Good afternoon, ladies and gentlemen. Welcome to the Plus Therapeutics First Quarter 2022 Results Call. At this time, all participants have been placed in a listen-only mode, and the floor will be open for your questions following the presentation. [Operator Instructions].

Before we begin, we want to advice 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 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 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..

Thank you very much, Gretchen. 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 2022 first 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 Norman who will provide commentary on our clinical progress for 2022. And then following Norman, Andrew will review our financials.

Despite the short interval since we last reported quarterly results, I continue to be very pleased with our overall progress as we work towards several meaningful catalysts and milestones throughout 2022. During the first quarter, we began enrolling patients in our ReSPECT-LM trial of 186RNL in patients with leptomeningeal metastases, or LM.

The trial is a multi-center Phase 1/2a dose escalation study to determine the MTD, maximum tolerated dose, and MFD and safety and efficacy of RNL186 in LM. LM is a typically fatal complication associated with advanced cancers that affect the fluid line structures of the central nervous system or leptomeninges.

Median survival with current aggressive treatment is about three to eight-and-a-half months depending on which primary tumor caused the LM and the one and two-year survival rate is 7% and 3%, respectively. Survival without treatment is only a few weeks. LM is diagnosed in approximately 5% of cancers with 20% of patients at autopsy. U.S.

annual incidence is about 110,000 patients and growing, and the prevalence of neurologic impairment in these patients is about 50%. Most common tumors giving rise to LM are breast cancer, lung cancer, melanoma, and gastrointestinal malignancies.

There are no FDA-approved therapies and standard treatment that is employed includes external beam radiation therapy to the affected sites, followed by chemotherapy given either orally or intravenously or even directly into the cerebrospinal fluid.

Although we can only draw limited conclusions from our initial experience, we’re very pleased with the outcome and the first patient receiving a single administration of 186RNL. Specifically, we found that the drug circulated rapidly throughout the cerebrospinal fluid space.

We found that radiation was released through leptomeninges and CSF for at least one week after treatment. The patient exhibited no adverse events, and 186RNL reduced the circulating tumor cell counts by over 90% at two weeks after treatment.

This is really about as good as it gets in a first-in-man -- first patient in a Phase 1 trial, so we’re very excited about this very preliminary result. We now have two active sites screening LM patients, with another six sites being onboarded, as we speak.

We’re on track to have at least the first two cohorts completed by the end of 2022, and hopefully a bit more than that. As to our ongoing clinical development program for 186RNL in recurrent glioblastoma, we have a number of updates.

First, as a reminder, that trial is a dual Phase 1/2a multi-center sequential cohort open label volume and dose escalation study for recurrent glioblastoma or GBM. The trial is currently funded to a significant degree, as many of you may know by the U.S. National Institutes of Health and NCI.

Glioblastoma affects about 13,000 patients annually in the U.S. and about the same number of patients in the EU, and it’s the most common and lethal form of brain cancer and treatment of this devastating disease remains a very significant unmet medical challenge.

In terms of the clinical data, 23 patients have been treated and 186RNL appears to be safe and well tolerated, and this data presented most recently back in March can be found in detail on our website and that’s accessible to anyone. In summary, no dose limiting toxicities have been observed.

Generally mild-to-moderate AEs have been seen in seven SAEs, all grade three or lower and most are not deem to be RNL-related.

In terms of drug delivery, we are now reliably able to deliver over 100 gray of absorbed radiation dose to tumors, which is our empirically-determined minimal dose threshold of adequate absorbed radiation, and we can get well over 80% and we think 90% is achievable in terms of reliable dose delivery of 100 gray.

Finally, we have observed both the median and mean overall survival signal that exceeds the best published rate for monotherapy bevacizumab. Based on this data, I’d like to just explain our big picture plan. We plan to bifurcate the current GBM clinical development plan based on tumor size.

So for tumors of approximately 15 to 20 CCs in volume, which represents about one-half to about two-thirds of all recurrent glioblastomas, we plan to use the cohort six dose of 22.3 millicuries and 8.8 CCs of volume as our recommended first Phase 2 registrational dose.

For tumors of larger size potentially requiring greater radiation dosages and treatment volumes, we intend to continue our Phase 1/2 dose escalation trial to establish the upper limits of dose and potential for DLTs or dose-limiting toxicities. In 2022, for GBM, we have two key regulatory milestones.

We have already in 2022 submitted and asked for the first of two FDA meetings, specifically a Type C CMC meeting to determine the sufficiency of our CMC package for GMP 186RNL to support a registrational trial. And then relatedly to the CMC development, our team continues to make excellent progress in our drug scale-up and manufacturing activities.

Specifically, the company has finalized key RNL drug development and characterization activities for GMP manufacturing to support our planned Phase 2 registrational trial and commercialization activities thereafter. The company remains on track to deliver GMP RNL by mid-2022.

The second FDA meeting is a clinically focused meeting planned for Q2, Q3 to solicit FDA feedback on our planned Phase 2 registrational trial using our recommended Phase 2 dose as mentioned 22.3 millicuries and a little less than 9 CCs of volume. Also during Q1, we completed another key milestone.

Specifically, we successfully completed the preliminary evaluation phase and entered into a broad partnership with Medidata to use its Synthetic Control Arm platform and Real World data as the comparators for our glioblastoma trials.

The primary goal of this partnership is to develop an FDA compliant control group of patients identical to the patients thus far treated in our Phase 1/2a trial and in the planned Phase 2 registrational trial. That data will be used to support our planned end-of--phase meeting with the FDA and proposed Phase 2 registrational trial.

More generally, Synthetic Control Arm or SCA platform facilitates the use of historical clinical trial data in a manner that has been favorably received by the FDA.

These SCAs reduce the time and cost associated with complex clinical trials in rare diseases such as glioblastoma, allowing for fewer patients to be exposed to placebos or existing standard of care treatments that might not be effective for them. It offers them greater access to potentially life extending therapies.

And although a recent advancement, the FDA has already agreed to recognize a Phase 3 clinical design incorporating an SCA in a registrational randomized control arm for recurrent glioblastoma.

Besides initiating our Phase 2 registrational trial with RNL and recurrent GBM, as I mentioned above, we also continued enrollment in our Phase 1/2a dose escalation GBM trial, and that will continue. Finally, this quarter, we intend to open a Phase 2 multi-dosing extension trial of RNL in recurrent glioblastoma.

As you know, if you follow the company, glioblastoma is notoriously difficult to cure and recurrent disease is the norm. This extension trial will give us important information about the utility of multiple potential doses of 186RNL in the overall treatment paradigm for these patients.

The goal of the trial is to determine the safety, feasibility and potential efficacy of using additional doses of RNA in patients following the initial single administration of RNL as we have done previously in the Phase 1/2a trial. This is really important to our big dream.

One day, if not curing GBM, returning it into a chronic disease in which we help patients live with brain cancer. Finally, in Q1, we announced our license of a novel radioembolic microparticle technology from the University of Texas.

As we’ve said many times, we believe the future of cancer therapy is precise targeting of tumors with the most potent cancer killing agents while minimizing damage to normal tissues. This transaction builds upon our existing Rhenium NanoLiposome technology.

And with this new technology, we can with a resorbable biomaterial embolic technology, coupled with a highly potent radiotherapeutic isotope, target almost any solid organ tumor in the body using the standard interventional radiologic means and leverage the breadth of the human vascular system.

Rhenium-188, not 186 but Rhenium-188 NanoLiposome Biodegradable Alginate Microspheres we call 188 RNL-BAM or just BAM for short, 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.

The BAM technology incorporates Rhenium-188 isotope for use as the radiotherapeutic source with a different admission criteria and characteristics than 186. It emits a high energy beta particle with a half life of only about 17 hours or longer path length of over 3 millimeters.

It also produces gamma energy that we can use for high quality real-time imaging of the BAM construct in the organ.

The company will initially focus on developing the BAM technology as a next-generation radioembolization therapy for liver cancer in which BAM blocks the hepatic artery segments that supply blood to the malignant tumor while also providing radiotherapy by directly irradiating the tumor.

Liver cancer is a rare disease with an increasing annual incidence and a five-year overall survival rate of only about 20%. The global opportunity for localized embolization, chemoembolization, radioembolization for primary and secondary cancer in the liver is about 1.3 billion opportunity globally.

We have three objectives in 2022 for our BAM program; the technology cancer phase, which has been completed and we are on track to complete key CMC feasibility studies, IND-enabling preclinical studies and an FDA pre-IND meeting this year. So with that, I’ll turn the call over to Dr. LaFrance.

Norman?.

the Society of Nuclear Medicine Meeting this June in Vancouver; the SNOW ASCO-sponsored Clinical Trials & Brain Mets Meeting in Toronto in August; EANO and ESMO in Vienna and Paris, respectively, both in September; and potentially EANM in Barcelona in October; and the SNOW Annual Meeting in Tampa in November.

Additionally, I’ll be participating at the Medidata Synthetic Control Arm Focused Industry Roundtable next week on April 26. As Marc mentioned, our clinical team and investigators were very pleased with the first patient outcome in the ReSPECT-LM trial.

Treating the first patient of any new condition with an investigational drug is always an exciting, but with many unknown. A few comments. The feedback from one of the very experienced investigators in the trial was that they had never seen such a clinical response in the first patient in the Phase 1 first-in-man trial.

The delivery of RNL in this trial is very simple and straightforward with five-minute outpatient procedure through an existing Ommaya reservoir. There are substantial existing biomarkers such as tumor cell count, which we are measuring CSF, which is simple to obtain in these patients.

There are also a number of additional exploratory biomarkers we are looking at as well.

Additionally, Plus will perform several preclinical studies to evaluate additional LM treatment paradigms with 186RNL, specifically multi-dose administrations and combination treatment with immunotherapy such as PARP and checkpoint inhibitors, both known to be synergistic with radiation.

Despite impressive initial results at the first dose with a single RNL monotherapy, Plus believes optimal patient benefit can be amplified with multiple RNL doses and/or combination therapies.

For our current trial, I’m optimistic enrollment will proceed rapidly based on the significant unmet medical need, very well tolerated and easy dose administration and the enthusiastic responses received from investigative clinical sites, along with other oncologists once they hear of our trial.

Developing preliminary clinical data and medical meeting presentations planned for LM in 2022 were presented a few minutes ago. And finally, RNL is being developed for pediatric brain cancer.

The key goal here is to obtain FDA IND approval to investigate the use of 186RNL for children with brain cancer and we are working with our lead site, Lurie Children’s Hospital in Chicago and are on track to hit this milestone later this year. Next, I’ll turn the floor to our CFO, Andrew Sims, who will review financials. Over to you, Andrew..

Thank you, Norman, and good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the 2022 first quarter ended March 31, 2022. As of March 31, 2022, cash and cash equivalents were $21.2 million compared to $18.4 million as of December 31, 2021.

This represents 18 to 24 months of cash on hand. Cash used in operations for the three months ended March 31, 2022 was $3.9 million compared to $2 million in the first quarter of 2021. The main changes between 2021 and 2022 as follows.

Total operating expenses for the first quarter 2022 were $3.9 million compared to total operating expenses of $2.5 million for the first quarter 2021. Approximately $0.7 million of this increase is due to research and development expenses and $0.6 million is due to legal, intellectual property and professional fees in 2022.

Interest expense decreased from 247,000 in the first quarter of 2021 to 198,000 in the first quarter of 2022. This decreased cost reflects the principal paydown that commenced in November 2021 on the Oxford debt.

Net loss for the first quarter of ‘22 was $4.1 million, or $0.19 per share, compared to a net loss of $2.7 million, or $0.33 per share for the first quarter of 2021. And now, I’ll turn it back to you, Marc..

Great. Thank you, Andrew. Before we move on to Q&A, let me just summarize key milestones anticipated for 2022.

First, with respect to the 186RNL GBM trial, we’re planning for a clinically focused FDA meeting mid-year 2022 to propose a Phase 2 registrational clinical trial and trial design using the cohort six 8.8/22.3 millicuries dose, as detailed earlier. We expect to initiate the Phase 2 towards the end of the year.

We anticipate the CMC focused FDA meeting in the second quarter of 2022 or perhaps the beginning of the third quarter. And to clarify, that’s to resolve any open CMC issues that may exist at that time. Regarding drug availability, very important that we have GMP drug availability to proceed with the trial. We’re on track with CMC activities for RNL.

We plan to complete those and have that GMP Phase 3 ready drug supply available by mid-2022. Also in 2022, we’ll report Phase 1/2 data and enrollment updates in an ongoing manner, as Norman mentioned, for the ReSPECT-LM trial and our goal is to complete enrollment in at least initial two cohorts this year.

Regarding the pediatric brain tumor trial, we plan to get our IND submitted relatively soon this year and be able to initiate that trial towards the end of the year.

Regarding our recently acquired rights to the 188RNL-BAM radioembolization therapy technology, we plan to complete key CMC and FDA IND-enabling studies and a pre-IND meeting also this year. So at that point, I think we’ll move to Q&A, and I’ll turn the call over to Gretchen. Gretchen, back to you..

[Operator Instructions]. Thank you. Our first question is coming from Ed Woo from Ascendiant. Your line is open..

Thanks for taking my question. I was wondering you have a couple of meetings planned with FDA this year.

Do you know if the timing has reverted back to normal post-COVID, or do you see that there’s still possible delays that is possibly running a little bit longer than you expect?.

Norman, would you answer that?.

Ed, that’s a great question. We won’t know until FDA gets back to us, but I’m anticipating they’ll probably follow their published guidance for these meetings, meaning they’ll provide an answer usually within three or four weeks and the meeting date by 75 days.

As you know, they have the right to actually move those meeting dates up sooner than the PDUFA guidance requires them. But I’m not anticipating those to be pushed out further than usual as they were occurring earlier in the pandemic..

Great. Thank you. And then my last question is your current GBM trial is funded by the NIH.

Do you anticipate trying to get additional funding for some of these other indications that you guys are working on?.

Ed, so one of the reasons we’re based in Texas is because there are opportunities to Texas-specific oncology-related grants, as I know you’re aware. That’s called CPRIT. And we’ve been very interested in obtaining CPRIT funding for our various programs.

Unfortunately for the GBM program, they typically don’t fund Phase 3 trials, but they will fund Phase 1 to Phase 2. So that’s definitely something that’s of interest. Where we’re up at the plate with CPRIT and will continue to be there, two funding cycles a year.

And so we spent a lot of time trying to find non-dilutive ways to obtain funding like CPRIT. So we’ll continue to do that. But as per our previous plan, we won’t talk about specific grants we commend. But once we and if we get something approved and funded, we’ll certainly talk about that once we’re notified..

Great. Well, thank you, and I wish you guys good luck. Thank you..

Thank you..

[Operator Instructions]. We’ll take our next question from Sean Lee at H.C. Wainwright..

This is Sean Lee from H.C. Wainwright. Thanks guys for taking my questions. My first one is on the LM study. It’s great to hear that the first patient is doing well.

And – but traditionally with chemotherapy – intrathecal chemotherapy to treat LM, all the issues that they face is that there is insufficient penetration of the drug into larger solid tumors. So I was wondering is that something that you guys could potentially face with RNL as well..

Hey, Sean, great question. So with leptomeningeal disease, there’s two types. One is linear and the other is nodular. The nodular tumors can be a few millimeters in focal whereas you have sort of more linear disease, which can be very thin, but it’s just on the lining of the leptomeninges.

So with that sort of as a background, one of the things we’re excited about with RNL is it does have some penetration characteristics. It’s delivered within the CSF. It has a path length, average path length of about 2 millimeters, but it can have path lengths up to closer to 4 millimeters.

So you can actually get some penetration in nodular disease as well as hitting the linear disease. So we think that this could have a better effect than chemotherapy because of some of the limitations of chemotherapy and some of the benefits of radiotherapeutic. And I would maybe solicit Dr.

LaFrance as he’s an expert in the CSF, see if he has anything to add..

I think it’s a great question. And one of the unique characteristics of the LM study design and unfortunately this tragic disease complication to these patients is the leptomeningeal metastases really spread along the leptomeningeal membrane throughout the subarachnoid space. And you’re absolutely right.

Whether you have chemotherapy and even CSF-administered chemotherapy, systemically administered has the challenge of getting there. So you have your spot on in that observation. And when administered intrathecally, it usually doesn’t -- it escapes the CSF very rapidly.

As you may know, the turnover volume of the CSF, which has a volume of about 125 ml is five times a day. So you have something in there that very quickly gets -- exits out with that kind of circulations. Think of it as the CSF physiology circulation physiology. The RNL nanoliposome design, it’s administered very easily through the Ommaya shunt.

Patient is not even aware of it. We use a 27-gauge pediatric butterfly needle. It goes in a five-minute administration time period. They get a little band-aid over in which they don’t really even need, but a band-aid over the administration side on the skin over the Ommaya, and it’s an outpatient procedure.

And we have seen as we predicted not only is there excellent distribution that you heard Marc described, the duration of time that Marc also alluded to in his comments at the beginning of the call, we have objective evidence, imaging evidence because of simultaneous gamma ray disintegration with the Rhenium-186 of RNL product staying in the subarachnoid space for over a week.

So given our half life, basically the product stays there during its effective energy particle decay period, and you get full benefit by three or four half life instead of the whole time. And you get kind of the full benefit of that product administration.

In hindsight, that’s probably why we saw this result – at this very early – at this first dose, which is a very small dose, 6 millicuries and they get this kind of response. I think as I mentioned, one of our experienced investigators, he has never seen this before. And that’s where we were pleasantly surprised. So thank you..

Thanks, Marc, and thanks, Dr. LaFrance. It’s very helpful. My second question is that because with LM, you’re using a slightly different method of delivery.

Would that place a limit on what kind of radiation dose you’re able to deliver compared to the GBM study?.

I appreciate that question, because that’s actually the benefit of the delivery in LM makes it so easy. So instead of having -- the amount that we will deliver is going to be part of our dose escalation trial, and we’ll find that out.

But I guess to really answer the quicker your question, we will go -- our next cohort doubles the dose we’re doing the administer dose and the next cohort asset doubles it again. So by – we hope by year-end, we’ll have experienced at four times the dose we’re using now.

Given the response we saw on the first patient and given the preclinical work we’re going to start on nation therapies or multiple dosing therapies, I don’t think the amount of administered dose delivered will be an issue. So you’re absolutely correct that we’re delivering it differently.

That actually turns this into an outpatient therapeutic process as opposed to the required inpatient, albeit only a few days for the CED delivery..

That’s great to hear and certainly looking forward to the results later this year. And my final question is on the upcoming Phase 2 GBM study.

So other than the CMC part and you waiting for the FDA meeting as well, so what else does the company need to prepare before you’re able to initiate that study?.

I’ll give an overview. I know what you’re saying actually. So a big part of what we need to do, Sean, is the – is our work with Medidata in terms of developing the Synthetic Control Arm.

That’s going to be an important part of the trial, not only in maximizing enrollment and the randomization scheme, making it more patient friendly, but also decreasing the cost. So that’s -- we’ve already done a feasibility assessment with them. We have a strong sense that it’s feasible.

That will be developed here relatively soon and a lot of that will go into the trial. I think that’s what you mean. Other than that, it’s really just preparing the meeting package and the protocol synopsis in the statistical analysis plan and so forth, and all of those are in progress..

We have the benefit of the ongoing trial. Sorry, go ahead..

No, that’s good to hear.

I’m just wondering as a quick follow-up, would the company seek to get a special protocol assessment with the FDA for this study?.

It’s possible. I don’t know that we need one, honestly.

Norman, do you have any thoughts about that?.

That’s a great question. People always look to the SPA. Given our Synthetic Control Arm approach, this being a rare orphan disease, we already have Fast Track the potential for breakthrough therapy certainly is there. Getting a special protocol assessment, you usually have to go to the FDA and that actually would probably add time.

So we’re in very good shape to proceed about as rapidly as possible in drug development, given what we have, given the preliminary efficacy signal, given a very solid control arm that already has precedent at FDA for being accepted in GBM, in particular.

So an SPA, I think would be kind of redundant and would require additional FDA meetings and some interactions and negotiations. We believe by summer, we’ll have an agreement, third quarter and be able to have sites initiated by the year-end. You’re very correct that we have to interact with FDA first, but we’re doing it the fastest way possible..

I see. Thanks for that, and that’s all the questions I have..

Thanks, Sean..

[Operator Instructions]. And it appears we have no further questions at this time. I will now turn the floor back over to Andrew Sims..

Thanks, Gretchen. I have a question that was emailed in on the GBM trial. So the question is, it sounds like you’re working towards a Phase 2 registrational trial on GBM towards the end of 2022.

What details can you provide about the trial design, including patient numbers?.

So the answer is I can’t tell you anything definitively because we haven’t talked to the FDA, but I can give you some guidance as to how we’re thinking about it. And I think there’s a pretty reasonable level of confidence at this point that we’re pretty close. Everything is dependent, of course, on what the FDA says.

So in terms of number of patients, as we said before, we think it’s possible to have a successful registrational trial with 100 patients. I think we’re going to be between 100 and 200 patients. We’ll know more after we talk to the FDA. Primary endpoint will be overall survival. I think that’s clear. And that is the goal in GBM trials.

On randomization scheme, typically for rare disease, you might see a 2:1 randomization scheme or more typically a 1:1 randomization.

One of the benefits of the Synthetic Control Arm is that the randomization scheme where it’s like a 3:2:1 perhaps, which has been done before where three patients get treated and two patients in the control group come from the Synthetic Control Arm, and then you actually randomize one patient who you’re likely your control arm.

So three out of four patients end up getting treated, which is very good for enrollment and good ethically for these patients. So that would certainly help cost and funding and so forth. So we’re kind of hoping it’s something more like that, which is something that a Synthetic Control Arm can provide.

On a control perspective, I think very likely we’ll go to comparison against MD preference, which is essentially a kitchen sink approach. That’s what these patients get, because there’s really no clear standard of care. These patients are in an extreme situation and there aren’t good options.

So from a – I guess a budget perspective, with a Synthetic Control Arm and a lower trial size, we think this trial could be closer to $10 million. We’ve been previously guiding to maybe closer to $20 million.

I would say $15 million is probably a pretty good number and what else? I think in terms of sites, I think probably 10 sites makes the most sense, particularly for the lower end of that 100 or so patients that are in the trial.

And those really respond with what we know are world-class sites in terms of convection-enhanced delivery, which is a key part of the therapeutic design. And finally in terms of timing, close to 100 patients, I think this trial could enroll 10 sites maybe in 12 months, if we get a good running start.

Just it could take 18 months, but 12 to 18 is reasonable. Depending on the outcome and what the clinical benefit is, I think we’re looking at kind of a 12 to 18-month follow-up period. So we’re looking at a trial that lasts 24 to 36 months, hopefully closer to 24 months.

So all that to say, this is what we’re thinking and kind of giving you ranges that’s going to be dependent on what the FDA says..

Gretchen, are there any other questions?.

No further questions over the phone..

Thanks. Thank you, Gretchen, and Andrew. So just to close, I want to say thank you to everybody that joined us on the call and for those that are listening on the recorded version. Thank you.

And on behalf of the Board, I just like to thank once again our employees and the broader members of our team, our consultants and so forth, the physicians that we work with and of course the patients that trust us. Thank you very much for your participation and 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..