Perspective Therapeutics, Inc. (CATX) Earnings Call Transcript & Summary

Good morning, and welcome to the Perspective Therapeutics Conference Call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Annie Cheng, Investor Relations at Perspective Therapeutics. Please go ahead.

Thank you, Drew. Welcome to the Perspective Therapeutics call to discuss the VMT01 clinical data being presented at the 21st International Congress of the Society for Melanoma Research. During the call, we may make forward-looking statements that are subject to risks and uncertainties. Factors that could cause actual results to differ materially from our expectations are detailed in our SEC filings, including the Risk Factors section of our most recent annual report on Form 10-K, quarterly report on Form 10-Q and our other SEC filings, which are available on the Investor Center section of our website. These forward-looking statements apply as of today, and we undertake no obligation to update these statements after the call. Today's call is being webcast and can be accessed on the Events page of our website. The call will be archived and be available for replay for a certain period of time after the conclusion of the call. With that, I will turn over the call to Thijs Spoor, CEO.

Thank you, Annie, and good morning, everybody. We're really excited to give this update and to talk about the results from our VMT01 program in patients with metastatic melanoma. We're joined on this call by various members of our executive team as well as we hope to hear from some of the investigators in the trial. To start things off, I'd like to introduce Dr. Markus Puhlmann, who's our Chief Medical Officer. So on the next slide, Markus, go ahead.

Good morning, everybody. My name is Markus Puhlmann. It is a pleasure to present the data to you today. I would like to start with the title of the presentation, First-in-Human Peptide Receptor Radionuclide Therapy of VMT01 for Patients with Previously Treated Unresectable or Metastatic Melanoma. We would like to start with some initial comments regarding the mechanism of action and some of our preclinical results before we continue with the actual data presentation. I would like to ask Dr. Frances Johnson to start with the initial 3 or 4 slides. Frances?

Thank you very much, Markus. So next slide, please. So Perspective makes radiopharmaceuticals that are targeted to biomarkers that are specific for the cancers of interest and deliver alpha-particle radiation to the tumor bed. There's a growing knowledge about the radiobiology of targeted alpha-particle therapy. Starting on the left-hand side of the slide, we have targeted cell death that is directly related to the radiation, crossing the nucleus and causing single- and double-stranded DNA breaks. Alpha-particle therapy causes more double-stranded DNA breaks and helps overcome radiation resistance. But there's also many other things that occur. We now also understand that there is a significant bystander effect, where damage-related microparticles are formed and can signal as well as an immune response, which stimulates a T cell or adaptive kind of immunity. So next slide, please. So as we began studying melanoma, we were very interested in overcoming some of the resistance mechanisms to standards of care therapy like MAP kinase inhibitors as well as checkpoint inhibitors. And what we found is we found evidence of both cytotoxic effects and immunostimulatory effects. In the top panel, you see our studies that we did in immunodeficient mice. And so what you see here is you see a direct cytotoxic effect. And you can see that as we added things that increased MC1R biomarker expression, you have delay in tumor growth and improvement in survival, which is directly proportional to the amount of the biomarker expressed on the cell. But when you go to explore the problem with checkpoint inhibitor resistance in an immunocompetent model that is uniformly resistant to that, then what you see is something that is nonlinear. And you can see, again, tumor growth versus time. And I want you to look at the red graph, where some of the animals have delayed tumor growth, but others have a complete and durable response. And so next slide, what we did is we looked at this further. Next slide, please. And we looked at what was going on in the tumor microenvironment itself. And what we found is we found a massive increase, and you'll see the treated animals, the treated tumors are in black bars and the control animals are in light gray bars. And CD45 is all leukocytes, so we have a massive increase in the number of leukocytes that are present in the tumor microenvironment, including more T cells and a switch from more T helper cells to a predominance of the CD8 or cytotoxic T cells. Next slide, please. We also looked at the dose response curves when we went into combination therapy with immune checkpoint inhibitors as opposed to monotherapy. So on the left, you will see, again, monotherapy, and we're looking at 3 different doses of VMT01. With the dark blue being 1.9 megabecs, stepping up to 3.7 in light blue and 5.6 in fuchsia. And again, you'll see that you have a linear relationship in terms of cytotoxicity. But all the tumors are escaping in 20 days. When you add this to immuno-oncology drugs, what you see is the opposite. So if you look at the far right, 1.9 megabecs, the lowest dose actually gave us the superior result. So what we're seeing, we think, is that on balance, we're seeing more immunostimulatory effects in this combination. So now I'll turn this back over for the next section.

Thank you very much, Frances. That was greatly with -- during the talk, we will understand a little bit more why we introduced our preclinical data here at this point. I would like to start and bring everybody just back to our current clinical trial design. We -- first of all, I want to emphasize that all the patients in our VMT01 trial have been selected by the expression for MC1R. We also have done some dosimetry evaluations of patients participating in Cohort 2. And we will present here the data of the first 2 cohorts. Jumping here to the patient characteristics. I want to emphasize that a total of 10 subjects were enrolled in these 2 cohorts. The patient demographics is what you would normally expect from a patient group that has been heavily pretreated. I want to draw your attention to the bottom of the page. We have -- we see that patients in average in both cohorts were treated with an average 5 prior lines of therapies, of which 3 were actually IO therapies. And none of these subjects had objective responses as part of their immediately prior line of therapies. This is a slide that depicts the treatment-emergent events. Now let me quickly run you through the design of the slides. You see the first 3 cohorts -- sorry, the first 3 columns depicts by grade, the AEs for the first cohort, where 3 millicurie dose level was tested. The next 3 columns show the second cohort where we tested the 5 millicurie dose level and the last 3 columns are the cumulative values. As you can see, the most frequent AEs listed if we keep looking at the cumulative columns, showing for the AEs of anemia, lymphocyte count decreased as well as nausea, some electrolyte imbalances and thrombocytopenia. We have depicted to clean up this particular table. We have only put in here the grade 1 events where at least 2 or more events occurred. Otherwise, the table would have been too long. Now if you look at the middle 3 columns, we see that we only had 3 grade 3 -- sorry, 4 grade 3 events. One was in lymphocyte count decreased in Cohort 2. The other 3 were also in the Cohort 2 with fatigue and one pneumonitis as well as our only SAE, which was a case of hemoptysis. This was a patient with a large pulmonary metastasis, and it was not related to our drug administration, but it was related to the underlying disease. Overall, I can conclude there were no DLTs. We only saw 1 SAE that was not related and no patient was discontinued due to AEs. Overall, this looks like a very -- or relatively benign side effect profile. Now when we did dosimetry analysis on -- and here, we have data on 3 patients from Cohort 2. We were a little bit surprised to see a higher-than-expected coefficient for the kidneys. As you can see, the coefficient for these 3 subjects were about 3 for the first 2 and about 2.5 to 2.6 for the third subject for a cumulative coefficient mean of about 2.87. If we calculate this to the total exposure, these patients in average, the patient 01-116 and 03-114 have received a total of 2 doses, whereas the middle patient 02-117 received a single dose. It does normally already get -- go over the 23 gray limit that we have initially learned from the external beam. However, we have not yet defined what the actual kidney limit is for the radiopharmaceutical approach. Even the FDA has been -- has said in a recent SNMMI FDA-sponsored meetings that we do not yet understand what the kidney limit is for this group of drugs. It is currently assumed to be somewhere in the 40 to mid-40 range. However, obviously, more data have to be generated. If we take the cumulative approach and calculate the exposure for 3 millicurie doses, then we get to about 25.8 cumulative estimate, as you can see here on the right side. Now I want to point out, we have not seen any clinical or laboratory deterioration in renal function in our patients. So this is a finding that may limit us to determine a maximum tolerated dose in this patient population. But so far, we have not seen any adverse events, as noted. Switching over to the efficacy. You -- this is here a swimmer plot that I would like to quickly describe to you. You can see that pink bars on top, these are the subjects from Cohort 1, the dark blue bars on the bottom are subject from Cohort 2. Now we did not quite expect this, certainly took us also by surprise looking at this particular outcome. I think if we look historically at the PFS values that we're seeing in this heavily pretreated patient group, we do see that PFS usually is around the 2.1- to 4.1-month range even with drugs like [indiscernible] which has a median PFS of 4.1. Checkpoint inhibitor combinations are somewhere between 2.1 and 4.1. But there is clearly a stark contrast. So why -- how can we explain really the differences. And I think we cannot explain it with a typical cytotoxic model where we would expect clearly higher and longer efficacy with higher doses. So we may recall Dr. Johnson's explanation what we've seen in the preclinical setting that especially in combination with checkpoint inhibitors, as we see a more immune stimulatory effect, lower doses seem to be more efficacious. Now this may just be one of the explanation that we're seeing here. And -- if we look at the next graph, this is actually and maybe I should go quickly back. There is -- we observed 1 objective response in one of the patients in the 3 millicurie cohort. That response came rather late as we can see in the scans of this patient's pulmonary metastasis. We see that at baseline, the metastasis is clearly visible and remained essentially unchanged throughout the course of the therapy, when after the end of the therapy, the metastasis is starting to shrink and almost disappear. The subject also had metastasis in the pelvis and -- in the small pelvis, and that almost -- that actually disappeared as well. So we have a delayed immune response here as part of this particular treatment. And so we hypothesize that what we are actually seeing here may be an unprecedented finding where we define between these 2 dose levels between Cohort 1 and 2, potentially a barrier where we see, on the one hand, an immune stimulatory effect; on the other, a slight immunosuppressive effect within the tumor microenvironment. The findings of the Cohort 1 subjects is very encouraging. We see really prolonged PFS courses, whereas in the higher cohort, these subjects all progress quite rapidly. We know by now, after the data cutoff date, that all the subjects in the 5 millicurie cohort have progressed. So that is an interesting finding that obviously will require more evaluations. Conversely, we are interested in pursuing and characterizing these very encouraging findings from Cohort 3. And as such, I would like to hand back to Thijs for the further discussion.

Great. Thank you, Markus, for going through that. We have a couple of questions as well, and also on the line, we have Dr. Zachary Morris, who is the Associate Professor and Chair of the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health. Dr. Morris is the principal investigator on the trial and has graciously agreed to come on the call as well. So Zach, good morning. I really appreciate you taking the time to be on the call here with us. I wanted to sort of talk a little bit about what you see in these patients. Dr. Puhlmann had mentioned before that patients who present in this post-second-line setting with multiple therapeutic brands that are in place do have a very sort of brief progression-free survival. Is this in line with your experience? And can you describe the patients that you're screening to come into the study?

Yes. We've had, like Dr. Puhlmann said, overall limited sign of any real toxicities, patients seem to tolerate this treatment quite well. And our observations clinically have been consistent with what you saw on the swimmer's plot there that those in the initial cohort, some of them have had some very good clinical responses and we saw stabilization and regression of disease in some of those patients. And I think it's very intriguing that those are patients I had known for a while before, and seemed to be those who have had an immune response in the past to immunotherapy and had developed acquired resistance to that but likely had some degree of latent antitumor immunity. And this may have, I think it's still hypothesis, but may have rekindled that and certainly had a clinical effect that you wouldn't expect or I wouldn't have expected from low dose of radiation if it was just the radiation itself doing the killing. So I think it was a really promising observation.

Terrific. And actually, operator, if you can just go to the next slide, please, in the presentation. And Dr. Morris for you, wanted to ask you a little bit on your enthusiasm for using a combination of radiopharmaceutical therapies and within the context of immuno-oncology, given that you've published an awful lot of research over the past few years looking into this field. And I want to get your thoughts on where you think the field is and can go if the radiopharmacy you think fundamentally makes sense?

Yes. Absolutely. I mean that's been kind of the premise of my lab's research and a number of groups that we've been collaborating across here at the University of Wisconsin and more broadly. And this idea that low-dose radiation can be immunostimulatory is something we've seen consistently in preclinical models. But there's also a fair bit of clinical data for this. Jim Welsh has run a number of studies at MD Anderson, looking at given low-dose radiation to distant tumor sites, effect he called the RadScopal effect. But I think radiopharmaceuticals are going to be much more effective means to targeting most patients' metastatic disease, whereas with external radiation, there are certainly limits to the number of sites we can target. The finding was shown in the preclinical data here and that we're seeing in the clinical data is altogether consistent with what we've seen as well, which is that if you push the dose too high, you -- in an effort to maybe kill more tumor cells, you also kill your immune cells. And you can have a net negative effect even though historically, we might have thought that higher-dose radiation would be more effective from a tumor standpoint. I think a more modern understanding of radiobiology has to incorporate both the direct cytotoxic effects of radiation as well as effects on host immunity, particularly in those patients where we know that they are getting or have gotten immunotherapy because we know that is a major modality of achieving cancer control. So yes, I have very, very high enthusiasm for the clinical potential for this. I think this is a direction that we will see multiple studies head over the coming years as we see more and more radiopharmaceuticals develop and be developed in disease sites where we had immunotherapies that are known to be effective but unfortunately, not effective for the majority of patients. And even in those that they are effective for may not lead to a cure outside of a small minority of those patients. And so I think it's a natural direction for this to take. And I would -- I have hypothesized and expect that a maximum tolerated dose will not be the most effective dose in combination with immunotherapy. I think this finding in this initial 2 cohorts is potentially supportive of that, and I'd be very interested to see this now move forward in combination. I think as was mentioned, these responses aren't on these patients necessarily. Durable, but if it is immune-mediated, that's also not unexpected because we know that checkpoint blockade is often required in patients to kind of maintain durability of immune response and avoid exhaustion. So I think that combination has a lot of promise for potentially taking this inflammatory effect and converting it into a more durable response in these patients.

Great. Thank you. One last thing. We've seen a lot of the statistics here from the study. I just wanted to ask you, how did your patients feel while in the study? Any anecdotes you can share about any of the patient journeys sort of given that this is such a tough disease and the expected PFS is quite low? Any anecdotes about your patient experience?

Yes. I mean the patients really felt generally quite well outside of some of the patients in the second cohort, in particular, were experiencing progressive disease and had symptoms and challenges related to that. And so I wouldn't sugarcoat it, some of these patients are very sick and have aggressive disease. And so some were not feeling well. But of the ones that I had in the first cohort, they were seeing response, and I don't think they had, to my perspective, anyways, any clear toxicities that were directly attributable to drug and that couldn't work more likely due to other potential things. We can't always rule it out. And when we attribute, we often have to attribute that it's possible or probable that something's related, but also possible problems related to other things. And overall, my sense was that there wasn't much toxicity we were seeing with these administrations and the patients tolerated quite well. So their experience was overall good, although like in any Phase I trial, I think they also get a bit annoyed with the number of blood draws and pokes and sticks and things like that because when they are feeling well, they feel like do we really need to check all this. That was sort of their sense of it, I think, a lot of the times.

Thank you. We're also very grateful for patients who do volunteer to come into these trials because we learned so much about what they do. And we also appreciate that there's a lot that they do contribute over time to help us advance the science. I think what we've always felt in drug development that the best way to get into combination studies was to show really clear demonstrable monotherapy, sort of safety and efficacy and really evaluate that before we move into combination. I want to turn over to Dr. Puhlmann and just think through next steps of development for this asset. In your mind, what makes the most sense? And are you excited about opening up the combination therapy?

Yes. Thank you very much, Thijs. So this finding is really exciting. I personally have to say that I didn't quite expect to see such an immune-stimulatory monotherapy effect. So I'm really super excited, especially for the combination. Now of course, now the question is, and Dr. Morris already suggested an MTD determination obviously doesn't make much sense given these results. What we focus now on is to really try to hone in on the optimal biologic dose. Now that may be for monotherapy, but also in particular, for the combination with the checkpoint inhibitor. Now we are combining with nivolumab in collaboration with BMS. And we really want to understand what is the dose that we actually have to combine with nivolumab. Do we need to go lower, maybe even much lower. That is something that we definitely have to figure out. The study is open for enrollment for the combination now and the initial dose level given by the SMC, it's precaution since we don't understand whether there is obviously long-term renal toxicity. In the moment, we don't see any. But the recommendation was to go a little bit lower now from 3 to 1.5. We may dose escalate, if necessary, in the future. But we also are thinking to amend the protocol that will allow us to actually evaluate also much lower doses, if necessary. So very excited about the direction the program is heading. And obviously, these preliminary results bode extremely well, especially for the combination.

Great. So I think if we go to the next slide, operator, if we can actually open up the call for Q&A.

[Operator Instructions] The first question comes from Gregory Renza with RBC Capital Markets.

Congrats on the progress. Thijs, just maybe on the response and that prolonged PFS. As you think about explaining the mechanism behind the late conversion to responders, maybe you could just add a little color on the drivers there and just build on the prior commentary. And mainly, what do you think that means for trial design? As you've indicated, higher dose cohorts and Markus just mentioning about MTB and sensibility there going low, how low do you plan to go? And then maybe just to broaden it, Thijs, as it certainly is an important milestone for the company. You talk about the versatility of the alpha-emitter platform. What do you think this means for other targets and other indications that you are pursuing or plan to pursue when it comes to the dosing strategy?

Sure. Thanks, Greg. We're really excited. And if we can just go to Slide 11 and to have it on screen. We're really excited about the fact that we're trying to find that fine balance between sort of cytotoxic effects and the immunostimulatory effects. We're really pleased that we actually found such a terrific response in those patients at that 3 millicurie level. And that means we should really try to drive things forward as much as we can. I'm going to ask Markus Puhlmann, if you can comment a little bit further on there. Given the context we've seen with the earlier work that Dr. Johnson showed, showing that in combination effects, there is a sort of an optimized dose for alphas that is not an immunotherapy, that is not the same as the highest dose you could give. So Markus?

Yes. So obviously, we have right now kind of delineated these dose levels where we see no effect versus where we do see an effect. The question now is, is this the optimal biologic dose level? Do we actually need to go lower? I already mentioned that we are planning to start the combination and as well as the next monotherapy dose level with 1.5 millicurie. In general, to really understand, at those levels you may want to go to evaluate those levels maybe within a lock. But again, the actual science and the actual observations will eventually guide us. So I would expect to potentially also evaluate those levels below the 1 millicurie level. How far? I cannot tell you in the moment, that remains to be seen. But clearly, we understand now what our higher ceiling is. We do not understand the lower, and I would expect there is a limit also what we need to deliver to the tumor. Dr. Morris and I, we have discussed this in the past. There is probably a necessary amount of radioactivity that need to be delivered to the tumor bed. How much that is with a radiopharm drug, we don't understand yet, but that's going to be very interesting to find out.

The next question comes from Louise Chen with Cantor Fitzgerald.

Congratulations on all the progress. So just kind of scratching our heads here. I thought that you had a great dataset, see the stock is trading lower. And I'm wondering if there's anything from the conference from a pros and cons side from physicians that you've spoken with that may be driving some of this weakness.

Thanks, Louise. And so the data has -- the poster has just been put up at the conference. And so we don't have any initial feedback from physicians. As we look about -- excuse me, as we look at what we're seeing here, we're really excited about the fact that we actually had such an extension of PFS so consistently in that 1 dosing arm. We know that immuno-oncology and cancer development is going to be so choppy in terms of our learnings as we try and figure out what happens in patients in a very, very delicate immune system. And so Dr. Puhlmann, if you can just sort of comment on any feedback you've heard from any of the other investigators in the trial since no one else would have seen the data.

Well, the data obviously was discussed during the STING Safety Monitoring Committee discussion. It was basically uniformly mentioned that this has to be an immune-stimulatory effect. One of the -- obviously, I'm currently sitting here in New Orleans at the SMR, where the poster has been put up. And we will discuss with a lot of immuno-oncologists here at the meeting these findings to understand a little bit more the ins and out, what we're seeing here and how to further explore it. There's a lot of brain power here at this meeting, also a lot of folks from my personal past here from my times at the surgery branch. So hopefully, we can get some additional insights here.

The next question comes from Justin Walsh with JonesTrading.

As patients are now being treated with the nivolumab combination, what should we be focused on there to evaluate early indications of clinical effect and potentially overlapping toxicities? And maybe anything that might help support this immunological hypothesis that you guys have outlined?

Thanks, Justin, for the question. And there's obviously a lot of things that are at play with these patients, and we don't release our data until we've allowed everything to mature within a patient group or 2 patient groups. So we can really not be sort of hyperreactive as the data matures. There are some different factors that will kick in, and I'm going to ask Dr. Johnson to comment on just what are some of the differences in the tumor types and the contribution. So we try and think through what are we looking for? At the end of the day, if we can increase PFS, terrific. If we can help with the overall survival, even better. And there's all these metrics that we track through as we establish an appropriate dosing regimen for these patients.

Yes. Thanks, Thijs. I think for advanced melanoma, when we did primary research with physicians, they really told us that it was all about progression-free survival and disease stabilization, knowing that a complete response was unusual. Certainly, if we can have complete and durable responses in a certain percentage of patients, there would be a lot of enthusiasm for that. But I think most physicians are looking at how long you can stabilize the disease. But different tumor types are different. And so the response that we saw preclinically in melanoma was very nuanced compared to, say, a tumor like a neuroendocrine tumor with very high receptor expression where the mechanism of action that's important is really getting more radiation and direct cytotoxicity. So each one of these tumor types is a little bit different, and we design our drugs with those differences in mind.

The next question comes from Alec Stranahan with Bank of America.

First, I guess, just curious if the SMC had any comments on any specific AEs observed from either Cohorts 1 or 2 in its recommendation to explore the lower dose? Or was this more driven by the observations on efficacy vis-a-vis minimizing radiation exposure? And then just curious how you guys are thinking about administration timing of the combo? Will VMT01 and OPDIVO be given concurrently as IV or maybe staggered, assuming here that VMT01 is maybe the primary driver to treatment timing?

Yes. Thank you very much for the question. I think -- Thijs, do you want me to take this?

Yes. Yes. Go ahead, Markus.

So first of all, the SMC was not particularly concerned about the AE profile. The recommendation to dose reduce was solely based on the dosimetry data and the higher-than-expected renal uptick. As I mentioned before, we do not understand yet fully what the -- overall, what the long-term effect is of alpha therapy on the renal function. So far, we do know from our programs that patients do not -- at least within a year, we have not really seen certainly at these dose levels, any deterioration. Regarding the timing of the doses. So what we are planning to do right now is to start actually with VMT01 and then at least for the first cycle stagger then the administration of the PD-1 checkpoint inhibitor by about 3 to 4 days. There are preclinical papers and experiments that suggest that you do want the immune system first to be stimulated. And then you want to support the ongoing immune response with the checkpoint inhibitor. Now because of the long half-life of nivolumab or other checkpoint inhibitors, such as pembrolizumab and others of about 22 to 25 days, it doesn't make sense to -- and we're using a Q4 weekly dose level here. So you will always have circulating blood levels with nivolumab during the combination phase. Hence, for the all subsequent 2 doses, we will give it then at the same day. So the first day will be staggered -- the first cycle, but the subsequent cycles will not.

The next question comes from Yuan Zhi with B. Riley.

We are curious about the dose responses between these 2 low and high doses level. Can you comment on the tumor-to-background ratio between these 2 cohorts based on the MC1R imaging data so far?

So we presented -- thanks, Yuan. We presented data in aggregate. And as we look at things, we did want to make sure we had MC1R positivity in order to have the patients actually enroll into the trial. We did try and track things through with the patient dosing. When we actually look at sort of tumor to background, we look at all the kind of calculated metrics, we're trying to do dosimetry across the board. And as we looked at the various degrees of receptor positivity, we also know that not every tumor would actually necessarily express MC1R positivity, but we need a certain degree of positivity on top of that to go ahead and dose. Dr. Puhlmann, you have any other comments about sort of the tumor scans?

Yes. So we are tracking the level of positivity. And what we've seen is there's no difference really between these 2 cohorts. Conversely, we actually had subjects in the 5 millicurie dose cohort that had the highest expression level that we could measure among these patients during the eligibility scan. So there was -- bottom line is there was no difference.

The next question comes from Nicole Germono with Truist -- Germino, excuse me.

Did you biopsy and look at the immune cell subsets and patients in both cohorts? And did you see any similar observations from the mouse data?

Dr. Puhlmann?

Yes. That's a very good question. Now part of the elegance of the theranostic approach is that you do not have to biopsy to determine patient eligibility. So for the first 2 cohorts, we did not include biopsies. We will, however, now include pre- and post-therapy biopsies in the upcoming combination cohorts. So unfortunately, we do not have biopsies for these first 2 cohorts.

The next question comes from Jeff Jones with Oppenheimer.

Congrats on the results. Just a little more on that renal accumulation you were seeing. How did this compare with maybe the mouse models with a more controlled environment? And did you see, for example, could this be an on-target effect with some of the MC1R expression in the kidney? And was there any correlation with tumor volume?

Sure. Thanks, Jeff, for the question. And I'll have Dr. Michael Schultz who's on the call, sort of answer that one. But first, when we look at the data that we showed, this is a theoretical calculated dose of the kidneys. There were no kidney safety issues or biomarkers of any kind that show that there's any damage to kidney. So we just really want to clarify that there's -- these are -- the calculated limits were there -- were presented in the presentation without any sign of any evidence of kidney damage. Mike, do you want to comment on the preclinical?

Yes, sure, happy to do that, and thanks for the question. So actually, in the -- in our biodistribution studies that we used to extrapolate doses for human therapy, we found the predicted maximum tolerated doses would be -- would far exceed what -- where we're actually at by maybe a factor of 10. So it is a little bit surprising that we're seeing this kind of renal accumulation and retention. But as I mentioned, in the mouse models, we didn't see this kind of retention.

The next question comes from Anshul Dhankher with LifeSci Capital.

So I guess can you just comment maybe on some of the pulmonary-related tox signals you saw like a pneumonitis, dyspnea and hemoptysis? Is this related to metastatic melanoma and MC1R expression in particular? And then kind of a follow-up on the previous question. How does some of that -- how do you think that kidney dosimetry data maybe translates? Or does it have any read-through to VMT-alpha-NET? Or do those biodistribution profiles between these 2 molecules are very different preclinical studies?

Thank you. I'll take the first part of the question, which is each of these drugs have their own biodistribution. And they are just fundamentally different chemical entities. They have their own biodistribution. And also within patients, you have very different biodistribution within patients and also within tumor types, depending on if there is a tumor sink or not and also depending on the patient's own profile. So the nice thing about independent molecules, they each have their own profile. We engineer each one for best possible biodistribution that we think will show up in humans. Regarding the lung question, Markus, can you take that one?

Sure. So I mentioned before that all these patients were heavily pretreated. In average, each patient received 3 lines of immuno checkpoint inhibitors. Now there are, of course, immune-mediated AEs that are associated with therapy of checkpoint inhibitors. Pneumonitis is one of them. We have not seen in any other patient, the side effect of pneumonitis in this particular program or in other programs. So my best bet would be that this could have been a hangover, so to speak, from additional therapies. But obviously, we will have to verify this with additional patients.

We have time for one last questioner, that is from David Nierengarten with Wedbush Securities.

I had one, again, back to the kidneys, but it's versus -- kidneys versus bone marrow. Is there any confidence we can take away from the difference in accumulation between those 2 organs that the isotope, the radioisotope is not kind of breaking free from the cage and circulating around giving background radiation? Or is that off base when you're thinking about the different organs of accumulation here?

Thank you. So I'm going to actually ask Dr. Schultz, if you can comment on what would isotope breakaway look like and stability of isotope in the body?

Sure. Thanks, Thijs. Yes, happy to answer that question. So we designed the proprietary chelator to not only have a stable coupling for the lead isotope, but also for the bismuth-212 in the decay series. So we -- in our preclinical models, we showed greater than 98% stability of the bismuths in formulation at up to 24 hours post-radiolabeling. So we feel really confident based on -- and we published this data in several journals comparing the stability of lead and bismuth to our chelator compared to other chelators and we find much better stability there. So I feel really confident that what we see here is a vehicle that directs the radiation to the tumor microenvironment and then an excretion through the renal system.

Thanks, Mike. So we don't see any evidence that there is free isotope or free daughter with any of the profiles we've seen. We do track pretty carefully. We thought the safety signal looked excellent in the study, and we're really pleased by the efficacy we saw at that 3 millicurie level. So I really want to respect everyone's time. We appreciate everyone getting on the call. But we are -- if we just go back to Slide 14, please. What we noticed is that the dose levels that we were given were safe. There were no DLTs observed anywhere. That's a really important takeaway. There are some calculated dose of the kidneys that did not show up into any kind of biomarkers for kidney damage. In that first cohort, we did get an objective response in the prolonged PFS at that 3 millicurie level, which makes us really excited. And most importantly, we can go full steam ahead into a combination cohort, and that cohort is now active and open for enrollment. So with that, I appreciate everyone's time. Thank you for dialing in the call. And operator, if you can close out the call.

Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.