Plus Therapeutics Inc (PSTV) 2021 Q1 法說會逐字稿

Good afternoon, ladies and gentlemen. Welcome to the Plus Therapeutics First 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 Plus Therapeutics' annual report on Form 10-K and quarterly reports on Form 10-Q filed with the Securities and Exchange Commission from time to time.

Plus Therapeutics advises you to review these risk factors in considering such statements. Plus Therapeutics assumes no responsibility to update or revise any forward-looking statements to reflect events, trends or circumstances after the date they are made.

It is now my pleasure to turn the floor over to Dr. Marc Hedrick, Plus Therapeutics' President and Chief Executive Officer. Sir, you may begin.

Great. Thank you, Catherine. Good afternoon, everyone, and thank you for taking the time to join us today as we provide an overview of recent business highlights and discuss our 2021 first quarter 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 earnings call.

For those of you new to the company, Plus develops complex, innovative therapeutics for rare and difficult-to-treat cancers such as cancers of the central nervous system. Our aspiration from a drug development perspective is to leverage our expertise in drug formulation, nanoparticle drug design, drug manufacturing and scale-up and expertise in novel delivery technologies to provide better tumor targeting and killing, a greater safety profile and ultimately better clinical outcomes.

Towards that goal, in 2020, we broadened our expertise in technology platform to include the use of radionuclides in our drug formulations. Our lead drug is RNL, Rhenium NanoLiposome, which is a proprietary liposomal encapsulated radionuclide. The active agent is the rhenium-186 isotope, which is a dual energy emitter, releasing both cancer-killing beta particles and gamma particles, which are useful for imaging. Our initial indication for RNL is recurrent glioblastoma, which affects approximately 12,000 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 medical challenge. Published studies indicate that external beam radiation provides the best incremental improvement in survival of all therapies currently used for glioblastoma, and it remains an essential component of multimodal therapy for both glioblastoma and, in fact, many other cancers.

In theory, though, glioblastoma, and indeed any tumor can be fundamentally controlled if a sufficient dose of radiation can be delivered to that tumor. With RNL, it may be possible to deliver a radiation dose only to the tumor that is perhaps 20x higher than can be given with external beam radiation therapy. And despite the super-high doses of radiation delivered by RNL and precisely because of its inherent tumor targeting capability, unwanted radiation exposure to nearby healthy tissue is actually reduced. This compares favorably to the most commonly used chemotherapies as well as external beam radiation, which is associated with significant side effects that occur due to their deleterious effects on normal tissues.

Preclinically, in animals, RNL has shown the ability to deliver almost 2,000 gray, substantially prolonging survival and ablating brain tumors such that cancerous cells cannot be observed in the microscope.

So our RNL product is currently under evaluation in the U.S. ReSPECT trial, which is a dual Phase I/II multi-center sequential cohort, open-label volume and dose-escalation study of the safety, tolerability and distribution of 186 RNL administered by convection enhanced delivery to patients with recurrent or progressive malignant glioma after standard surgical, radiation and/or chemotherapeutic treatment.

The study uses a modified 3 plus 3 Fibonacci dose escalation scheme, followed by an expansion at the MTD, or maximum tolerated dose, to determine efficacy. In addition, the trial is funded to a significant degree by the U.S. National Cancer Institute. And in short, the trial is progressing nicely. In November 2020, we provided an interim analysis on the first 15 patients enrolled in ReSPECT, specifically going to the fifth cohort. And that data set can be found on our website.

In this interim look, it showed that intratumoral RNL can successfully deliver approximately 15x the absorbed dose of radiation that can be administered by standard external beam radiation therapy without significant toxicity. RNL was well tolerated with no dose-limiting toxicity observed, despite markedly higher absorbed doses of radiation compared to EBRT.

Most recently, in March of this year, in our BIO-Europe corporate presentation that can also be found on our website, we provided an interim update through Cohort 6. In summary, we found that it's feasible to deliver 8.8 ccs of RNL loaded with 22.3 millicuries of radiation safety -- safely without treatment-related serious adverse events. In fact, most adverse events were causally unrelated to RNL, except scalp discomfort considered related to the surgical procedure itself, but not the drug.

High absorbed doses were delivered to the brain, nearly 600 gray, but only with very limited systemic radiation outside the brain. In fact, there was about approximately 3,000-fold difference between radiation to the brain versus the body, hence the absence of systemic effects of the radiation. There were 2 long-term survivors greater than 30 months. And in terms of overall survival, median and mean survival duration in subjects with tumor coverage greater than 75% was at the time 8.3 months and 12.9 months, respectively, with 6 patients still alive. Median survival duration with tumor coverage less than 60%, which was largely the BEV-failure patients was 4.9 months, with 1 patient still alive.

Rather than escalate the Cohort 7 after Cohort 6, the DMSB, the Data Monitoring Safety Board, (sic) [DSMB, the Data and Safety Monitoring Board] elected to treat an additional 3 patients at the Cohort 6 dose in volume, but increased the convection rate to 20 microliters per minute. Based on the physics of convection, the presumption is that enhanced RNL distribution in the brain will be observed, and therefore, better coverage of the residual non-enhancing tumor cells achieved and, in theory, ultimately better patient outcomes.

Our experience thus far points to tumor coverage correlating with length of survival, which makes sense, because 90% of recurrences occur within about 2 centimeters or less of the primary. Furthermore, the increased convection flow rate will shorten the time to deliver the drug and make it easier on the patient and hospital staff. Thus far, 2 of the 3 planned additional patients at 20 microliters per minute have been successfully treated with others in screening. Thereafter, the DSMB will evaluate the data and discuss and make recommendations.

Potential next steps, assuming no emergent dose-limiting toxicities are observed, include, but are not limited to, escalating to dosing Cohort 7, enrolling additional patients at the current levels with further changes in the delivery parameters or simply moving directly to the Phase II expansion cohort at the recommended Phase II dose.

As an aside and running in parallel to the Phase I and besides -- sort of outside the direct clinical objectives of the trial, also being developed in conjunction with academic collaborators is a mathematical model to better predict the spatial and temporal distribution of RNL delivered by convection. Data collected by the Phase I by imaging, when interpreted and analyzed, will help create a mechanism-based model of delivery, and hopefully, facilitate the increasingly more accurate delivery of RNL in the Phase II expansion component of the trial, and therefore, maximize the clinical outcomes.

Regarding additional clinical development programs for RNL, a priority for us in 2021, as we've explained previously, has been to begin development clinically with RNL in additional indications. To that end, we submitted 2 RNL pre-IND meeting briefing packages to the FDA, one for leptomeningeal metastases, the other for pediatric brain cancers, including ependymoma, high-grade glioma and diffuse intrinsic pontine glioma. We plan to conduct these pre-IND meetings with the FDA for both indications in 2021, understand any gaps that may exist in the preclinical data, fill those as needed and initiate those trials as soon as 2021.

Both indications represent significant unmet medical needs. And for example, in LM or leptomeningeal metastases, that affects about 110,000 patients in the U.S. and has no clear standard of care. And these patients actually die very rapidly despite the care that is currently provided to them. As for pediatric brain cancer, still much rarer, they carry an equally poor prognosis. And the treatment approach we envision for pediatric brain cancer would mirror our approach in adults with glioblastoma using the direct targeting of the tumor and convection enhanced delivery.

Now regarding our manufacturing and supply chain development, which has been a key focus of our team of late. In the first quarter this year, we entered into a master services agreement with Piramal Pharma Solutions for the development, manufacturing and supply of RNL intermediate drug product. Essentially, they'll make the liposome for us for the long term. We anticipate that this will lead to clinical and commercial supply agreements for the drug product at the appropriate future stage of development. And we are working on those, and we are on track in terms of our development and CMC time line.

Now at this point, I'll turn the call over to Andrew for a brief review of our first 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 first quarter ended March 31, 2021.

As of March 31, 2021, cash and cash equivalents were $14.4 million compared to $8.3 million as of December 31, 2020. Cash used in operations for the first quarter 2021 was approximately $3 million compared to $1.5 million in 2020. This difference is mainly due to timing differences on when certain accounts payable and accrued expenses were paid in 2020, in particular relating to BARDA and professional fees. There were no revenues in the first quarter of 2021 as compared to approximately $118,000 in the same period last year. This decrease was due to the closeout of the BARDA contract, as previously disclosed.

The research and development expenses were $1.1 million for the first quarter 2021 as compared to $0.9 million for 2020. The increase was primarily due to the additional RNL development costs. G&A expense was $1.4 million for the first quarter 2021 as compared to $1.6 million for 2020. The decrease was primarily driven by a reduction in professional fees and recruiting expenses.

Interest expense decreased for the first quarter of 2021 to approximately $247,000 from approximately $349,000 for the same period in 2020, reflecting the principal paid down in 2020.

Net loss for the first quarter 2021 was $2.7 million as compared to a net loss of $1.1 million for the first quarter 2020. The net loss was consistent year-on-year when excluding the book gains on the warrants reported in the first quarter of 2020. This required book transaction was eliminated in the second quarter 2020 when the Series U warrants were amended. And now I'll turn it back to you, Marc.

Great, Andrew. Thank you. So let me just summarize our forthcoming milestones, and then we'll move to Q&A. So we intend to complete enrollment of the ReSPECT Phase I study in recurrent glioblastoma as soon as we get to the recommended Phase II dose and then proceed with the trial. We plan to complete the pivotal trial planning with the FDA in parallel for RNL for recurrent glioblastoma and then complete the key CMC activities, as I mentioned before.

We also plan to complete the pre-IND meetings, as mentioned, with the FDA, execute any IND-enabling studies if needed and move into clinical trials for our follow-on RNL indications, leptomeningeal metastases and pediatric brain cancer. We also plan to continue to develop and evaluate additional external and internal drug development candidates to bolster our pipeline. And then we continue to explore through our partnership discussions for our 3 clinical-stage injectable drugs, RNL, DocePLUS and generic DoxoPLUS. And with that, those are our prepared remarks. I'll turn it back over to you, Catherine, for Q&A.

(Operator Instructions) And your first question is coming from Sean Lee with H.C. Wainwright.

My first question is on the ReSPECT study. So you mentioned that the DMC has decided to do an expansion cohort on #6 instead of going to Cohort 7. So should we take it that the doses used in Cohort 6 is likely going to be the ones you guys use in the next phase?

Sean, it could be. I presented what I thought were the most likely outcomes in the script. And so where we did not see dose-limiting toxicity in the sixth cohort. And typically, that would be the reason to stop there and take that dose forward. But we're kind of using the Phase I not only to get the recommended Phase II dose, but also to ensure that we go into the next trial with the appropriate delivery parameters. And so I think we're maybe getting a little bit greedy here, but we're delivering so much radiation that we can where essentially how many times can you kill the same cancer cell.

So part of what we're trying to do is to get that microscopic disease that's non-enhancing on the scans. And then -- and we do that effectively by increasing the flow rate, which is -- correlates to increasing the pressure and pushing the leading edge of the radiation out into that microscopic disease. So it may be that this current dose of 22.3 millicuries at about almost 9 ccs is what we take forward. But I think we'll just have to see. We could -- we couldn't conceivably go to a Cohort 7 as well but -- with this increased flow rate.

Got it. When do you think we'll be able to get the next updates on Cohort 6 in terms of data?

Yes. We actually -- the Snowmaggedon in Texas at the end of February, because all 3 of our sites are in Texas actually made the February and March light months. So things are covered in April. There are a lot of patients in screening. We've -- as I mentioned, we've got -- we've treated 2 out of the 3 patients. So I think we may -- it may be the next earnings call. Or if we make a decision prior to that, we may just put that news out at that time. So either before or likely the next earnings call.

Thanks for that. My next question is on the CMC side. So with the tech transfer and the master services agreement with Piramal, what's the expected time line on that? Then when do you expect you have CMC ready drug -- ready for the -- like, for example, a pivotal study?

So yes, good question. We're on track from a time line perspective. So we've sort of said we want to have drug ready for a registrational trial by around the end of 2021. And so we're on track to do that. Phase II drug supply, as we contemplate an expansion cohort of the Phase I, that will -- we'll be ready for that as well, but that's a different -- that will be a different supply chain, if you will, for that. So we're on track for both of those with kind of the end of 2021, early '22 is sort of the time line to have that drug available.

I see. My last question is on the next -- potential for the next pivotal study. So what are your thoughts on the designs of this study? Would you be looking to go at it with a traditional randomized Phase III or an adaptive Phase II/III with adaptive design? Or would you participating in one of the other studies that are going on such as GBM AGILE?

Yes. So let me break that down, because actually -- so the -- in terms of the Phase I/II, that trial is fairly locked in at 55 patients, estimated 21 to get to the maximum tolerated dose and up to another 34 patients at the recommended Phase II dose. So that's fairly well locked in. I don't see as likely to make many changes there.

In terms of the Phase III I think -- what I think I could say is we're likely to look at overall survival as a primary endpoint. The number of patients is going to be based on what we see in the combination of the Phase I, Phase II at the recommended Phase II dose. I anticipate we'll use a synthetic control arm.

In that, those will be patients that are very likely have had no more than one recurrence in their BEV-naive patients. As you know, those do very poorly, and they don't conduct very well. So I don't see us kind of randomizing 1:1 against standard of care. I see us using potentially a synthetic control arm or participating in the agile control.

Our next question comes from the line of Ed Woo with Ascendiant Capital.

I had a question more on the 3 sites that you have running. I know you mentioned that there was this Snowmaggedon kind of delayed things. But is everything back on track, any COVID issues? And also, have you thought about potentially expanding the sites?

Yes. I mean it was really just maybe 4- or 5-week delay. Just -- we typically screen patients every week, so just patients couldn't travel. All of our sites are in Texas. Texas got hit pretty bad. So we're back to normal. We're screening multiple patients a week now. So things are going well. We're doing a lot of work to get the word out about the trial. And I think that's helping us, and we're looking at some other ways to do that.

And then to your point about trial expansion, so yes, we absolutely are talking to additional sites. Probably not thinking as much about the Phase I as an expansion cohort at the recommended Phase II dose so that when that decision is made, we'll be ready to get those sites onboard and trained. And then those sites ultimately will go into a registrational trial, assuming we get there. Convection enhanced delivery, there -- we know who the high-volume sites are, and we'll be going to those sites early on in that process if we haven't gone to them already.

Great. And then you mentioned that there's additional indications that you have -- that you plan to file on IND. (technical difficulty)

Edward, you're cutting out.

I'm sorry, can you hear me now?

Yes, I think so. Yes, go ahead. Catherine, maybe if Edward maybe can call back in or jump back in, that would be great. Maybe if there's somebody else in the queue, we could go to them.

And there are no further questions at this time. I'd like to turn the floor back over to you, Dr. Hedrick, for any additional or closing remarks.

Okay. Great. Thank you, Catherine. Sorry about those technical difficulties. Just want to thank everyone that joined us on the call and the analysts that participated in the call. And also, I'd just like to take a moment to say thank you to our employees who worked so hard and so dedicated to trying to find a solution for glioblastoma and other rare cancers.

And then also, I'd like to specifically thank the patients and the doctors and the hospital staff who we spend a lot of time with and they help really support and make our clinical trials happen. So thanks again, and please have a good evening.

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