient stays overnight in the hospital. The drug is infused into the tumor in the region of interest, then the catheters are pulled out. That takes about two to four hours, and then the patient's monitored by SPECT imaging over time to calculate dosimetry and the adequacy of treatment. This is a patient in the upper left, patient 14 in the phase 1. You can see the three different images of the tumor in the upper left. You can see the dosimetry cloud showing the radiation, that we can compute a radiation dose to the tumor, which is superimposed over the tumor MRI. That's typically what we see in these patients. We see the tumor, three views, we see the dosimetry, we measure the radiation, and we can assess the adequacy of treatment. So this trial is being funded, phase 1 all the way through phase 2 by the NIH. And currently, we're in phase 1 dose escalating now in cohort eight, which is probably right at the maximum tolerated dose, although we're not there yet. And then we've taken cohort six, 8.8 milliliters and 22.3 millicuries into phase 2, and we're currently in phase 2. I'll show you that data in a moment. Thus far, in the phase 1, the treatment has been generally safe and well-tolerated in over 28 patients through eight dosing cohorts. No evidence of systemic radiation toxicity, and the phase 2 safety profile is tracking with phase 1. It's been quite safe. The average absorbed dose to the tumor by cohort is, through cohort eight, represented on the right, and it shows why we selected the cohort six dose to go into phase 2 for tumors of 20 CCs or less. Think very high doses of radiation, on average, about three to 400 gray of radiation delivered to these tumors reliably. The tumors greater than 20 CCs that we'll continue to evaluate in the phase 1, you see a drop-off in average absorbed dose, and that's because the tumors are bigger. So that even though you're giving more radiation, it's disseminated over much bigger tumors, and you're getting an average absorbed dose to the tumor that's slightly lower. In terms of response, differentiation of tumor responses is very difficult. Identifying progression versus pseudoprogression is hard. You can use qualitative response techniques such as cerebral blood volume, and you can see a patient here, this is cohort 17, or cohort one, patient 17, where you see the tumor in the pre-treatment MRI, at the top. You can see the loss of that tumor gadolinium uptake, at day 56, but you can see a corresponding reduction in perfusion that shows response. But that's, that's qualitative, not quantitative. We've adapted a technique where we use a multiparameter analysis, and we can actually, we can actually assess response, not just at the patient level, but at the tumor and essentially the pixel level. And when we do that and look at... Assess whether the individual tumors are receiving greater or less than 100 gray, which is our empirically derived dose, assessing adequacy of the radiation in these patients. There's a statistically significant difference in tumor volume rate change in those getting greater than 100 gray, represented on the left, versus those that got a subtherapeutic volume. So you essentially look at the part of the tumor that got a high dose. It's responding. The part of the tumor that, in some cases, didn't get a high dose, and it's not responding, and that response assessment is shown on the right panel. So in terms of overall survival, I'll just point you to the Kaplan-Meier curves on the right, and it shows that in the phase 1, for all comers, the median overall survival was 11 months, so that's through the entirety of the dose escalation phase. However, if you look at patients that got a therapeutic dose greater than 100 gray, as described in the response data I showed you before, those patients lived a median OS of 17 months, so that's over double the standard of care for patients with recurrent GBM. And then what we showed, which is in the box below, is that when you adjust these patients for age, ECOG status, tumor volume, and so forth, that the overall survival increased by 27%. For each 10% increase in the percentage of tumor covered. In other words, the better you cover a tumor, the better the patient does, and then the overall survival increased by 31% for each 100 gray increase in the absorbed dose. So the better you cover the tumor, the more radiation you get to the tumor. It's highly statistically correlates with improvement in overall survival, and then presented last November, the interim phase 2 data showed a median progression-free survival of 11 months through about halfway through the phase 2 trial, and a median overall survival of 13 months, and so where does that stand in terms of standard of care? So if you look at the most current meta-analysis of bevacizumab monotherapy for recurrent GBM, or you look at two real-world control arms that we've done, propensity match to our trials, the median overall survival is about eight months, however you look at it. And we've showed in the phase 1, in those with a therapeutic dose, there's about a 113% improvement over real-world controls in therapeutically dosed patients. And then in the phase 2, we're over 60% improvement. Again, very promising efficacy signals in the phase 1 and the phase 2. So where are we with this trial? We've shown that we can reliably deliver up to 20 times the amount of radiation with this approach versus the gold standard, EBRT. There's minimal systemic toxicity. We've derived a recommended phase 2 dose, and we're well into phase 2 for tumor volumes of about 20 CCs or less, and that's over about two-thirds of the market opportunity. We, at the behest of the FDA, we continue to dose escalate to failure, to maximum tolerated dose. We have not reached that thus far, but the tumor imaging response data highly correlates with absorbed radiation dose and median overall survival, and the median overall survival signal in both the phase 1 and phase 2 thus far are very promising. And we think longer term, this represents a new paradigm for delivery of radiation over EBRT for solid CNS malignancies. The next step with this trial is to complete the phase 1. We've got one more patient left to do six patients in the cohort eight. Phase 2 is winding down. Interim data will be presented at the Congress of Neurological Surgeons as a podium presentation, late September, early October, and we're close to having a finalized phase 3 design with the FDA, and then finally, we have a pediatric brain cancer trial that's funded by the DOD, that is likely gonna start this year. Now, just in finishing up, a bit about our preclinical pipeline that I didn't have time to talk about, so we continue to develop our lead drug, rhenium obisbemeda, for a number of other indications. Not only in the CNS, such as primary GBM and brain metastases, but also for malignant peritonitis and pleural effusions and head and neck cancers. We have a second drug. It's a next generation selective internal radiotherapeutic, radioembolic, regulated as a device called rhenium biodegradable alginate microspheres for recurrent GBM, primary GBM, and liver cancers, and that's in preclinical. And as I mentioned, we recently acquired a novel CNSide diagnostic and biomarker, and we're on track to commercialize that actually later this year. So then finally, in terms of the cap table, the company has just under $10 million in cash, and in combination with our active grant funding of $25 million, as I mentioned, that gets us funds operations into 2026, and we have just under 8 million shares outstanding. And then finally, in terms of key milestones, just to reiterate those, for our LM program, our intention is to finish the LM phase 1 single administration trial and report that data at Society for Neuro-Oncology in Q4 2024, and then be prepared to go into a phase 2 registrational trial next year. A multiple-dose interval compression trial is in front of the FDA, and we hope to talk about that more soon. The GBM program, we hope to finish the phase 1 and the phase 2 relatively soon, and then we'll be presenting data at the CNS meeting in late September. I mentioned the pediatric brain cancer program, hopefully starting up this year, and the CNSide diagnostic, of which we just presented top line data on that trial. So in the utility trial, which met its primary endpoint at SNO/ ASCO this past August, and that's on track for commercial availability by Q4 2024. So thank you very much for tuning in, and Sean, thanks for the introduction, and appreciate your time. Thank you, Marc, for that very productive and informative presentation. We appreciate the time and effort that went into preparing it, and I would like to thank all of our presenters for their flexibility and presence at our conference this year. So thank you again from the H.C. Wainwright team.