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spk04: Good afternoon, ladies and gentlemen. Welcome to the Plus Therapeutics second 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 positions. All such statements are subject to risks and uncertainties, including the risks and uncertainties described under the risk factors section included in the PLUS Therapeutics annual report on Form 10-K and quarterly report 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, circumstances after the date they are made. It is now my pleasure to turn the floor over to Dr. Mark Hendrick, PLUS Therapeutics President and Chief Executive Officer. Sir, you may begin.
spk01: Thank you, Jonathan. Appreciate it. Good afternoon, everyone. Thank you for once again joining us today as we provide an overview of recent business highlights and discuss our 2022 second quarter financial results. Joining me on 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 and clinical progress before turning the call over to Andrew to review our financials. And Dr. LaFrance will be joining us for a question and answer period. I can say with a tremendous amount of certainty that 2022 is shaping up to be an outstanding year of progress for PLUS Therapeutics across all fronts. I continue to be very pleased with our team's performance in critical areas such as drug manufacture and clinical development. Also, I'm very excited about the performance of our 186, RNL drug in our two active clinical indications, glioblastoma and leptomeningeal metastases. While still in the early to mid-stage of clinical development, 186-RNL is functioning biologically in a manner that is very consistent with its original design objectives and showing a solid safety profile coupled with a biologic response. So let's start with our rhenium-186 nanoliposome development program and specifically our CMC activities. In July 2022, the company completed the technology transfer and initiation of cGMP manufacturing of the 186-RNL drug intermediate with Pyramol Pharma Solutions. Additionally, the intermediate drug product is testing and we believe it to be compliant with FDA guidance for manufacture of nanoliposomal drug products for use in late-stage clinical trials and even commercialization. We expect to have GMP drug availability in the second half of 2022 on time for ongoing and planned Phase II clinical trials in adults with recurrent glioblastoma, leptomeningeal metastases, and all future disease targets. In Q2, The company submitted a briefing package to the FDA to seek their opinion on the sufficiency of the 186 RNL CMC development plans for GMP drug manufacture. The company anticipates making a summary of those meeting minutes public when finalized. Regarding the GBM program, this trial is enrolling currently, and it's a dual Phase I-II multicenter sequential cohort open-label Volume and Dose Escalation Study for Recurrent Glioblastoma. The trial is currently funded to a significant degree by the U.S. NIH and the National Cancer Institute. In July of 2022, at the Society for Nuclear Medicine and Molecular Imaging Annual Meeting, Dr. Bill Phillips presented positive interim data on our lead investigational drug, 186-RNL, for the RESPECT-GBM trial in patients with recurrent GBM. During the presentation, the company noted that the trial has evaluated 23 adult patients with recurrent GBM across seven cohorts of increasing dose. To date, after a single administration, there have been no dose-limiting toxicities and promising efficacy signals have been observed in patients receiving an average absorbed dose of radiation of greater than 100 gray. As presented in Q2, the most recent data shows a two-year improvement in median overall survival in patients receiving greater than 100 gray versus those receiving less than 100 gray. Furthermore, in the greater than 100 gray subset of patients, the median overall survival of 130 weeks compares favorably with real-world data in a recent meta-analysis of similar patients receiving monotherapy bevucizumab, and that was about 32 weeks median overall survival. And this data is referenced in detail on our website. As planned, we submitted a second briefing package to the FDA for the purpose of defining the clinical development plan for 186. This is the company's first formal detailed clinical correspondence and interaction with the agency since the end license of R&L in mid-2020. Based on the positive safety profile and promising efficacy signals observed thus far in what is a very poorly met medical need, we'd like to determine the agency's opinion of the best next steps for ongoing clinical development. From this, we intend to craft a collaborative longer-term plan leading to a potential new drug approval for what is a very unique and novel combination of a radiopharmaceutical and novel delivery methodology. The company anticipates making a summary of those meeting minutes as well, public, when finalized. Big picture, based on the data observed thus far, we believe the best overall clinical development path forward would incorporate at least a three-prong approach. First, to continue the current phase 1-2 trial to explore further dose escalation as we have yet to observe dose-limiting toxicities and also continue to work to further optimize the delivery and dosing parameters. Second, we intend to explore serial dosing And in Q2, the FDA allowed the company to proceed to a multi-dose extension trial to go after tumors, again, either if they recur or if in key areas of the tumor were incompletely treated with a single administration. This is going to allow us to potentially treat larger tumors or those with significant morphologic or geometric complexity that may be difficult to completely treat in a single administration. Finally, we feel the cohort dose and volume is likely appropriate to move forward as a recommended phase two dose to treat patients with small to medium-sized tumors. Whether that's in the current phase two NIH-sponsored trial that's ongoing or combined phase two or phase two three trial design sponsored by the company, that'll be up to our discussions with the FDA. Taking a step back and putting this in big picture, The combination of studies I just mentioned allows us to begin to explore and solve for our big dream, which is to transform brain cancer from a death sentence, as it sits today, to a chronic disease managed by serial RNL treatments as needed for each patient throughout their disease course. This fall, the trial's principal investigator, Dr. Andrew Brenner, will provide a full data update on the Phase I-II Respect GBM trial at the European Society of Medical Oncology in Paris, France, and that's going to be September 9th to 13th. We don't have the exact date and time, but that will be a podium presentation. As to our leptomeningeal metastases or LM development program, this trial, as a reminder, is a multicenter Phase I-II dose escalation study to determine the maximum tolerated dose safety and efficacy of 186-RNL and LM. To remind you, LM is an end stage, typically 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. Median survival with current aggressive treatment is about three to eight months, depending on which primary tumor actually caused the LM. The one- and two-year survival rates are about 7% and 3% respectively, and survival without treatment is about four to six weeks. The most common tumors giving rise to LN are gastrointestinal malignancies and melanoma. There are no approved therapies, and standard treatment includes a grab bag of things, such as external beam radiation therapy to the affected sites, followed potentially by chemotherapy that can be given orally, intravenously, or commonly administered twice weekly directly into the cerebral spinal fluid space until the patient can no longer tolerate the therapy or passes away. In Q2, the company completed enrollment on time of Cohort 1 of the Respect LM Phase 1-2 Dose Escalation Trial of 186-RNL. 186-RNL was successfully delivered without dose-limiting toxicities in its initial cohort, and the independent RESPECT-LM Trial Data Safety and Monitoring Board has approved the plan to move ahead with Cohort 2, which we're in the process of doing. Also in Q2, the company announced that we had entered into a multi-year agreement with BioCEP Incorporated to employ its cerebral spinal fluid assay system in the RESPECT-LM trial. Biceps assay provides a highly sensitive method to assess and quantify tumor cell burden in LM of the central nervous system and also allows us to look at specific tumor cell markers and indicators of radiation damage. Assay results will be used to evaluate biologic response to the treatment and treatment efficacy and ultimately potential determination of the timing or cadence of re-treatment in patients enrolled in the trial. Finally, regarding our novel, recently in-licensed radioembolic microparticle technology called 188-RNL-BAM, or just BAM, we have completed the technology transfer phase and are on track to complete key CMC feasibility activities and certain IND-enabling preclinical studies by the end of the year, and we're on track for that. We are planning to meet with the FDA for a pre-IND meeting this year as well. With this resolvable biomaterial embolic technology coupled with a highly potent radiotherapeutic isotope, we believe we can target almost any solid organ tumor in the body using standard interventional radiologic means and leverage the breadth of the human vascular system to selectively reach only the tumor without having to incur a systemically circulating radiotherapeutic that could harm the bone marrow or other organs of the body. 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's been out there for many decades for the treatment of liver cancer. And our plan is to initially focus developing the BAM technology as a next-generation bioresorbable radial embolization therapy for nonoperable liver cancer, which has a very low five-year survival rate of about only 20%. And the drugs that are out there are not bioresorbable. They're permanent. So with that, I'll turn the floor over to Andrew, our CFO, who will review the financials. Andrew?
spk02: Thank you, Mark. Good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the 2022 second quarter ended June 30, 2022. As of June 30, 2022, cash and cash equivalents were $18.1 million compared to $18.4 million as of December 31, 2021. This represents 18 to 20 months of cash on hand. Cash used in operations for the same 30, 2022 was $6.5 million compared to $5.4 million in the same period for the previous year. The main changes between the second quarters of 2022 and 2021 are as follows. Total operating expenses for the second quarter of 2022 were $5.1 million compared to $2.6 million for the second quarter of 2021. The increase is due primarily to the following. increased one-time development expenditures on CMC-related activities to develop and produce GMP-quality RNL drug material. The overall cost of this development program is in line with our original forecast of approximately $5.5 million. Expenditures are scheduled to be completed in late Q3 2022. with only minimal additional stability testing expenses required on a go-forward basis thereafter. One million related to a combination of third-party professional services and consulting in preparation for our planned FDA meetings, as Mark mentioned, and for clinical trial planning activities to support the ongoing and future glioblastoma development program. The expenditures will be completed as planned in Q3 2022. And to a lesser extent, an increase in legal, IP, and other general corporate expenses. Interest expense decreased from $229,000 in the second quarter of 2021 to $181,000 in the second quarter of 2022. This decrease reflects the continued principal pay down that commenced in November 2021 on the company's Oxford debt. Net loss for the second quarter of 2022 was 5.3 million or 24 cents per share compared to a net loss of 2.8 million or 25 cents per share for the second quarter of 2021. Now I'll turn it back to you, Mark.
spk01: Great. Thank you, Andrew. Before we move on to Q&A, let me just summarize key milestones anticipated for the remainder of 2022. So besides, of course, continuing to work to meet our clinical enrollment goals, we intend to present RESPECT-LM cohort one data at the Society of Neuro-Oncology Brain Mats meeting August 12th to 13th in Toronto. We also intend to present the RESPECT-GBM phase one data at the European Society of Medical Oncology in September in Paris. We intend to report on our two planned FDA meeting minutes in Q3, one for CMC and one for the RESPECT-GBM ongoing clinical program. We anticipate achievement of our GMP 186 R&L manufacturing capability goal soon, and we'll make that public. We also will communicate our planning process in an ongoing manner and the beginning of execution of phase two activities for Respect GBM. We intend to submit, as mentioned, Protocol for Respect Pediatric Brain Cancer, the Respect PBC trial. Later in the year, we'll announce that. And then finally, we'll announce a 188 BAM pre-IND submission for planned clinical introduction in liver cancer. And that will be right around the end of the year. So at this point, Jonathan, let me turn it back over to you, and we'll take some Q&A.
spk04: Certainly. Ladies and gentlemen, if you have a question at this time, please press star then 1. One moment for our first question. And our first question comes from the line of James McCarthy from Maxim Group. Your question, please.
spk03: Hey, guys. Thank you for taking the question. This is Michael Okunowich on the line for Jason. I'd like to see if you could provide a bit more on the mechanism behind the BAM program and how it behaves differently in the body to enable that targeted use in solid organ cancers?
spk01: Hey, Michael. Yeah, so right now the data we have is preclinical only, but the idea is that unlike the two products on the market that are permanent, glass or polymeric, that are used for radioembolization, this product would be bioresorbable. And so we're still in the process of defining the curve and timing of that bioresorbability. But as I mentioned, the idea is that you would identify the tumor, you would embolize the area around the tumor to incorporate the tumor in the radiation delivery area And then sometime after the radiation has been fully delivered and there's been full decay, then the body will resorb that and reestablish perfusion, which then would potentially allow you to come back and retreat if you needed to or there was further recurrence. So that's sort of the general idea. Does that answer your question?
spk04: I believe he dropped off and then rejoined the call.
spk01: Okay, no worries. He knows how to find me.
spk04: Thank you. One moment for our next question. And our next question comes from the line of Ed Wu from Ascendant Capital. Your question, please.
spk00: Yeah, for the cohort one of the RESPECT-LM trial, how many patients was that, and did the enrollment go according to plan? And what do you think would be the challenges to do cohort number two?
spk01: Hey, Ed, thank you. It did. To take a step back, the FDA has asked us to have a three-month period between the first patient in one cohort, three months, and the first patient in the next cohort. So we sort of have this mandatory wait. We also have a 30-day delay between the first patient in the new cohort, and the second patient. But we can do two and three relatively quickly. So in best case, we could get the first nine patients enrolled around the end of the year. And that's kind of going at the maximum rate depending on kind of following that FDA dictated schedule. And then the trial design incorporates At that point, and this was a great suggestion by the FDA, to come back to the FDA and then we will amend the, based on the safety data, we'll amend the data collection and provide the opportunity for re-treatment to these patients. So potentially we could come back and start providing additional treatments as we get increasingly more comfortable with the safety profile. So the idea is, again, just we'll try to get the first nine patients enrolled quickly, assuming there are no safety issues, of course. And that's kind of around the end of the year. And then we'll go to the FDA. There'll be a pause while we interact with the FDA. And then we plan to come back with quite a bit number of sites. There's a lot of interest in the trial. And then we'll move to hopefully additional doses in each patient in an expanded treatment profile.
spk00: Great. And then the next question is, you obviously had a lot of interactions with the FDA, and you're looking forward to, you know, putting out the notes that you guys have. What has been a timetable with interacting with FDA? Have things pretty much gone back to normal, you know, post-COVID, or are you still seeing possible delays here and there?
spk01: Yeah, so most of our interaction with the FDA has been more recent. And to answer your question, it's both to myself and to our chief medical officer and our regulatory consultant. So I think we've been very happy with the turnaround and the interaction. It's been great. It seems totally normal.
spk00: Great. That's good to hear. Well, that's all the questions I have. I wish you guys good luck. Thank you.
spk04: Thank you. Thank you. Once again, if you have a question at this time, please press start. And we have a follow-up from Jason McCarthy from Maxim Group. One moment.
spk03: Sorry about that. I got bumped off the call floor. No problem. I'd like to see if you could discuss a bit further what the collaboration with BioSTEP does for your clinical trial in LM. How do regulators view the use of C&Side to guide treatment, and can this be used as a surrogate endpoint for response monitoring? Is it more targeted at just collecting additional data to support your development?
spk01: Yeah, so the ultimate use of this is yet to be determined. We do think there's an opportunity to potentially use it as a surrogate endpoint. In fact, I'm sure it will be. Now, whether it ultimately becomes a primary endpoint or secondary endpoint or something else, it remains to be seen. We'll see what the data shows. I think that would be BIOSEP, so it would be a meaningful follow-up endpoint in these patients. I can... The way I look at it is that this is an interesting disease because all of these patients have my reservoirs in them that we use both therapeutically and, as I mentioned, I think that the current treatment that's typically important is patients come back twice a week and have chemotherapy injected into the port. Well, there's also the opportunity at any point in time to withdraw CSF and measure certain things. What we've done thus far with BICEP is simply measure tumor cells per ml and report that. And I didn't mention this, you'll see the full data set in August, but in all three patients we've treated, we've seen dramatic reductions in tumor cells that are persistent out a month with a single administration. So that these tumor cell data is looking like it's providing information that supports biologic activity of the radiotherapeutic in the CSF. We're also looking at other tumor cell markers more in exploratory phase and also intend to look at markers of radiation-related damage and do that again as exploratory phase with BIOCEP. They have a much greater capability beyond just the... physical counting of tumor cells. We think it has a lot of potential utility and potentially even guiding therapy. I mean, one could imagine that a patient gets treated, you follow their certain markers, including tumor cell count, over a period of time, and you make your redosing decisions based on the data you find from repeated or serials All right.
spk03: Thank you very much. And then just one last one from me. I'd like to just ask if there are any unique challenges associated with the treatment of LM compared to something like glioblastoma.
spk01: Yeah. So I would say, you know, on the downside relative to GBM, These patients can be very fragile. And so we've had a couple of patients who we were on track to treat and they decompensated because their survivals are very low, even with treatment low. But from the time they've had their Maya reservoir placed, They've had their, we do a flow study just to make sure there's good flow from the ventricle to the rest of the CSF space. The patients have decompensated and they no longer match the inclusion-exclusion criteria. So for us, the key there is simply to make sure that we compress the time down. And then also we make sure that we ideally have more patients than we have patients. that we have drugs so that we don't slow down the enrollment of trial. You didn't ask about this, but on the flip side, I'll just volunteer that these are much easier patients to enroll in the sense that physicians are very interested in this trial. There's a lot of interest in participating. The physicians that we talk to see multiple patients a week that would qualify I think this trial could enroll very quickly once we get a more mature phase of the development plan. And there's a lot of physician interest in this drug.
spk03: All right. Thank you very much. I really appreciate the additional color.
spk01: Yep.
spk04: Thanks for the question, Michael. Thank you. Once again, if you have a question, please press star then 1. And this does conclude the question and answer session of today's program. I'd like to hand the program back to Dr. Mark Hendrick for any further remarks.
spk01: Thank you, Jonathan. Just to close, I want to thank everybody that joined us on the call today and provide my appreciation also to stockholders, employees, physicians and consultants with whom we work, and the patients who trust us. So as always, we'll work to provide full and frequent updates as we move forward with these various programs. Thank you once again.
spk04: Thank you, ladies and gentlemen, for your participation at today's conference. This does include the program. You may now disconnect. Good day.
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