Plus Therapeutics, Inc. (PSTV) Earnings Call Transcript & Summary

Good afternoon. Welcome to our investor update call on our Phase I ReSPECT trial for recurrent glioblastoma. As a reminder, please review our forward-looking statements language that can be found in this investor deck or other investor-oriented presentations. My name is Marc Hedrick. I'm President and CEO of Plus Therapeutics. I'll lead the call through our planned 1-hour agenda. First, I'll present a brief overview on Plus, then the team will talk about recurrent glioblastoma as a disease target. And then we'll talk about the results of the ReSPECT trial thus far, and then we'll hear from a patient. Following the patient, we'll then have time for Q&A. Joining me this afternoon are Dr. Gregory Stein, Senior Vice President of Clinical Development at Plus Therapeutics; and also, we're fortunate to have Dr. Andrew Brenner, Associate Professor of Medicine, Neurology and Neurosurgery at UT Health Science Center at San Antonio. So with regard to Plus Therapeutics, our focus is on the discovering, developing and delivering complex and innovative treatments for patients battling against rare cancers. For those of you that are new to the company, we are a NASDAQ-traded company based in Austin, Texas, with a proprietary nanoparticle drug development platform. We have 3 clinical stage oncology drugs in development, and our lead drug, RNL is funded by the NIH and specifically the national cancer institutes. Our technology platform is based on our expertise in developing, manufacturing and scaling up liposomal or nanoparticle drugs containing a variety of active pharmaceutical ingredients. Most recently, we added proprietary technology to our platform that allows us to encapsulate a variety of radionuclides in our liposomal constructs. We have 3 clinical development stage drugs, but today, our plan is to focus only on our investigational drug, RNL for recurrent glioblastoma. And so with that, I'd like to introduce Dr. Greg Stein, Senior Vice President of Clinical Development, who will present an overview on the use of RNL-186 for recurrent GBM. Dr. Stein?

Thanks, Marc. Appreciate that. So glioblastoma and recurrent glioblastoma, unfortunately, is almost universally fatal. The incidence rate is about 6.5 per 100,000, and in the U.S., that translates to approximately 12,000 patients a year. In the EU 5, about 11,000 and probably 12,000, 13,000 more broadly across the EU and close to 5,000 patients in Japan. Nearly 100% of patients were diagnosed with glioblastoma ultimately have recurrence. And once recurrence occurs, overall survival is measured in months, somewhere in the range of 5.6 to 10 months depending on a variety of factors. Now following standard of care treatment and recurrence, the treatment options for the patients is somewhat less well defined. There is the opportunity to have a second surgery. The patient can be retreated with radiation. They can be treated again with temozolomide. Those 3 therapies really form the core of the initial upfront therapy. They can also be treated with bevacizumab or other drugs such as lomustine. These drugs do provide some palliation, but in general, provide very limited benefit in terms of overall survival. And because of this, there is a significant unmet need in recurrent glioblastoma for an effective therapy. Now briefly, RNL or rhenium-186 nanoliposome has 3 core components and a unique delivery system. At the heart is rhenium-186. This is already a nuclei that is a beta and gamma energy emitter. 90% of the energy is beta energy, and these are high energy electrons that travel, on average, in tissue, about 1 to 2 millimeters in distance. So we can control very tightly where the radiation energy goes. And the rhenium-186 has a half-life of 90 hours, meaning that within -- over the course of a couple of weeks, most of the activity has decayed. Now rhenium-186 is bound to a molecule called BMEDA. And BMEDA allows us to secure the rhenium-186 in a small 100-nanometer liposome, which is stable and retains the rhenium-186. And we deliver this via a method called convection-enhanced delivery. And this is simply a catheter that is inserted by a neurosurgeon directly into the tumor mass or very close to it. And then using a hydrostatic pressure wave, the drug is dispersed throughout the tumor and surrounding tissue as needed. Now the core value proposition for RNL is -- really covers 2 key aspects, but the retention of the drug in the tumor and the effective dispersion of the drug throughout the tumor. Now if we look here at the graph and these photos down here, rhenium that is not in a liposome quickly clears, here is time from the tissue and is very highly concentrated. Once we put it in a nanoliposome, it stays for a long period of time, and we're able to much more easily get good dispersion throughout the tumor, and these are from rat models here. Now preclinically, we see a survival benefit in both U87 and U251 models. And in the pictures here, we can see the tumor going away and actual ablation of the tumor over time. Whereas in the control, the tumor continues to grow. RNL preclinically has also been shown to be quite safe. In a GLP toxicology study, doses up to 6 millicuries were administered and the absorbed dose was 360 Gray, which is about 10x what is typically given in the recurrent setting for humans. And at that dose, we saw no adverse effect limit and this was the dose that was taken into the clinical trial. So very briefly, the clinical plan is one in which we preoperatively take the patient's scan and the neurosurgeon and Dr. Brenner plan out where the catheters will be placed, and there is very complex software that allows them to do this. The patients then admitted to the hospital and then for us, this becomes day 1, neurosurgeon, using stereotactic surgery equipment, drills a very small hole in the patient's skull and advances the catheters into the tumor. These are secured and the patient then returns to their room. The following day, the patient then is transferred down to the nuclear medicine department where RNL is delivered by convection-enhanced delivery. And in real time, we can visualize that delivery. And 2 days later, the patient is discharged home and able then to continue on with their normal activities. And with that, I'll turn it back over to you, Marc.

Thanks, Greg. So now I'd like to take the time to introduce Dr. Andrew Brenner. Dr. Brenner, as I mentioned, is the principal investigator of the ReSPECT trial and associate professor at UT San Antonio. Dr. Brenner? Dr. Brenner, are you still with us? Dr. Brenner? Chantel, the operator, could you mind just checking if you still see Dr. Brenner's image on the -- on your...

Sorry, I froze up.

Oh, there he is. Hey, Dr. Brenner, can you hear me, okay?

Yes. I can hear you fine. Sorry, I froze up just for a second here.

Okay. I was going to tell a Texas A&M joke. So good thing, I didn't have to do that. So -- as you resume, please kick it off whenever you're ready.

Let me just get the slides back up here because it's not showing anything.

No worries.

What slide number are we on? We're on...

17, I believe?

Okay. Now I can see the slide.

It's title, ReSPECT U.S. Phase I clinical trial.

Yes, advanced. But it's not showing on mine, but I'll just use -- I have them here. So the clinical trial was designed as a multicenter study with the open label. So everybody knew what they were getting and it's an escalation in both the volume administering as well as the dose. And the idea is to find the safety, the tolerability and the distribution of the drug using this convection-enhanced delivery technique that Dr. Stein talked about a moment ago. And the patient population is a recurrent glioblastoma patient population after they've already received standard surgery, radiation and chemotherapy. Study design, again, is a prospective study. We use something called the modified Fibonacci scheme where we're doubling the dose, and then we increase in fractions thereafter. And the idea is to find the recommended Phase II dose, the dose we're going to evaluate more broadly. We plan for up to 55 patients, and the 55 patients includes both the dose escalation part as well as a planned expansion or a Phase II portion, where we're looking at the activity. The fifth cohort has just recently been completed. We're now in the sixth cohort. And I'll move on to the next slide here. So this just show...

I'll advance for you, Andrew. So just go ahead and just give me the heads up, I'll advance.

So in terms of dose escalation, this is showing what the different dose levels we're looking at. We are currently at the cohort 6, which we're infusing a dose of 22.3 millicuries in a volume of 8.8 milliliters. I'm showing the data today up to 13.4 millicuries in a volume of 5.28 milliliters. Next slide. This is a summary of the patients and shows what we've seen both in terms of outcomes as well as the patients, what they received. We started at a dose of 1 millicurie in a volume of 0.6 mls. We saw a very small volume, sort of with a single catheter and a low flow rate, and we have subsequently with each cohort, increased the dose that we administered by dose doubling, and now we're in this fractionation portion. So it went from 1 to 2 to 4 to 8 and now -- and then 13.4, and the volume went up as well to 5.28. We increased the number of catheters starting with 1 catheter to make sure that we could describe the distribution of the drug. And now we're at 3 catheters and we've also increased the infusion rate, which is important both for the timing of the procedure to shorten the length of the procedure as well as to increase the volume of treatment. With higher rates, we can get a higher treatment volume. And you can see here some encouraging signs for survival, and I'll show more of that on that in a moment. Next slide, please. So this shows the safety data from the patients treated through cohort 5. It's important to note here that, as indicated below, that neither the incidence nor the severity of the adverse effects appear to increase with increasing doses of RNL. So that's a very promising signal that with increasing doses, we're not seeing increasing toxicity, which means this is a safe drug. And most of the AEs were considered to be causly unrelated to rhenium nanoliposome with the exception of scalp discomfort, which is an expected potential side effect from having the catheters placed surgically. Next slide. So as we went up on the volume, we went up on the size of the tumors we were treating. We did not want to treat larger tumors, which could not be adequately covered by the therapy. And you can see here that with each cohort, the size of tumors went up, and we are now routinely treating patients with tumors between 15 and 20 milliliters, which corresponds to almost a 3-centimeter tumor. And when we look at the doses that were achieved to the tumor volume, we see that we are getting now in the most recent cohorts, routinely between 300 and just over 500 Gray of absorbed. And it's important to note that in the recurrent setting by external beam radiation, we typically only use doses around 30 Gray. So anywhere from 15 to 20-fold the customary external beam dose that we would give. The median absorbed dose to the tumor volume across all subjects was 15 and patients who failed bevacizumab, it was much lower 38 Gray. And we think this is due to the effect of the bevacizumab on the convection volume that actually interferes with the convection and when there's some biology behind that. For patients who were bevacizumab naive, the dose that was achieved to the tumor volume was around 367 Gray and the maximum dose to the tumor volume was 593 Gray. Next slide, please. This just shows the absorbed doses in the tumor compared to the brain as a whole as well as the entire body. And so in green there is the -- to the tumor volume. And you can see with the most recent cohort that we're reporting 13.4 millicurie, cohort 5, patients had a total absorbed dose to the tumor volume of 423 Gray, whereas, their -- surrounding a brain only received the total dose of less than 1 Gray, 0.4 Gray. And to the whole body, it was very negligible at 0.1 Gray. These are insignificant doses. And the ratio of the dose to the tumor volume compared to the body is greater than 3,000. Next slide. This gives you an idea of the delivery of the rhenium nanoliposome. So on the top row there, you see the patient's MRI. In the first column is the axial plane. The middle column is the sagittal plane, and the last column in the -- a coronal plane. And you could see 24 hours after the infusion, you see the distribution in the middle row of the rhenium nanoliposome. It's based on SPECT/CT imaging. And you can see on the MRI above it we have the outline of that to correspond to the area that was treated. And then when you look at 120 hours, we see excellent retention. All of the radioactivity remains within the tumor volume. So excellent coverage as well as retention. And in this case, a tumor volume was 6.5 mls, and the coverage was greater than 98% with an absorbed dose of tumor volume of nearly 420 Gray. Next slide, please. So this shows one of our patients over time. Again, this is in the axial plane, and you can see that patient who had excellent coverage, has tumor initially day minus 5, which is 5 days before the treatment. The second image is day 28, then day 118 and then day 362. And so over a year out, we're seeing some decrease in the enhancement or the tumor volume. And the patient remains alive and is nearly 2 years out from his initial treatment. Next slide. This is one of our more recent patients. And you can see on top, the image of the tumor, the large enhancing volume there. Again, axial in the first, sagittal in the second and the coronal in the third column. And then 24 hours later, we see the absorbed dose to the tumor. And at 120 hours in the bottom row, you can see it's actually spread out a little bit evenly, even get better coverage at 120 hours. So excellent retention, good tumor coverage. The tumor volume, in this case, was higher than that last patient I showed you and it was almost 19 milliliters, and the coverage was 87%. The amount that was absorbed to the tumor was 336 Gray. At 24 hours, even the most anterior portion that we were -- maybe not covering was covered as we distribute. And the entire tumor was in the distribution and the purple line on the top figure there. Next slide. This shows the effect. And so you see in the first column before treatment, and day 56 on the second column. And you see the loss of all that white there, which is the enhancement and corresponds to tumor. We know that, that's a loss of tumor because in the figure below it, you'll see what we call is rCBV map, which shows the perfusion or the blood vessel supply. And so we see a loss of that perfusion in that image below. And then in another image, in the second grouping there, you see the enhancing tumor and the third column and the loss of that enhancement in the fourth column. And again, associated below that with an increased rCBV or increased blood flow to the tumor, pretreatment and a complete loss of that blood flow post-treatment at day 56. Next slide, this is a review of the survival to date, looking at the patients who had not received bevacizumab and who have received bevacizumab. It's important to note that for patients who fail bevacizumab, their survival at that point is significantly shorter and ranges from 90 to 120 days. The typical survival for patients who have not received bevacizumab yet is about 8.3 months, depending on what studies we look at. And we can see some very encouraging signs in terms of survival in these patients. The patients, indicated by the green circles, are patients such as our patients here today, who has been recently treated and continue to be followed for their survival, and who will continue to do very well, but we do have some encouraging signs here. The median survival duration of the subjects that had failed bevacizumab was 4.8 months, which is just a little bit above what we see for the general population. And then median and mean survival duration in subjects that were bevacizumab-naive was 11 months and 15.4 months, with 4 of our patients still recently ongoing and recently treated. Next slide. So with this the conclusion is that we can deliver up to 15x and maybe even if we consider the recurrent doses up to the 20x in short doses of radiation administered by external beam radiation therapy, and we're not seeing significant evidence of toxicity. It's also important to note that this is administered within a few days, whereas, external beam radiation is administered over weeks. These data indicate that intratumoral administration of RNL by CED at doses up to 13.4 millicuries is safe and well tolerated. No treatment related adverse effects noted thus far and maximum tolerated dose not yet reached. Prior administration of bevacizumab seems to negatively impact convection of RNL. And in the subsequent survival study and the Phase II study, we do not plan to enroll patients with bevacizumab, and that's pretty standard for Phase II studies. And the current status we are on cohort 6, we've recently administered 22.3 millicuries and 8.8 mls, and we have 2 more patients upcoming in the upcoming 2 weeks. With that, I'll stop.

Thank you, Dr. Brenner. So yesterday, I actually had the opportunity to speak with Phyllis, who is a ReSPECT clinical trial patient. She is 1 of the 2 patients that have been most recently treated that Dr. Brenner had referred to previously. She's had 2 previous surgeries, prior to getting into the trial, chemo and radiation. And I felt like it was good to get her to talk about her experience with RNL as it related to the other treatments she'd have. So I'd like to just let her talk in her own words. There we are. Hi, Phyllis. Are you able to hear and see me okay?

Yes.

Okay. Good. Well, hey, thank you for taking the time, and you are currently a patient that's participating in the ReSPECT clinical trial for RNL-186 for patients with recurrent glioblastoma. So first of all, I just want to thank you for participating in the trial and then agreeing to just talk for a few minutes.

Okay. You're welcome.

How are you doing generally?

I'm hanging in there. I haven't had any major side effects that had caused me to be incapacitated?

Yes. Well, you look good from here. So, we've got -- Phyllis, we've got a couple of questions for you that I thought might be a good way to kind of assess the -- how things are going with you with respect to the treatment. So maybe kind of going backwards a little bit, would you mind telling us a little bit about how you found out that you were sick? And then how the treatments and the overall experience that you've had thus far?

Sure. So my initial diagnosis was through a seizure. I was actually working as a veterinarian technician, which was my career. And I went into work that day, not really knowing what was going on with me. Physically, I was kind of out of it. It happened to be a surgery day. So my coworkers noticed that I wasn't myself, and brought me into the surgical unit and kind of talked to me and said, "Something's not right with you." So they called my husband. And he actually came picked me up, and we went to the medical center. And that's where they did the first scan and saw something suspicious. So they then transferred me to a different hospital by ambulance. And then that's where I stayed, and that's where I was diagnosed with suspicious growth, but not diagnosed at the time. So we went ahead and did the first surgery. At that time, I was diagnosed with the astrocytoma Grade II, and it looked like we had got it all. And fortunately, we know now that wasn't the case. So from there, I did the at-home Temodar radiation treatment [ once in ] 30 days of the recommended treatment. And then in August, found out that the tumor wasn't responding. It actually had grown quite a bit. So then that's where [ Dr. Floyd ], my surgeon came into the case, which Dr. Brenner was already on the case with me. So then [ Dr. Floyd ] agreed to go in and basically, kind of redo the section and kind of try to give us a fresh start. And then at that time, I went on study of the -- it's a long name, but it's sassy, you probably have some history there. That was used in case where breast cancer metastasize, they were finding ever having some results when it went to the brain. So this was a new study that we started. I had the first treatment. Basically, the night before my surgery, excuse me. And did that and did that for several months, then found out I wasn't responding to that anymore. So that's when the next study was offered to me with catheters, with radiation straight into the tumor.

So like you've had a couple of surgeries, so far, before you even got into the study.

Correct. This last one, yes.

So you found out about the trial with the catheters and the radiation, the RNL trial through [ Dr. Floyd ] and Dr. Brenner?

Correct.

So how did you find that treatment experience with the RNL? That's a little different than having surgery, I guess.

Yes, it was -- I had it right there at my birthday. So it was a little scary, but -- so I found it a lot easier than actually having surgery. I recovered really well. It was a low pain level. So -- and they said I was one of the best patients. So I took pride in that.

Well, that's great. And you were in the hospital for a couple of days around the time that you had the catheters and the infusion?

Correct. So I think I went in on the 14th and actually had it on the 15th, which was my birthday, so that's easy to remember. So they did the actual placement of the brain and stuff on my birthday and then took all the pictures and everything. And then I had -- once I got discharged, I came back every day and got like a scan to make sure that we were getting good absorption, that it wasn't leaking out. So they were very happy with how much they were able to get in there and how much it retained. So I would say I'm a success story so far.

You look good to me from here. So whatever you're doing, keep doing it. How do -- how is RNL treatment kind of versus radiation? It sounds like you had a -- about a month-long course of radiation.

No. The radiation, it does make you really tired. So that was probably the toughest part. And then as far as side effects afterwards, there was some side effects like just forgetting things and of course, I had to be on kind of the high-dose steroids to keep the brain swelling down. So that would probably be my thing that I disliked the most is the side effects from the steroids. But nothing that I would call major like where I can't function or -- yes, there were some things that I would've liked and done without, but things have side effects. It's just part of most medical procedures, I think.

Did the catheters bother you when they took them out? And was the infusion difficult for you or...

No. I mean it was more patience. I felt like the center of attention, I was everybody's center of attention with the doctor. So yes, I mean it was kind of a slow process. I was in there for several hours. But that was probably -- the most trying time was just the patience of laying there, why they did all that.

They were infusing into the catheters, right, the RNL?

No, I think I missed some of the trial and error was prior -- that they had gone through with prior patients, so I was kind of at an advantage there.

So would you recommend this to other patients, let's say, that other patients that might be interested in the trial? Or maybe 1 day, hopefully, if this gets approved by the FDA, would you recommend that treatment to other patients?