Plus Therapeutics Inc (PSTV) 2021 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Plus Therapeutics Third Quarter 2021 Results Call. (Operator Instructions)

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 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. Marc Hedrick, Plus Therapeutics' President and Chief Executive Officer. Sir, you may begin.

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 our Investigational New Drug application for the use of RNL186 (sic) [186RNL] in patients with leptomeningeal metastases.

We also entered into an agreement for the commercial production of our radiopharmaceutical, RNL186, 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 SNO. 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 3-dimensional convection-enhanced delivery. It is administered directly to the tumor. The active agent is a 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 20x the radiation dose one can deliver with traditional external beam radiation. Our initial indication for RNL is recurrent glioblastoma, which affects approximately 13,000 patients annually in the U.S. 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 5 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 I and Phase II multicenter sequential cohort, open label, volume and dose escalation study of the safety, tolerability and distribution of 186RNL. The trial is currently funded to a significant degree by the U.S. National Cancer Institute. We are now into an 8 dosing cohorts 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 8 represents a 40% increase in both dose and radiation compared to cohort 7. 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 4 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 20x the radiation dose typically delivered by EBRT in the recurrent setting.

Regarding safety, and this data is 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 1 or 2 in intensity and nonserious. The adverse events or AEs with the highest incidence were fatigue, muscular weakness, headache and also gait disturbance. Most AEs were considered causally unrelated to RNL except one case of scalp discomfort, which was considered related to the surgical procedure, and one case of cerebral edema.

AEs with Grade 3 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 2 subjects in cohort 2, namely seizure and vasogenic cerebral edema; one subject each in cohort 4 and 5, both seizure; and 2 subjects in cohort 6, 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 appeared to be -- appeared 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 4 catheters can be used for delivery, and the mean percent tumor coverage with the radiation is 90%.

Although the Phase I 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 pseudoprogression. While we analyze the imaging results in an ongoing manner, we look closely also at the gold standard endpoint survival. 3 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 8 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 conducted 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 1, 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 have 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 5 patients was 769 days or about 25 months. And 2 patients are still alive in this cohort.

In the more recent cohort, really since we took over the trial, of those 9 patients treated, enrolled since 2020, 7 of 9 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 7 patients is 173 days, but 6 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 RadioMedix, Inc. for the commercial production and logistical support of the company's investigational radiopharmaceuticals. Thus far in 2021, the company has entered into 5 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 186RNL investigational drug. The company remains on track to deliver GMP 186RNL by mid-2022.

Looking forward, the company will present interim data from its ReSPECT-GBM 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 of this year. In addition, at 4:00 p.m. Eastern Standard Time on November 18 this year at SNO in Boston, the company will sponsor an in-person and virtual scientific roundtable discussion and Q&A period with ReSPECT 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 8 this year, ideally completing this cohort in Q4 of this year. And based on that time line, 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 186RNL for the treatment of LM. We expect to initiate patient accrual in a Phase I dose escalation trial in the fourth quarter of 2021. The trial will be called ReSPECT-LM. It will be a multicenter, sequential cohort, open-label, single-dose, dose escalation Phase I study of the safety and tolerability, biodistribution, dosimetry and antitumor activity of 186RNL given intraventricularly via the standard Ommaya 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 or response -- excuse me, 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 common indwelling catheter, as I mentioned, a reservoir called the Ommaya 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 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 RNL. Based on our pre-IND meeting feedback received earlier this year, we intend to submit an IND in early 2022 to investigate the use of RNL in kids with brain cancer.

Finally, as mentioned in September, the Board and I are pleased to welcome Dr. Norman LaFrance to the Board 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 the 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 life cycle 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?

Thank you, Marc, 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 9 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 9 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 9 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 cGMP drug product for the plans for pivotal registration trial. G&A expense was $4.8 million for the first 9 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 9 months of 2021 to approximately $708,000 from approximately $854,000 for the same period in 2020, reflecting the paydown of debt principal to $4.3 million in 2020.

Net loss for the 9 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, Marc.

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 the ReSPECT-GBM trial, we intend to complete the current cohort and present a comprehensive trial update at SNO, 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 RNL, 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 the 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 accrual 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 manner if and when we have news to report on that front.

So Ashley, I think at this point, we'll move on to Q&A.

(Operator Instructions) And we'll take our first question from Jason McCarthy with Maxim Group.

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, what Dr. LaFrance sees in the RNL platform and why he's excited to join?

Jason, thanks for the question. 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 will be difficult. Physician CMOs that have an oncology background 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 yes, I think we went through a recruiter, who did a great job, identified a number of candidates, but -- 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, 2 to 3 months in looking at the data. 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, a very good job, he was -- I think he was highly motivated. And we're -- we feel very lucky and fortunate to have him on board and think he'll be worth this wait going forward on -- starting on day 1.

Great. And going back to the ReSPECT-GBM study. Can you talk a little bit maybe about how high the absorbed dose really could be pushed? Because you're at 740. When you change the flow rate and the concentration and the volume, 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?

Yes, 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.

We think that granular data is going to be very important going forward. I just wanted to make that clear that this is -- given these high doses of radiation, 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, this trial escalated relatively slowly. It started in 2015. I think there was a concern about potentially delivering well past the 35 Gray that's typical in their current setting and then the 60 to 80 Gray in the primary setting for external beam 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 is 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 that will 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 maintained 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.

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 where 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?

Yes, it's a good question. And the delivery is totally different than in GBM. And the -- one of the benefits of studying this disease therapeutically is that almost all of these patients that are diagnosed with LM end up getting an Ommaya reservoir. So they have a long-term built-in reservoir that is -- that terminates in the ventricle and allows simply 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 that in an outpatient setting in the span of 5 minutes delivering this drug. A nurse could do it. 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.

We'll take our next question from Ed Woo with Ascendiant Capital.

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?

Ed, it's Marc. That really just depends on how quickly we enroll these last patients. It's possible, but I just -- I can't predict. And I can't predict whether we'll have the 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.

Great. And then congratulations on getting the recent IND for RNL for another indication. Pretty soon, it looks like you'll have 3 indications. Are you going to pretty much just focus on those 3? Or are you guys going to be working on other indications at the same time?

We're, big picture, interested in building out the targeted radiotherapeutics platform. We think that 186RNL for these narrowly focused CNS indications are -- we're 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, but we want to balance that with being able to appropriately finance that in a shareholder-friendly way.

So we're very happy, and we're -- 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.

And there are no further questions, and I will turn the call back over to Dr. Hedrick for any additional or closing remarks.

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 for your participation, and have a good evening.

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