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spk01: Good afternoon, ladies and gentlemen, and welcome to the PLUS Therapeutics third quarter 2021 results call. At this time, all participants have been placed in a listen-only mode, and the floor will be open for your questions following the presentation. If you would like to ask a question at that time, please press star 1 on your telephone keypad. If at any point your question has been answered, you may remove yourself from the queue by pressing the pound key. We ask that you please pick up your handset to allow optimal sound quality If you should require operator assistance, please press star zero. 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 said statements are subject to risk and uncertainties, including the risk and uncertainties described under the risk factors section included in the PLUS Therapeutics annual reports 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 risks and 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 that they are made. It is now my pleasure to turn the floor over to Dr. Mark Hedrick,
spk02: plus Therapeutics President and Chief Executive Officer. Sir, you may begin.
spk07: Thank you very much, Ashley. Good afternoon, everyone. Thank you once again for taking the time to join us today as we provide an overview of recent business highlights and discuss our 2021 third quarter financial results. Joining me on the call today is Mr. Andrew Sims, our Chief Financial Officer. Before Andrew provides a summary of our financial performance, I would like to provide an update on the company's business activities since our last call. Big picture, in the third quarter, we made good incremental progress toward our mission to become a global leader in developing and delivering precision-targeted radiotherapeutics for cancer. Specifically, we received clearance from the FDA for investigational new drug application for the use of RNL-186 in patients with leptomeningeal metastases. We also entered into an agreement for the commercial production of our radiopharmaceutical, RNL-186, and we continue to strengthen our leadership team with the appointment of a highly experienced chief medical officer, Dr. Norman LaFrance. Finally, we presented data at the AANS meeting, as well as obtained acceptances to present data from the RESPECT-GBM trial at both ASTRO and SNOW. I'll cover these achievements in more detail in a moment, but let me first provide a summary of plus for those new to the company. Our lead investigational targeted radiotherapeutic is RNL, or rhenium nanoliposome. This is a proprietary liposomal encapsulated radionuclide that is delivered local regionally via targeted three-dimensional convection enhanced delivery. It is administered directly to the tumors. The active agent is rhenium-186 isotope, which is a dual energy emitter releasing both cancer-killing beta particles, which are high-energy electrons, and gamma particles, which are useful for imaging and dosimetry. Rhenium is a very unique isotope, in part because of its energy profile. Its beta energy has a short path link, which provides delivery precision, a low dose rate, which provides a margin of safety, and a high energy density, which is particularly toxic for highly mitotic cells like cancer, which can overwhelm the DNA repair mechanisms that could otherwise contribute to radio resistance. Thus far, we've shown that we can successfully deliver 20 times the radiation dose one can deliver with traditional external beam irradiation. Our initial indication for RNL is recurrent glioblastoma. which affects approximately 13,000 patients annually in the US, and about the same number of patients in the EU. It is the most common and lethal form of brain cancer, and the treatment of this devastating disease remains a significant unmet medical challenge. Published studies indicate that external beam radiation provides the best incremental improvement in survival of all therapies currently used for glioblastoma, which is about five months, and it remains an essential component of multimodal therapy for both glioblastoma and, in fact, many other cancers, but is limited by the complications from higher dosages. RNL is currently under evaluation in our U.S. RESPECT GBM trial, which is a dual phase one and phase two multicenter sequential cohort, open label, volume and dose escalation study of the safety, tolerability, and distribution of 186 RNL. The trial is currently funded to a significant degree by the U.S. National Cancer Institute. We are now into an eighth dosing cohort following the Data and Safety Monitoring Board recommendation to proceed to the next incremental cohort, and to date, we have treated 22 total patients. We provided interim results during the recent Canaccord, Genuity, and Wainwright investor meetings and that data can be found on our website. Notably, cohort eight represents a 40 percent increase in both dose and radiation compared to cohort seven. Thus far in the RESPECT trial, highly targeted and continuously infused or convected volumes of up to 12.3 milliliters containing 31.2 millicuries of radiation have been well tolerated. Up to four catheters can be successfully placed for delivery to best accommodate a variety of tumor sizes and geometries. RNL has been shown thus far to be safe and well-tolerated, despite delivering up to 740 gray of absorbed radiation to the tumor, which again by comparison is 20 times the radiation dose typically delivered by EBRT in the recurrent setting. Regarding safety, and this data as of August 1, 2021, there have been no adverse events or AEs with the outcome of death or discontinuations due to AEs. The majority of AEs reported were mild and moderate, that's grade one or two, in intensity, and non-serious. The adverse events or AEs with the highest incidence were fatigue, muscular weakness, and headache, and also gait disturbance. Most AEs were considered causally unrelated to R and L, except one case of scalp discomfort, which was considered related to the surgical procedure, and one case of cerebral edema. AEs with grade three or leukocytosis, hyperglycemia, muscular weakness, seizure, brain edema, worsening avascular necrosis of the shoulder, vasogenic cerebral edema, and pneumonia. All of these events were considered unrelated to RNL by the investigator, with the exception of brain edema for one subject, which was considered possibly related to RNL. Serious adverse events, or SAEs, were reported for two subjects in cohort two, namely seizure and vasogenic cerebral edema. One subject each in cohort four and five, both seizure, and two subjects in cohort six, pneumonia and worsening avascular shoulder necrosis and cerebral edema. All these events were considered unrelated to RNL by the investigator, with the exception of cerebral edema for one subject, which was considered possibly related to RNL, and or tapering of oral corticosteroids, and none led to study discontinuation. There were no meaningful differences or patterns in the incidence of related treatment emergent AEs reported across individual treatment groups or cohorts. Neither the incidence nor severity of AEs appear to increase with increasing doses of RNL. As to the important issue of drug delivery feasibility, there have been no delivery failures thus far. We can safely deliver up to an average absorbed dose of 740 gray of radiation to tumors. The mean absorbed radiation dose to the tumor is 392 gray. Up to four catheters can be used for delivery, and the mean percent tumor coverage with the radiation is 90%. Although the phase one trial is not designed nor powered for efficacy, we see promising signals of biological effect and potential efficacy. As mentioned previously, imaging-based measures of progression are challenging, as the substantial tissue effects of the treatment often show pseudo progression. While we analyze the imaging results in an ongoing manner, we look closely also at the gold standard endpoint, survival. Three of 22 patients have survived up to 30 months or more, where average survival for the current GBM with standard of care is only about eight to 10 months. Because many of those patients have been treated relatively recently and at the higher dosing and volume cohorts, it understandably makes definitive efficacy determinations on overall survival challenging. But as to the issue of overall survival, what I can say is that we have observed that increases in both convective volumes and radiation dosage seem to correlate with better tumor coverage and higher tumor-absorbed doses. And this, in turn, seems to correlate with overall survival. And this is what one would expect based on the biology of radiation therapy in these tumors. Again, as of August 1st, 2021, 8 of 22 patients remained alive. In the early cohort of 13 patients enrolled between 2015, when the trial started, prior to our involvement, to 2019, where we had the longest follow-up, only 5 of 13 had absorbed tumor radiation doses greater than 100 gray and tumor coverage percentage greater than 75%. which in our view are key biological thresholds. The average survival, overall survival in these five patients was 769 days or about 25 months. And two patients are still alive in this cohort. In the more recent cohort, really since we took over the trial, of those nine patients treated, enrolled since 2020, seven of nine had both absorbed tumor radiation doses greater than 100 gray and a tumor coverage percentage of greater than 75%, a much better delivery success percentage because, obviously, of the higher volumes and radiation doses we're administering in these higher dosing cohorts. The average overall survival in these seven patients is 173 days, but six of these patients are still alive. We will provide a full update at the November Society for Neuro-Oncology meeting in Boston later this year. Furthermore, our team continues to make excellent progress in our drug scale-up and manufacturing activities and is simultaneously putting in place the essentials for commercial readiness. Specifically during the third quarter of 2021, the company entered into an agreement with Radiomedics Incorporated for the commercial production and logistical support of the company's investigational radiopharmaceuticals. Thus far in 2021, the company has entered into five collaboration agreements to support its process development and analytical chemistry activities, as well as to strengthen its supply chain in compliance with good manufacturing practices for the manufacture of the 186 RNL investigational drug. The company remains on track to deliver GMP 186 RNL by mid-2022. Looking forward, The company will present interim data from its RespectGBM clinical trial at the 2021 ASTRO annual meeting scheduled for October 24 to 27 this year, and at the 2021 Society for Neuro-Oncology Annual Meeting and Education Day scheduled for November 18 to 21 also this year. In addition, at 4 p.m. Eastern Standard Time on November 18 this year at Snow in Boston, The company will sponsor an in-person and virtual scientific roundtable discussion and Q&A period with respect to trial principal investigators. At that time, we'll provide a substantial clinical update on the safety and potential efficacy data as of that time point, including a discussion of potential next steps. In parallel, we expect to continue to enroll patients in cohort eight this year, ideally completing this cohort in Q4 of this year. And based on that timeline, We intend to present the clinical data set to the FDA in the first half of next year and determine next steps. Regarding additional indications, RNL is also being developed for other diseases, including leptomeningeal metastases and pediatric brain cancer. Leptomeningeal metastases, or LM, is an increasingly common secondary cancer complicating from other cancers, and based on their increasing overall survival rates that we're seeing with better therapies for primary solid and hematologic tumors. LM affects over 100,000 patients per year in the U.S., and patients can present with a broad range of signs and symptoms due to simultaneous involvement in multiple areas of the craniospinal axis. Earlier this week, we announced clearance of our IND application from the FDA for 186-RNL for the treatment of LM. We expect to initiate patient accrual in a phase one dose escalation trial in the fourth quarter of 2021. The trial will be called RESPECT-LM. It'll be a multicenter, sequential cohort, open-label, single-dose dose escalation phase one study of the safety, tolerability, biodistribution, dosimetry, and anti-tumor activity of 186-RNL given interventricularly via the standard OMAIA reservoir to subjects over 18 years of age with LM. The primary endpoints of the study are the incidence and severity of adverse events and SAEs, and the incidence of dose-limiting toxicities. The secondary endpoints are the overall response rate, duration of response, progression-free survival, and overall survival. In the planned forthcoming trial, really just speaking as a practical matter to help you understand what we're doing. We intend to administer RNL via a common end-going catheter, as I mentioned, a reservoir called the Elmira Reservoir that sits under the skin on the head and communicates directly with the ventricle in the leptomeningeal or cerebrospinal fluid space. And as I mentioned, this is commonly placed in all of these patients with LM and really makes the delivery a very straightforward issue. Furthermore, the reservoir allows periodic CSF, or cerebrospinal fluid sampling, to occur and facilitates the use of tumor-related biomarkers to follow patient response and enables the potential use of related surrogate outcome measures. Additionally, we believe there's an opportunity to help patients with pediatric brain cancer using Ardell. Based on our pre-MD meeting feedback received earlier this year, We intend to submit an IND in early 2022 to investigate the use of R&L in kids with brain cancer. Finally, as mentioned in September, the Board and I are pleased to welcome Dr. Norman LaFrance aboard as the company's Chief Medical Officer. Dr. LaFrance will join Andrew and me on our forthcoming earnings calls. Dr. LaFrance brings several decades of unique and highly relevant clinical, regulatory, and commercial expertise to the PLUS Therapeutics management team. He's actually a nuclear engineer, a board-certified internist, and a nuclear medicine physician. He joined industry a while back after leaving his clinical practice at Johns Hopkins in Baltimore. He has a proven track record in radiotherapeutics and drug development, regulatory affairs, drug lifecycle management, and related commercial experience. He has brought numerous radiotherapeutics successfully to market, and his background will be important to our success as we expand our pipeline, move key programs to late stage clinical development, and position the company for long-term regulatory and commercial success. At this point, I'll stop and turn the call over to my colleague, Andrew, for a brief review of the third quarter financial results. Andrew?
spk03: Thank you, Mark, and 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 30, 2021. As of September 30, 2021, cash and cash equivalents were 21.3 million compared to 8.3 million as of December 31, 2020. Cash used in operations for the first nine months of 2021 was approximately 7.6 million compared to $5.2 million in the same period in 2020, with the key components of the cash used in operations and main changes between 2020 and 2021 as follows. There was no revenue in the first nine months of 2021 as compared to approximately $303,000 in the same period last year. This decrease was due to the closeout of the legacy government contract as previously disclosed. Research and development expenses were 3.7 million for the first nine months of 2021, as compared to 1.6 million in the same period of 2020. The increase of 2.1 million was anticipated and reflects additional RNL CMC development costs to obtain the cGMP drug product for the plans for pivotal registration trial. G&A expense was 4.8 million for the first nine months of 2021, as compared to 4.1 million for the same period in 2020. This increase is mainly due to an increase in legal and other professional fees. Interest expense decreased for the first nine months of 2021 to approximately 708,000 from approximately 854,000 for the same period in 2020, reflecting the pay down debt principle to 4.3 million in 2020. Net loss for the nine months to September 30, 2021 was 9.2 million, as compared to a net loss of 4.6 million for the equivalent period in 2020. Excluding the book gains on the warrants of 2.3 million that were reported in the first quarter of 2020, the change in net loss reflects the incremental R&D and G&A spend, as I mentioned earlier. And now I'll turn it back to you, Mark.
spk07: Thank you, Andrew. Before we move on to Q&A, let me just summarize the milestones we anticipate over the next few quarters. I've mentioned many of these already, but I'll summarize those here. First of all, with respect to your respect GBN trial, we intend to complete the current cohort and present a comprehensive trial update as mentioned. Upon completion of the current trial and data analysis, we plan a clinical meeting with the FDA in the first half of 2022 to finalize the ongoing clinical trial plan. Regarding the CMC activities for R and L, We are working toward completing key GMP manufacturing activities and remain on track to begin stability testing this year, with GMP investigational drug products anticipated to be available middle of 2022. We currently plan a CMC-focused FDA meeting for the first quarter of 2022 to clarify and resolve any open CMC issues that may exist at that time. Regarding the RESPECT-LM trial for leptomeningeal disease, With the IND approval, we plan beginning April as soon as this quarter, 2021. Regarding pediatric brain tumor therapy, an IND submission is planned for early 2022. In terms of our business development activities, we continue to be active in assessing in-licensing and out-licensing opportunities, and we'll provide updates in an ongoing matter if and when we have news to report on that front. So actually, I think at this point, we'll move on to Q&A.
spk02: And at this time, the floor is now open for your questions.
spk01: At this time, if you would like to ask a question, please press the star and 1 on your test cell phone. If at any point your question has been answered, you may have removed yourself from the queue by pressing the pound key. Again, we do ask that you pose your question. Please pick up your handset to provide optimal sound quality. We'll pause a moment to allow any questions to queue. And we'll take our first question from Jason McCarthy with Maxim Group. Please go ahead.
spk05: Hi, Mark. Thanks for taking the question. Just a brief question on Norman LaFrance. He looks like he's a very experienced guy in nuclear medicine. Can you talk to us a little bit about what that recruitment process is like? Just Dr. LaFrance sees in the R&L platform and why he's excited to join.
spk06: Hey, Jason. Thanks for the question.
spk07: So this is a pivotal hire for us, as you might imagine. I've been functioning in the role as CMO and CEO for a number of months. And we knew that finding somebody with the right qualifications would be difficult. Physician CMOs that have an oncology background are are much more common, but having somebody, A, that's got relevant nuclear medicine experience and then has brought multiple products to market, it's a very small universe of experienced individuals. And so, yeah, I think we went through a recruiter who did a great job, identified a number of candidates, and very good candidates, but Dr. LaFrance, who spends a lot of his current day at his previous employer doing business development and due diligence on various assets. Took, I'd say, two to three months in looking at the data. And I think he was impressed with the technology and impressed in the resurgence of this field in targeted radiotherapeutics. And so even at this point in his career, He did a very good job. I think he was highly motivated, and we feel very lucky and fortunate to have him on board and think he'll be worth his weight going forward starting on day one.
spk05: Great. And going back to the Respect GBM study, can you talk a little bit maybe about how high the absorbed dose is? really could be pushed, because if you're at 740, when you change the flow rate and the concentration and the volume, you know, you're really getting to a significantly high number, well over, right, external beam radiation. What are regulators and physicians comfortable with? Because you've had no DLTs. Can you just continue to go higher, or do you just stop and then go to FDA and see where things are at?
spk07: Yeah, it's a good question. And the way we currently analyze average absorbed dose, while a very good approximation of what we're delivering to the tumor, and frankly, we can assess the surrounding brain, is a good estimate. But we're in the process, and I can't speak too much about this, but we're looking more deeply at the amount of radiation delivered on a much smaller scale, rather than defining what's average absorbed dose to the tumor, looking at it in a much more detailed fashion. I think that granular data is going to be very important going forward. I just wanted to make that clear that this is, given these doses of radiation, that the dosimetry evaluation and the radiologic feedback is going to improve very significantly, I think, for us in the next 12 months or so. But having said that, You know, this trial escalated relatively slowly. It started in 2015. I think there was a concern about potentially delivering, you know, well past the 35 gray that's typical in their current setting and maybe 60 to 80 gray in the primary setting for external radiation for GBM. I think there was some nervousness with respect to the FDA, but obviously we've gone way past that. The safety profile looks very promising at this point. The way to think about it, We sort of put this average absorbed dose number that's very high, but really the question is what's the amount that you need to kill the tumor and then also essentially sterilize the transformed cells that are sitting in the periphery of the tumor that you can't visualize, but are very likely there and they'll be the culprit that will cause the recurrence. And so it looks like, based on the data, that an average absorbed dose of 100 gray is probably a good threshold. Does it make sense to go up beyond that? Probably not. What's more important really is the volume. And that's why, but as you increase the volume, we keep the radiation percentage that we deliver currently 2.5 millicuries per cc. So we maintain that from the last cohort to this course cohort. So we're delivering more volume, but also more radiation, but at the same concentration. So the key is to try to not only treat the tumor, but treat that surrounding area. So I know that's a long answer, but bottom line is I think we're near the end of what's feasible in terms of volume and radiation and what's necessary to optimally do the job, and I think this probably is the last cohort, although we'll see what the data looks like.
spk05: And then just last question on the LM program that's coming up. Are there any different sets of circumstances or challenges in terms of catheter placement LM can find its way into, it's very different than GBM, right? You can have some spinal cord involvement or other different, more difficult to reach areas of the brain. Or is that not an issue?
spk07: Yeah, it's a good question. And the delivery is totally different than in GBM. And one of the benefits of studying this disease therapeutically is that almost all of these patients that are diagnosed with LM end up getting in a Meyer reservoir. So they have a long-term built-in reservoir that terminates in the ventricle and allows essentially real-time access with a small-bore needle directly through the skin into the ventricular system. So on one hand, it allows you to deliver in an outpatient setting in the span of five minutes delivering this drug, a nurse could do. It's very straightforward. It also allows for the ability to sample the CSF for cell count, protein, glucose, and other DNA-based markers to look at tumor response as biomarkers. So, the delivery sophistication and challenge is much lower in this group of patients. than it is with respect to GBM.
spk05: Great, Mark. Thanks for taking the question.
spk07: Thanks, Jason. Appreciate it.
spk01: And we'll take our next question from Ed Wu with Ascendant Capital. Please go ahead.
spk04: Yeah, thanks for taking my question. You mentioned that this is probably the last cohort you guys have. Will you be able to know when you release, I guess, the data in November whether you'll go for a ninth cohort or not?
spk07: Hey, Ed, it's Mark. That really just depends on how quickly we enroll these last patients. It's possible, but I just can't predict. And I can't predict whether we'll have a dose limiting toxicity or any safety issues at the current dose. We've treated one patient in this current cohort. Patient did well, but it really depends. So I just can't predict that. But if we know more about that particular issue, we'll certainly discuss that at the time of the call.
spk04: Great. And then congratulations on getting, you know, the recent IMD, you know, for R&L for another indication. Pretty soon, it looks like you'll have three indications. Are you going to pretty much just focus on those three, or are you guys going to be, you know, working on other indications at the same time?
spk07: We're big picture interested in building out the targeted radiotherapeutics platform. We think that 186 R&L for these narrowly focused CNS indications are just scratching the surface. Part of the reason to bring Norman or Dr. LaFrance into the loop is he is probably as experienced as anyone in evaluating new technologies in this field. So, we continue to kick the tires on new things that could augment the portfolio. We want to balance that with being able to appropriately finance that in a shareholder-friendly way. So we're very happy and our hands are very full with what we have, but we're still looking towards the future and building out the portfolio in new and interesting and value-creating ways.
spk04: Great. Well, thanks for answering my question, but good luck.
spk06: Thanks, Ed.
spk01: There are no further questions, and I will turn the call back over to Dr. Hedrick for any additional or closing remarks.
spk07: Thank you so much, Ashley. Just want to say thank you to everybody that joined us on the call or that are listening to the call in the recorded version. On behalf of the board, I'd like to just thank our employees and our team members and the physicians that we work with and the patients that trust us to enter into these trials. Thank you very much.
spk01: Thank you, and this does conclude today's conference call. Please disconnect your line at this time and have a wonderful day.
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