Plus Therapeutics Inc (PSTV) 2022 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen. Welcome to the Plus Therapeutics Third Quarter 2022 Results Call. 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 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. Marc Hedrick, Plus Therapeutics' President and Chief Executive Officer. Sir, you may begin.

Thank you, Josh. 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 2022 third quarter financial results.

Joining me for the call today is Dr. Norman LaFrance, our Chief Medical Officer; and Andrew Sims, our Chief Financial Officer.

I'll begin the call by reviewing our recent corporate clinical progress before turning the call over to Andrew to review our financials, and Dr. LaFrance will be joining us for Q&A.

The company made perhaps the most progress ever in a single quarter that I can remember. First, in September 2022, results from the company's Phase I ReSPECT trial for recurrent GBM was presented at the European Society for Medical Oncology meeting in Paris by Dr. Andrew Brenner, the trial PI.

In summary, 21 patients across 6 dosing cohorts received 1 to 22 millicuries of radiation and 0.6 to 8.8 milliliters of volume. The mean tumors treated in those 21 patients was 8.3 milliliters and patients had a mean of 1.7 recurrences and very poor prognostic factors.

All recurrent glioma patients had computerized treatment planning and up to 4 intracranial catheters placed in each patient. Each patient received a single administration of 186RNL by convection enhanced delivery and whole body planar SPECT/CT imaging on days 1 through 8 following treatment assessed dosimetry and radiation distribution.

Patients were followed for safe radiation delivery and overall survival. The mean absorb radiation dose to the tumor was 271 grade with negligible systemic exposure. There were no dose-limiting toxicities, and the overall safety profile was favorable.

Patients were stratified by mean absorbed radiation dose to the tumor, those receiving greater than 100 grade mean therapeutic dose and equals 12 in that group, had a median and mean overall survival of 129.7 and 106.4 weeks, respectively, with 4 patients still alive in that group.

Patients receiving less than 100 Gy mean absorbed dose essentially a subtherapeutic dose and was equal to 9 in that group, had a median and mean overall survival of 22.3 and 24.6 weeks, respectively, none of those patients remain alive.

Kaplan-Meier analysis of patients receiving mean absorb dose greater than 100 Gy or therapeutic dose versus those with less than 100 Gy a nontherapeutic dose showed a statistically significant difference in overall survival favoring those that received a therapeutic dose.

The study concluded that a single administration of 186RNL by convection-enhanced delivery in recurrent glioma patients with poor prognosis is feasible, safe and potentially effective in increasing overall survival when a therapeutic dose of radiation is delivered to the tumor.

A recommended Phase II dose of 22.3 millicuries and 8.8 milliliters was selected for patients with tumors of up to 20 ccs or 20 milliliters in the Phase II trial planned for later this year, and I'll discuss the Phase II plan further in a moment.

Also during Q3, we received guidance from 2 Type C meetings with the FDA on the next steps in our program for the development of our lead investigational drug Rhenium-186 NanoLiposome. The first Type C meeting focused on the company's current good manufacturing practice, or cGMP, clinical and commercial manufacturing process for 186RNL.

The FDA indicated agreement with our proposed application of cGMP guidance for radio therapeutics, small molecule drug products and liposomal drug products for 186RNL in support of our ongoing and future glioblastoma clinical trials, manufacturing scale-up and commercialization.

We expect that this FDA feedback will apply to 186RNL used in other clinical development programs, including leptomeningeal metastases and pediatric brain cancer. I'm happy to report that we have now completed all key manufacturing objectives for cGMP 186RNL production to support ongoing and planned clinical trials in 2022 and beyond.

During a separate clinically focused Type C meeting, the FDA and Plus agreed the ReSPECT GBM clinical trial should proceed to the planned Phase II. The key focus areas of ongoing clinical investigation in the recurrent GBM development program will be further dose exploration, including both increased dosing, i.e. advancing to cohort 8 and study of multiple doses and also collecting additional safety and efficacy data to inform the design of the future registrational trial.

In addition, during the meeting, there was agreement that in a planned future registrational trial, overall survival should be used as a primary endpoint. The company and the FDA also agreed to hold future meetings to consider the use of external data to augment the control arm in the registrational trial facilitated by our Orphan and Fast-Track designations.

Earlier this month, an IND amendment was submitted regarding this plan, and that sits with the FDA as of today. The planned Phase II trial design will incorporate the following features. The Cohort 6 dose will be used, which is also the recommended Phase II dose from Cohort 6, as mentioned, which will be 22.3 millicuries and 8.8 milliliters of volume.

The study will enroll up to an additional 31 patients at 5 planned sites including the current 3 sites plus an additional 2 sites which are currently in process of coming online.

Subjects will remain on study into disease progression by RANO criteria, recognizing, of course, the potential for pseudo progression that complicates the use RANO criteria. And we're working on the imaging analysis today to be able to resolve that issue or potentially a PI decision that's in the best interest of the patient.

The primary endpoint, as mentioned will be overall survival following single administration. Secondary endpoints will assess the safety, tolerability, objective response rate, partial response, serious treatment, emergent adverse events up to 3 event free survival and progression-free survival at 6 months.

We'll make now in the final details pending further feedback from our IND amendment, which is with FDA as mentioned. I'll now pivot to discuss our leptomeningeal metastases program. Our team was very honored to learn in the third quarter that we had been awarded a $17.6 million product development research funding award from the Cancer Prevention and Research Institute of Texas, also called CPRIT.

This award will cover the majority of the development costs, including funding for up to 150 enrolled patients for our leptomeningeal metastases program over 3 years. For those that you aren't familiar with CPRIT, CPRIT is the second largest global public funder of Cancer Research in the world after the NIH with $6 billion allocated by the state.

And also of note, plus the $17.6 million grant award is the largest in the most recent CPRIT review cycle in 1 of the top 10 largest all-time awarded by CPRIT in its history.

Besides of the asset, the award is a material source of nondilutive funding that significantly strengthens the company's balance sheet and extends our expected cash runway.

Andrew will provide some greater perspective on that momentarily. While this is all exciting news, let me just back up a bit and recap our current development plan, starting with Rhenium-186 NanoLiposome development.

As I mentioned, the company recently completed key manufacturing objectives for cGMP 186RNL to support ongoing and planned clinical trials in 2022 and beyond. Drug of sufficient quality and scale to enable the completion of all further clinical investigation, including for ongoing and planned Phase II and Phase III clinical trials in patients with glioblastoma, leptomeningeal metastases, pediatric brain cancer and really any conceivable future disease targets.

Having access to cGMP drug is an important milestone as we prepare to transition from early to late-stage clinical investigation and commercialization. Relatedly, I'm pleased to announce that the World Health Organization has approved Rhenium-186 [Bispemeta] as a generic name for 186RNL.

As required, this generic name will be used in all future IND and NDA submissions and brand development and related go-to-market planning is currently in process. And here to forward, we will now use the 186 Rhenium Bispemeta name in lieu of the 186RNL research name.

Regarding the GBM program, based on the positive safety profile and promising efficacy signals observed thus far and with clear feedback from the FDA. Most importantly, we intend to move into Phase II in the U.S. by the end of 2022, and that effort will be funded by us to a significant degree as it has in the past by the U.S. NIH National Cancer Institute.

Second, pursuant to FDA guidance, we intend to continue the dose escalation to Cohort 8, and that's a 16.6 milliliter volume and 41.5 millicurie infused dose. That's an approximate 33% increase in both volume infused in radiation dosage. Notably, we recently received DSMB approval to advance to Cohort 8 from Cohort 7.

Any further escalations in volume or dosage will be based on observations from Cohort 8, but again, the overarching goal here is to dose escalate until we reach dose-limiting toxicity or the maximum practical dose. The ongoing Phase I is intended to explore further dose escalation on large tumors as we have yet to observe any dose-limiting toxicities, and we also continue to work to further optimize the delivery and dosing approach.

This week, at the 35th Annual Congress for the European Association of Nuclear Medicine, the company presented data, which indicated that the direct administration of Rhenium Bispemeta is safe in patients with recurrent GBM with no dose-limiting toxicities in 24 total patients. That's the total patient set treated thus far, and I refer you to that press release for further information.

So now on to our leptomeningeal metastases or LM development program. That trial is a multicenter Phase I/II dose escalation study to determine the maximum tolerated dose, safety and efficacy of 186 Rhenium Bispemeta . LM is an end-stage fatal complication associated with advanced cancers that infiltrate the fluid line structures of the central nervous system or leptomeninges.

The incidence of LM is growing with better local cancer care, and there are no FDA-approved therapies. Standard treatment includes external beam radiation therapy to the affected sites, followed by chemotherapy given either orally, intravenously or often administered twice weekly directly into the CSF space.

In the third quarter of 2022, the company initiated enrollment of Cohort 2, that's a doubling of the dose over Cohort 1 in the ReSPECT-LM dose escalation trial. We anticipate completing enrollment of Cohort 2 by the end of 2022. And in Cohort 3 by the end of Q1 2023.

In Cohort 1, 186 Rhenium Bispemeta was successfully delivered without dose-limiting toxicities and the independent respect LM DSMB, approved the plan to move forward with Cohort 2. By the way, also at the Annual Congress of the European Association of Nuclear Medicine this week, the company presented from the podium data demonstrating that 186 Rhenium Bispemeta administered through an intraventricular catheter at 6.6 millicuries in 5 cc achieved absorbed dosages of 1 point -- excuse me, 18.7 to 29 Gy to the ventricles in cranial subarachnoid space, which was well tolerated with no treatment-related adverse events greater than grade 1.

Additionally, all 3 patients in the cohort were observed to have prompt and complete 186 Rhenium Bispemeta distribution throughout the CSF that was durable past 1 week and very well tolerated. All patients showed a decrease in CSF cell count by microfluidic chamber assay after treatment ranging from a decrease to 45% up to 92%, which was also durable.

Now regarding our development program in pediatric brain cancer. The company is on track to meet its objectives to submit an investigational new drug application in the fourth quarter of 2022 for what will be called the ReSPECT-PBC Phase I dose finding and efficacy study of 186 Rhenium Bispemeta for pediatric brain tumors, and that will be submitted in conjunction with our lead academic institution, hospital of Northwestern University in Chicago.

Finally, regarding our novel in-licensed radio embolic microparticle technology called 188RNL-BAM, we have completed the technology transfer phase and key CMC feasibility studies, and we are on track to submit a pre-IND meeting and have that meeting by year-end.

With this resorbable biomaterial embolic technology, coupled with a highly potent radio therapeutic, in this case, 188 Rhenium, we can target almost any solid organ tumor in the body using standard interventional radiologic beams and leverage the breadth of the human vascular system to selectively reach almost any tumor.

Rhenium-188 NanoLiposome biodegradable alginate microspheres is a next-generation fully resorbable technology that solves many of the existing problems with current radioembolic technology that have been in the market for many decades and represents an existing total addressable market of about $1.3 billion.

The company will initially focus on developing the BAM technology as a next-generation radio embolic therapy for liver cancer. Liver cancer is a rare disease with an increasing annual incidence globally in a 5-year overall survival rate of only about 20%.

So with that summary, I'll turn the floor over to our Chief Financial Officer, Andrew Sims, who will review the financials. Andrew?

Thank you, Marc. Good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the 2022 third quarter ended September 30, 2022.

As of September 30, 2022, cash and cash equivalents were $20.3 million compared to $18.4 million as of December 31, 2021. The company believes the combination of current cash, committed grant funding in conjunction with existing discretionary capital sources, secures our cash runway through 2025.

Cash used in operations for the 9 months ended September 30, 2022, was $10.7 million compared to $7.7 million in the same period for the previous year.

The main year-over-year changes between the third quarters of 2022 and 2021 are as follows: Grant revenue of $73,000 was reported related entirely to CPRIT. Total operating expenses for the third quarter of 2022 were $5.2 million compared to $3.5 million for the third quarter of 2021.

The increase is due primarily to the following: CMC-related activities to develop and produce cGMP quality drug material as well as expenses associated with the development of the synthetic control arm platform for future clinical trials. These projects and related spend have now been substantially completed.

To a lesser extent, an increase in legal, IP and other general corporate expenses. Interest expense decreased from $232,000 in the third quarter of 2021 to $173,000 in the third quarter of 2022. This decrease reflects the continued principal paydown that commenced in November 2021 on the company's Oxford debt.

Net loss for the third quarter of 2022 was $5.2 million or $0.19 per share compared to a net loss of $3.7 million or $0.28 per share for the third quarter of 2021. I'd also like to take this opportunity to provide an overview of the positive impact on cash and the financial statements of the $17.6 million CPRIT grant to develop the ReSPECT-LM indication.

As disclosed in the September 22, 2022 press release, this grant covers the 3-year period ending August 31, 2025, with the funding tracking the company proposed clinical development plan. The total planned grant for year 1 is $3.7 million, increasing to $6.7 million in year 2 and $7.2 million in year 3.

Let me walk you through the cash impact of CPRIT and the process to access to $17.6 million. CPRIT initially funds 50% of the first year budget, which for pluses just under $1.9 million.

The request for this $1.9 million has been submitted, and we expect to receive this funding within the next 1 to 2 weeks. Once greater than 90% of this initial $1.9 million is utilized, the next request will be submitted.

CPRIT typically takes less than 2 weeks to advance the requested funds. The design of the funding is to ensure the company is not out of pocket for grant related expenses, which will obviously be substantial. Quarterly reports are submitted summarizing payments and development progress during the previous quarter, and CPRIT has the right to conduct an annual audit of expenses.

These are typical requirements, especially for such substantial levels of funding. As Plus incurs costs, the costs will be reported in our income statement under the research and development line item and the matching CPRIT grant will be reported as revenue in the grant revenue line on the income statement. Note 7 on Page 11 of Form 10-Q, outlines the accounting and financial for the grant and associated project-specific costs.

Now I'll turn it back to Marc.

Thanks, Andrew. Before we move to Q&A, let me just summarize key milestones anticipated for the remainder of 2022. We plan to the trial of 186 Rhenium [Bispemeta] for recurrent GBM as mentioned. We plan to present updated data from the ReSPECT-GBM trial, the LM trial and forthcoming pediatric brain cancer trials at the Society for Neuro-Oncology Annual Meeting and Education Day that will be held in Tampa on November 7, presentations and one poster presentation there.

We'll complete Cohort 2 of ReSPECT-LM Phase I/II dose escalation trial in Q4. We'll submit an IND for the study of 186 Rhenium Bispemeta in patients with pediatric brain cancer as mentioned, and we plan to complete key CMC and IND-enabling studies for the BAM program and complete our related pre-IND meeting as planned, all on track.

At this point, now let me turn it back to Josh for a Q&A session. Josh, let's have questions if there are any.

(Operator Instructions) Our first question comes from Justin Walsh with JonesTrading.

Congrats on all the progress. My first one, it's great that we're seeing decreases in the CSF tumor cell count in the LM patients. But it looks like the cell counts have rebounded in at least some of these patients treated so far. I know that we're in the early phases of dose escalation here and repeat dosing might be key.

But how do you think we should think about interpreting these readouts? Is there a reason to expect some potential benefit from a temporary reduction in the CSF tumor cell count? Or do you think the major takeaway is that we're just potentially seeing some antitumor effects, and we need to wait a little longer for clinically meaningful readouts.

So I'm going to -- thanks, Justin. Appreciate the question. I wanted to buy that up. I wanted to divide that up. I'm going to take a little bit of it, and I'm going to refer to Dr. LaFrance, to talk about a recent patient experience. So First of all, one of the great aspects of the LM indication is the ability to check tumor markers. The first of which is the tumor cell count, which we do over time in all these patients.

And it's heartening to see it even the lowest possible dose of what I would consider almost, maybe just north of a homeopathic dose, we're seeing decreases a pretty significant magnitude in all patients. Every patient had a reduction. So that's important. Number 2 is that there is a duration of that effect. So it looks like it's lasting for a month. We know from the dosimetry data that radiation is there for at least a week, probably longer.

It seems to mirror what we've sort of seen in GBM patients. So there's a duration of effect. There's a meaningful effect even at a very low dose. Now the question is, is that the right tumor marker to look at?

And the answer is maybe but we're actually working with the principal investigator, we filed -- grant's been filed to look at additional tumor markers and evidence of radiation damage. And our plan is to look at that with or without the grant. There's a lot of opportunity here to look at tumor markers in this clinical model.

And then finally, I would just say it's -- we don't know at this point what these tumor cell markers actually mean. Dr. LaFrance, I think mentioned in Barcelona at his recent meeting that one of the patients had a pretty significant improvement in clinical symptoms. And that was the one that had the lowest decrease in tumor cell. Maybe you want to comment on that, Norman.

Well, I'll start with then -- thanks, Marc. And I think it's a great question, by the way. And I'll start with the last patient Marc just alluded to. One caveat that Marc didn't mention, this patient was heavily intrathecal chemotherapy. So in fact, his cell counts were much higher and our continued therapy, and he didn't tolerate that chemotherapy, came off of it but we maintained that benefit.

But more importantly, this unfortunate patient who is wheelchair bound, quite -- he had lots of pain, other LM neurological manifestations, unfortunate manifestations. And after the therapy within a few days, his doctor who's the PI at the particular site, reported that the patient was out of the wheelchair, walking, albeit with some assistance, but minimal assistance and his pain was significantly decreased.

And your point about, well, the duration of the benefit, I want to really emphasize Marc's point, we're at the absolute lowest dose. We will -- we will continue the other cohorts, already in cohort 2 and doubling it, and we will double again in cohort 3. So it's really crucial to see these next cohorts, and we'll have a fourfold range of doses that will give us a pretty good idea. The ultimate registrational trial, which we don't know how that will look.

We need, obviously, this dose escalation trial. Maybe an overall survival. There may be another surrogate endpoint that depends on FDA discussions.

And you raised a point that we've already talked about internally, the best way for this LM is a devastating complication and it may make more sense to have multiple doses to make it a controllable devastating complication because these really impact these patients' quality of life. They get this leptomeningeal complication.

And even though there's some chemotherapy that works, they will discontinue it just because of the tolerability. So multiple doses make sense, and that will be one of our analyses.

Got it. A couple more questions, if that's all right. Sticking on the trial design, I believe that the ReSPECT-LM trial is enrolling LM patients with any primary tumor type. I'm wondering if you think that it's possible that 186RNL could receive a broad LM label upon a potential approval? Or do you think primary tumor type will play an important role and maybe limit the breadth of the label down the line?

Good question. As you probably know, FDA almost always wants a disease-specific indication. And currently, we -- and by the way, although all solid tumors have the potential for leptomeningeal complications.

Breast and lung by far, are the most common etiologies. Based on that and what we know now, we will certainly drive those, which will represent probably the most significant commercial application. We will discuss with FDA depending on the findings, and these first patients will be all comers and we can show with other tumor types that there potentially is a benefit.

We'll have that conversation with FDA but it may make regulatory sense maybe regulatorily required that we be disease-specific and we've already selected those that are the highest incidence contributors. But there are others we've -- there's other grant capabilities we have for further funding.

I like your idea of a broad indication, but we are the most highly regulated industry on the planet and FDA has their criteria. And repeat myself, it's usually disease-specific.

Got it. And one more for me. I'm just wondering if you can provide any color on what we might expect to see at the [SNOW] conference. Obviously, there isn't a lot of time between SNOW and the EANM conference. So I was just wondering if you think that maybe we'll see 1 or 2 more patients or just what we can kind of look forward to there?

Yes. I mean I wouldn't expect transformational news. I think the goal here will be to provide incremental news. And I think the -- just so you can understand the rationale behind it is we're very much in the marketing phase. We're going from sleepy academic study to try to -- going into Phase II in GBM and trying to accelerate enrollment in LM.

So part of what we're trying to do here is get the word out to the neuro-oncology community where we'll have an investigator dinner. We'll bring in new sites into these trials very soon, both the GBM trial and the LM trial as well as the pediatric brain cancer trial.

We have an opportunity to talk with them one-on-one and to go into detail on the data. So the -- there are multiple reasons to present at a meeting like this, and I think this is less about presenting significant changes in the data. It will be incremental data, but to be able to really get the word out to the community and I think thus far, the community has been very accepting but we've got to go through the work to get that news out. And Dr. LaFrance, would you like to add anything?

You're right. The time between the meeting is close. Of course, the likelihood of a tumor patients is there and we'll share that. Importantly, the data we've had is remarkably consistent, both in the GBM as we get to these higher efficacious dose levels.

And what's remarkable for these earliest doses in LM, every patient has behaved the same way. They've had decreases in CSF tumor counts and their distribution and the durability of distribution and their tolerability have all been right on target and exactly the same.

So usually, you see a little more variability. But one of the strengths of radiopharmaceuticals once you have some of this proof and preliminary data there's -- and particularly the way we're giving it, we expect more of the same. Of course, we've got to develop that data, but a few more patients, but we already have a very good signal.

Our next question comes from Edward Woo with Ascendiant.

I just want to clarify a question. You mentioned that with the grant and your current source of cash, you have enough cash to last you through 2025. Does that include all 3 clinical trial cost?

Thanks, Ed. I appreciate the question. So the short answer is, yes, it does. We are -- I'm still pinching myself from the kind of recovering from the announcement of the CPRIT grant, which is obviously kind of transformational for the company. So we're in a position today where the lead indication GBM by the NIH. Our second indication leptomeningeal metastases Phase II for up to (inaudible). Then the third indication, pediatric brain cancer, we expect a fairly slow enrollment for that typically kind of 6 to 10 patients per year at most.

And I think what I would add is on that, we do not yet have funding or grant funding for that indication. But I think as Marc and I have said in previous earnings calls, the management team is focused on looking for nondilutive funding sources. And given the success that we've had, we will continue that approach, and we take that very seriously.

Great. Well, definitely, congratulations for all of you guys. That grant is definitely a game changer. Investors are getting too excited or whatnot, but what are the opportunities and other grants that are out there? Are there other stuff? Or is this pretty much the main thing that you guys were focused on. Are there other grants and opportunities for stuff like that?

Yes, there are Ed, it's Marc. So kind of look at it in kind of 2 axes. One axis is to work with our academic collaborators to develop grants to study -- maybe not specifically to fund clinical research but also potentially to the fund side projects.

And we're working on one specifically as it relates to looking at novel biomarkers in the LM trial. So that would be kind of one area of pursuit. Another area of pursuit is frankly, CPRIT. And one of the reasons we decided to move the company to Texas is we felt like there was a real opportunity there to leverage an awful lot of state support for cancer funding. And fortunately, we were able to land a nice amount of support early on.

We know one company that has 3 CPRIT grants. So now that I think we've cracked the code on that, I think we have the ability to go back and get more.

Furthermore, I think there's some opportunities corporately beyond CPRIT in terms of NIH, Department of Energy. These are radiopharmaceuticals and nuclear energy. So there's some opportunities there. So that becomes an area of significant interest, and we've actually just brought on a real superstar, Dr. Melissa Moore, who is Director of Clinical Operations, but she has a PhD from UCLA molecular imaging and knows this space very well. So that brings an added dimension to the team.

Our next question comes from Sean Lee with H.C. Wainright.

And congrats on all the progress. My first question is on the repeat dosing. That's something that you've been mentioning for the last couple of quarters. So I was wondering whether that's something that you look to try in the upcoming Phase II study? Or is it going to be a separate cohort in the current Phase I study? Or is it -- do you plan to start another -- a new study just for the repeat dosing?

Yes. Sean, thanks. It will be a separate study. The protocol has been approved by the FDA. As you can imagine, for repeat dosing, it's based on recurrence.

And so with a relatively small number of patients that have received the treatment so far, and this being relatively recent development, that will -- it will be sporadic. But part of the rationale here is to explore safety of multiple doses and get the FDA comfortable with that.

The other way to look at that is, are there instances where maybe there's some areas of the tumor that we don't cover for whatever reason, for example, if the tumor has a very unique or difficult morphology, it may be difficult to address it with 3 or even 4 catheters or as we get to bigger tumors, the morphology and the size of the tumor starts driving delivery efficiency.

So having a protocol in place that allows us to potentially go back and treat a patient that we -- that our dose symmetry evaluation postoperatively clearly shows that there's a nidus, potential recurrence that we want to treat that.

So I think I mentioned in the previous call, this idea that of getting really long-term survivors here as possible. But it's likely because of the peskiness of eradication of all the malignant cells is so difficult that we might have to provide some sort of retreatment strategy either 2 or 3 years later when a well-treated tumor actually recurs or maybe early in the postoperative phase after a single administration where maybe the tumor was so difficult.

We just couldn't cover the whole thing reliably. So that's the approach, but that will be separate to the Phase II. The Phase II data is strong enough to support -- the -- moving that forward as a single administration trial for small- to medium-sized tumors and can -- we think can succeed on its own as a single administration.

With regards to the LM study, as you mentioned, [DSD] is likely going to favor a more primary to a specific indication. Is there any one that you are leaning towards at this point?

Just to be clear, is that an LM indication you're speaking about -- great question. And yes, -- and for LM, the most prominent demographic contributors are breast and lung.

Right behind them are GI, some head and neck, another area that would be potentially of great interest would be melanoma. And we all know those melanomas increased way. But for focus and the way we have CPRIT funding. So we already have funding in place for the 2 biggest contributors to leptomeningeal metastases.

I think maybe if I could just add. The way the current IND is written, and we plan to continue this -- it would be that we'll have all comers in the first 9 patients and then after 9 patients will be restricting down to breast and lung.

(Operator Instructions) Our next question comes from [Youan G.] with B. Riley.

This is Brandon on for [Youan.] So you mentioned earlier about the GBM study with a large or complex morphology, we're wondering what percentage of patients you see that have those like very large tumors or the morphology that might be too complex to address with a single dose?

Thanks for the question. Our current Phase II will proceed at the dose as Marc mentioned, we are putting a conservative volume limit at 20 cubic centimeters, you'll probably get a little bit more tumor volume with that of our data showing. That's about 2/3 to 3/4 of all the glioblastoma presentations, and that's a conservative number.

So I would then break down the answer. For complex morphology, you'd think, oh, nice spherical tumors, how they present, and many of them do or ellipsoid or whatever. Once in a while, you get funnier shapes. Those are the ones -- that's a small percentage, almost single-digit percentages that look funky and different.

But even the regular tumors might benefit from additional administrations. And Marc went over the basic example of -- there's 2 options. One is our retreatment on recurrence, which is already approved for those patients who might qualify.

And the second would be a more forward-looking study where we'll have a multiple dose paradigm based on tumor coverage. So we have most of the tumors already covered, and that's why we're continuing dose escalation to get those last 25% or 30%.

That's helpful. And then regarding the LM study, I think you mentioned the potential for repeat dosing that earlier. We just wondering if you would continue the single dose escalation beyond the cohort 3 before attempting multi-dosing? Or if you would be able to do those simultaneously?

Brandon, good question. The agreement with the FDA was that we would do 9 patients. We dose escalate twice through 3 cohorts, doubling each time, single administration, as you mentioned, and then go back to the agency. So the plan is to do that once that Cohort 3 is completed.

My view, and that's subject to agency approval would be that we would continue single dose escalation until we get the dose-limiting toxicity. I think there's a good chance we're going to see something similar to what we're seeing in GBM that we can get to supernormal dosages without significant toxicity.

So that's based on the nature of Rhenium, how it works. Its dose rate and dose density and the anatomy of the CSF space and that you don't have the dose length of Rhenium it's only about 2 millimeters. So your penetration is going to be pretty small. So you're really going to -- you're going to coat the CSF space and minimize damage to the white matter.

So I think the plan would be to continue to dose escalate to DLTs and then add a multiple dose treatment. As you may know, some products that are in investigation that are sort of similar nature, include multi-dosing paradigms up to 4 doses in those patients. One can envision perhaps maybe titrating dosing to cell counts. That's one of the benefits of having biomarkers that we hopefully will show that there's something we could use to titrate dosing.

So that's kind of how I'm looking at it, but that will be subject to the data and feedback from the FDA.

That's helpful. So the cell count thing that you just mentioned, does that mean you think that it's possible that the cadence of the multiple dosing would be on a per patient basis rather than as a set cadence for all patients.

Yes. I think -- so like Norman mentioned the patient prior to a pretty significant symptomatic improvement and not much of a cell count. But they had a much higher cell count, I think, prior to that -- and that receipt some other therapy, but didn't tolerate it.

So I think you would ultimately as a doctor, speaking as a doctor, you're ultimately going to go on clinical symptomatology. But if you've got a patient that is asymptomatic and has -- cell count of 0 maybe from a previous treatment or 2, I think you'd be lowed to retreat them.

But if you have a patient that's -- those symptoms have worsen and their cell counts going up, that might be a trigger to retreat them. So I don't think it will be a simplistic model, just using cell count alone. It will take clinical factors in that. But hey, it's great to have more data than -- right now, imaging is a poor measure of this extended disease. These patients have debilitating neurologic symptoms.

They're -- they survived 4 to 6 weeks untreated. So I think we'll use -- adding additional diagnostic to determine dosing cadence is going to be important going forward and making a big impact in these patients.

And I'm not showing any further questions at this time. I would now like to turn the call back over to Marc Hedrick for any further remarks.

Thank you, Josh. Just to close, I want to, as usual, thank everybody to join us on the call today. We appreciate your interest in the company and what we're doing. I also want to make sure to remember our employees, the physicians and scientists we work with on a daily basis.

And of course, the patients who enter into these trials and trust us to deliver. So look forward to updating everyone as we move forward and thank all of our stockholders also for their continued support and confidence. Back to you, Josh.

Thank you. This does conclude today's conference call. Please disconnect your line at this time, and have a wonderful day.