Good morning, everybody. Thank you so much for joining us. We've got Perspective Therapeutics with us here on day three, last day of our conference. I hope you had a good conference so far, and I can't wait to get into some of the details on Perspective with you.
No, thank you. I really appreciate the invitation, and it's been a terrific conference in somewhere that doesn't have New York weather, so we're quite grateful for that.
That's rude. All right, let's get started with a high-level overview. I'd love to get into some of the recent clinical data, certainly, but I'd like to start. Obviously, you are a radiotherapeutics company, and I think you're probably best known for being lead partisans in the alpha particle wars that people have spent the past year arguing over. So from a high-level perspective, could you maybe give us your quick take on why lead and how you feel your clinical data so far has borne out your, I won't call it a bias, but your choice of isotope?
I mean, in theory, we're actually isotope agnostic, but we just love lead for a whole bunch of reasons. For one reason, lead actually has a perfectly matched elemental twin, Lead-203, and that means for development work and dosimetry work, we can get a perfectly predictive scan with the same composition of matter, the same molecule, and see in advance before a patient gets dosed if they are suitable for therapy or not. That's a nice plus on the development side. But in terms of actually being effective as an isotope, Lead-212 has a 10 and a half hour half-life.
That means that it's going to hit the tumor hard and fast with a really significant punch with the alpha, and then disappear over two days and let the tumor microenvironment heal, have the innate immune response kick in, the adaptive immune response kicks in, and not have those lymphocytes come into a hostile environment. The nice thing about alpha versus beta, alpha is a hard fast punch. It's very neoantigenic, and so it creates an awful lot of material for the immune system to kick into. In any radioactive decay, you always want to be mindful of what happens next. What's happening with the daughters? Lead goes to bismuth, where the alpha actually comes from. We've designed our programs to actually use a proprietary chelator that holds the bismuth there too.
So wherever the lead goes, the bismuth goes, and that's where the alpha comes from. So whenever we get asked the question, what's better isotope-wise, it really depends. It's the whole construct that's so important because you need to make sure that the bismuth also goes on track. Actinium, if I can just make a comment there, has four other daughters that do not get held by the chelator. And so those daughters will have almost guaranteed off-target impacts, and that impacts the safety profile. So it's not like the first alpha doesn't work well. It's what happens next with all the others.
Excellent. Well, let's get into some of your recent clinical data. You showed some melanoma data pretty recently, actually, which I'd like to get into in some detail. But this is an MC1R target. It's not as familiar as a target in the melanoma space for a lot of folks, I think, these days. So can you give us a little perspective on your choice of ligand and your choice of target?
Yeah. So everything we do has our proprietary chelator. So we like that for holding the Lead-203 or Lead-212. We can tune the length of the whole molecule, but really the peptide makes the most sense. The peptide is how it targets. We pick peptides that accumulate very, very rapidly. Usually in about 30 minutes, all the drug is either bound to tumor or it's being washed out of the body. MC1R on its own, though, is a different kind of target because MC1R doesn't show up in all melanomas. It only shows up in about half of melanoma patients. And not even patients that are positive for MC1R will actually have that in, they'll only usually have it in one tumor. They may not have it in all their tumors. We have some extraordinary cases where every patient's tumor we could find had MC1R expression.
But the nice thing about the MOA is that we only need one to light up. And if one of the tumors has MC1R, we then have the ability to go in and hit it hard with an alpha, create a neoantigen storm, and do the equivalent of turning a cold tumor hot, especially as it relates to all the other things that are going on in the body. So on its own, you wouldn't say every patient should go for it. But if you can screen them in advance, if there's some magical way to actually see in advance if they had MC1R expression with a drug you're targeting with, and what's amazing is we do Lead-203. It actually lets us see in advance if the patient has it.
Now, there's a couple of directions I want to take that. Certainly, patient screening is one of them. But there's something else that you mentioned in there which I think is really, really critical, which is this immunostimulatory aspect. The immunostimulatory response, both to radioisotope therapy, but also to radiation therapy, is something we've been hearing in the industry for a while that has not quite seemed to be borne out. Certainly, we've discussed the Keytruda external beam radiation studies that notably failed and a couple of others in the same vein. But that's not necessarily what you're observing, and you think you've got some early PD to back that up. So let's talk about the trial that you've run.
Sure, and actually, if you don't mind, just to contextualize then, external beam is a gamma. It's not a particle, right? Beta is a very, very small, lightweight particle. Alpha is a very large destructive particle. And so you are going to see huge differences in how this gets applied and the relative degree of neoantigen formation. You also have the situation of saying what's happening in the tumor microenvironment. Hitting a patient regularly with external beam or a longer-lived beta or alpha will have this sort of radiation field in the tumor microenvironment that will damage these various fragile TILs trying to come. They're being recruited for the cause. Previous studies have failed. They get recruited for the cause. They come in, and then they get hit and damaged by the other radiation that's there.
So what we really like about the fact is we can actually go in and hit it hard, fast, disappear, and recruit. We've seen some great data that shows that turning the cold tumor hot means you actually have a lot more antigens for the antigen-presenting cells to then present a signal to the rest of the organism.
It's important when we think about the data set that you presented, you have some clinical activity that you've shown you said at least one response in those recent melanoma cohorts, but interestingly, sort of a reverse dose response where the more radiation you're delivering, you seem to see more rapid progression, and this you contextualized for me as being related to that immunostimulatory path.
It's related to the immunostimulatory and also the overall immune status and what's happening within each tumor. And so it's not an inverse function. It's a bell-shaped curve, meaning there's a peak point at which point you get your most benefit. And then quite rapidly, if you give more, the patients fall off. What we think is happening in the tumor microenvironment there is that this battle between the lymphocytes and the tumor itself, very aggressive tumor growing like crazy, and the lymphocytes are holding that tumor at bay. If we give enough radiation to that area, then you're actually damaging those lymphocytes that are holding it at bay. And therefore, the disease goes unchecked.
And so we should be careful here because what you're, as you said, the MC1R target is not universally expressed, not even in every tumor for these patients. You're not giving a sufficient dose of radiation to do a lot of radiation-induced debulking.
Correct.
So we shouldn't be thinking about this as necessarily primarily a direct cell kill mechanism in melanoma, at least.
Correct. And the two mechanisms, you're either going cytoreductive or immunostimulatory. In a few cases, you might look for both. But tumors are so different, right? And some are so immune-dependent, and some are not. The nice thing about the neuroendocrine program, for example, is that's not really an immune-mediated tumor complex that we get concerned about. Melanoma really is. And if there's any tumor type that's highly dependent upon what's happening with the immune system, it is melanoma. The nice thing about what we showed with that monotherapy is that we're trying to identify monotherapy safety and efficacy. Because if we go into a combination study without separating out the components, we're going to be nonstop questions.
Of course.
What we really loved about what we saw was that we had patients with. These are post-second-line patients that had seen many prior lines of therapy. Their expected PFS was about 2.5-4 .5 months. Now that sweet spot dose of 3 mCi, we actually had those patients totally doing well at nine, 11, 13 months post. To get a tripling of the PFS in a monotherapy clearly shows activity. We didn't see any AEs that were really relevant. In dose finding, we found that dose. We know higher, we're getting problems. Go lower.
So you say, well, yeah, let's dive in there a second. The two doses that we've seen data from so far are 3 mCi, which is that lower dose where we saw the clinical benefit, and 5 mCi, the higher dose where maybe you were doing too much damage to the local immune system. The go forward doses are actually even lower than that. You're moving in monotherapy cohorts and combo with 1.5 mCi.
Correct.
Is that right? So how do you feel confident? You mentioned a bell-shaped response curve earlier. How do you know what the sweet spot is and you're dosing down even from three? How much more dose finding is there to do?
Dose finding is just that, trying to find where it goes. We don't know until we actually do the work in humans. In general, in combination, if you're starting with a level where you're seeing it makes sense for monotherapy activity and safety issues, you always want to go in at a lower amount so you don't stack your safety effects on top of each other when you're throwing a combination there as well. That 1.5 mCi dose, we don't know if that's the right dose. We might go lower. We might go down to 0.75. The animal data has been extraordinary. It's shown really to quite low levels. We can actually still get even better responses to the immune system. We're following the preclinical data, and it's exactly on track with all the preclinical work.
What drove you to start your dosing at three and five?
So we do best case correlates between what else we can think through. How do we go from a mouse to a human? And that's a relative.
Not a trivial challenge.
As in oncology, it's learned so we do a relative basis. We've seen that kind of three-to-five range has shown some promise in patients with other targeted therapies with lead, and so order of magnitude-wise, we think we're in the red zone, and then it's a matter of doing that ranging work.
Okay. Makes sense. Let's touch briefly on the update schedule for this program, and then we'll move to the other program. I want to make sure we have some time.
Yeah. So we were really excited about getting those initial results in those patients. It was extraordinary. All three patients at 3 mCi, almost a year later, were doing very well. Disease frozen in time. It's extraordinary for melanoma. Keep going forward. We've opened for enrollment the cohort at the 1.5 level. Melanoma physicians, when we were trying to get the sites activated, said, "We like the idea. We wouldn't want to be in mono. Tell us when the combination's open." And so what's great is that combination cohort is now open, and all the various kind of protocol amendments are rippling through all the sites.
I should also dive into the fact that the trial enrolled second-line plus, as you say, but you actually got much more advanced patients than that. Most of these patients are fifth-line in melanoma, right?
Correct. Yeah, and that's why we're calling it second-line plus, meaning if they were BRAF positive, they would have already received that. If they were appropriate, they all received multiple lines of checkpoint inhibitors, so they'd failed everything else that was out there.
Okay. But that's very relevant as we start to think about checkpoint combos if these patients are multiply exposed, what the right combo is. So as you go into Nivo combo, do you have an expectation that you'll start seeing more of a true second or third-line population instead of the super league?
We would hope that we would. And ultimately, in drug development, the earlier we can use it, the better. The animal models tell us, great, the earlier, the better. But out of an abundance of caution and care, we want to start to lock it up. If we show very, very good combination effect with checkpoint inhibitor as a third-line checkpoint inhibitor, the rational argument is go earlier. Try it in second, try it first. And even at the very first point, you're giving a checkpoint inhibitor. If you can then really have a huge boost to the immune system.
Why not take it?
Right. Exactly.
All right. Great. So let's move now to the neuroendocrine indication with an SSTR2 target, maybe more familiar in the radioligand space. Obviously, there's already approved agents there, multiple folks in development with alpha particles as well. And here, the mechanism of action is primarily cytoreductive. Okay. So can you walk me through why you choose one approach with one tumor and the other with the other? What's driving you to SSTR2 as the target given crowding in the space? Put the program in some context for me.
Yeah. So the company actually started as a spin-out from the University of Iowa, which is the Pediatric Center of Excellence for Neuroendocrine Tumors, and so the company founders thought, can they make a safer drug for kids targeting SSTR2 for pediatric programs? And by thinking about that, they designed a drug with a very, very broad therapeutic window, so the broader the therapeutic window, that means we can either get the same response rate at lower doses and hopefully safer for kids, and as it turns out, that means it should be safer for adults as well, so the thought was, okay, what can we do? And by changing the construct of the molecule, changing the peptide, changing the chelator as well so that you have a net zero charge of the molecule, really important with any radiopharm, look at the biodistribution.
It's all about biodistribution, how much of the drug goes to the tumor, how much goes somewhere else. The somewhere else is where you get your safety issues, how long it stays on tumor is your therapeutic impact. Looking at Lutathera, 13% ORR, approved drug. For whatever reasons, it can't really dose higher. They can't seem to get a better response rate because there appear to be DLTs that kick in more at the heme level. The actinium dotatate program's out there targeting SSTR2. The FDA has only allowed that in a post-Lutetium environment. Actinium has those toxic daughters that are of great concern from a safety basis. For whatever reasons that the FDA has seen, it has not moved into that.
At least so far.
So far.
While the actinium folks say they're going to go there.
Yeah. And again, we have to learn as we go through.
Sure. But you haven't been limited in that way?
We have not. And actually, we asked for that post- Lutetium environment. And the FDA told us, no, we actually are encouraging you to go in the pre- Lutetium environment, just like another competitor, RadioMedix, has. So they had a very similar approach, different chelator, charge on their protein. From everything we've seen on the preclinical side, we have a much broader therapeutic window than they do. So a broader therapeutic window means we need to dose find, escalate, get to where we get to. Their program at the first three dose levels didn't show any efficacy. It's only at their fourth dose that they got good responses, but it also appeared like there were dose-limiting toxicities. So narrow therapeutic window.
But it took them a while to get up to even the active doses.
Absolutely.
Where are you in dosing from a delivered radiation perspective relative to those competitors?
So what we're learning as we go, we started with a fixed dose approach. We're learning that there appears to be a signal that correlates with weight-based dosing as well. So we're learning as we go. We found that patients that were dosed in a line closer to where their program was and also very similar to an investigator-initiated trial that we just ran or that was run in India that was all done at a higher weight microcurie per kilo level. At those higher levels, you get more response. All the animal data shows dose higher, you get more response. And so on a per-weight basis, it appears that we're still dose finding.
Now, I'm curious, if you get really good biodistribution, to your point, if you get really good uptake in the tumor and not anywhere else, why would you expect to see weight-based dosing be the best correlate rather than tumor volume or tumor?
It's a great question. There's a lot of ways to do it. There's actually an investigator-initiated study in Iowa looking at kidney function-based dosing.
Sure.
And so you can either look at overall tumor burden. You can look at kidney.
That seems like a safety-limited approach.
Yeah. And they're doing a safety-limited approach in post- Lutetium patients. Across oncology, some people do body surface area. Some people do blood volume. There's a lot of different metrics.
Although most of those metrics, when I think about this from a traditional therapeutics area, I often imagine that being driven by the challenges of systemic distribution.
Correct.
So if you're doing surface area or weight-based dosing for a systemic therapy that isn't well concentrated in the tumor, that's safety-limited. But if you have really good tumor concentration, would you expect to see flatter response curves with?
We would hope so. And this is why we're doing the dose ranging. And so we actually did our program initially with flat dosing, 2.5, 5, 7.5. In extreme cases, kids, very, very small people, someone who's 40 kilos, for example, you may want to consider going down a bit with weight-informed ranges. And so we're learning as we go.
Now, all of these doses that we're talking about, the numbers sound very familiar, but of course, the units are very different. These are millicurie doses. This is radiation-delivered dose, not a milligram, not a weight dose.
Correct.
So, can you put that into context relative to an ADC or a more traditional therapeutic dosed in the milligram ranges? How much material are you delivering?
The actual physical material is in the picomolar levels. And so it's not detectable if it's not radioactive. That's how low it is. The FDA considered this to be microdosing. They do not want us to do metabolite studies or talk studies because there is no pharmacologic effect from this. Picomolar levels of material, picogram levels. So nothing really shows up on a physical basis. Really, what it comes down to, that millicurie is a rate, is an amount, and a rate of decay. That, combined with the half-life, tells you what an area of the curve looks like. So short half-life, you go higher millicuries and you get a hard fast punch. Longer half-life products, you always lower that rate down because total area of the curve is what counts for safety.
Makes delivered radiation to the target.
Correct.
Makes sense. Great. And this cohort, you're just getting to relevant doses in the neuroendocrine space. When should we expect to see data from where you would expect active delivery data?
We think we're actually seeing some nice activity here. Eight out of nine patients that we studied so far had disease control. Patients that were stable historically started to progress. Eight out of nine immediately had disease control in our drug. Now we're pushing towards getting reduction of tumor burden and tumor mass. We're starting to see signals of that. We had a response already after only three cycles. Generally, you want to wait until several months after the fourth cycle to truly evaluate the efficacy. That data is maturing. We expect to report that out next year.
Next year. Makes sense. In our last seconds, I know you have an IND opening for a FAP program as well. Lots of interest in that target. In a couple of minutes, maybe, can you tell me what to expect on the pipeline?
Yeah. So pipeline-wise, with FAP starting, IND open, enrolling patients in a basket study, looking at a whole range of tumor types, colorectal, pancreatic, ovarian, breast, sarcoma, a whole range of tumor types that are all really interesting and seeing where that goes. And then we also have new molecules with other receptor targets we're going after as well.
Excellent. Can't wait to see the data as it develops next year. I think everybody is still very interested in the radioligand space at this point and can't wait to see how it develops.
Great. Well, thanks so much for having us.
Thank you so much.