Right. Good afternoon, everyone, and welcome back. I'm Jeff Jones, one of the analysts here on the Oppenheimer Biotech team, and I'm delighted to be joined by Thijs Spoor, CEO of Perspective Therapeutics. Thijs, doing a fireside, why don't we jump right into it and have you give a little bit of an overview of Perspective from the perspective, unfortunately, of, you know, you guys have really been a leader in advancing lead-212-based targeted radiopharmaceuticals.
Maybe tell us a little bit about what makes lead-212 such an attractive isotope for you guys. And then maybe we can talk a little bit about some of the proprietary technologies and platforms that Perspective brings to the table.
Thanks, Jeff. I appreciate being invited to talk about one of my favorite topics, which is, what are we doing at Perspective Therapeutics? You know, I've been a nuclear pharmacist now for almost 30 years and seen a little sort of, you know, various isotopes being explored and some great academic isotopes. Really what we're trying to get into is what's the best possible way to get something to a patient. That always sounds like everyone says that.
The reality is with lead-212, we, you know, looked at the SEGRE chart, you know, sort of 15 years ago and said, really, what's the best way to, how do we solve for this? How do we get the most bang for our buck? How do we get the most on target, the least off target? The reality from that is it's not just the isotope, it's about everything else that's designed around there. What we like about lead-212 is that it's got a phenomenal imaging surrogate. You can use lead-203.
That means for identical composition matter, you can get a perfectly predictive scan of what's going to happen in a patient if you give them a lead-212 labeled medicine. We like lead-212 because it's an alpha emitter predominantly. There is a bit of a beta in there too, but that, you know, incredible potency of the alpha is really, really compelling. It lets us hit those cells directly with a particle that's neoantigen. We think that's going to be very differentiating in the future of cancer care.
We like the fact that it disappears very quickly. You don't have a lingering radiation zone to the tumor microenvironment. Independent of anything else, the ability to hit a tumor hard and fast, how that really helped the body disappear quickly and presumably safely from the body as well while staying on target makes it really, really interesting. The nice thing too is it actually has a relatively long half-life. You know, we often hear people say, what about the, you know, isn't the half-life too short?
It's really, we want to think about two concepts of half-life versus shelf life of a medicine. The half-life of lead-212 at 10 hours is actually pretty reasonable for distribution. You know, there are 18 million procedures in the U.S. that are done with isotopes that have between 2 hours and 6-hour half-lives. The distribution and getting things to a patient just in time is nothing new for the US healthcare system, the global healthcare system, anything that we're trying to do for delivering medicines to patients.
All right. Obviously, as you look at Perspective, or as we look at Perspective from the outside, you guys have developed some proprietary technologies and platforms around working with lead-212 and your generator and your chelator. Could you speak to how that positions you within the lead-212 universe and some of the advantages that gives you?
Sure. I'll, if it's okay, just share a visual just to help sort of put it all into perspective, if you pardon the pun. You know, as we look at sort of really what's there, the biggest thing to remember with any radiopharmaceutical is that overall as a medicine, it's not a matter of the chelator, it's not a matter of the targeting moiety, it's not a matter of the isotope. It's how do all three things together work. With lead-212, we feel really comfortable that we've been able to innovate by saying much earlier on, we need the best possible chelator for lead-212.
Big fans of lead-212, if you're going to use lead, chelate it properly. What does that mean? That first decay off of lead-212 is actually a beta. When the lead-212 turns into bismuth-212, the bismuth-212 is really where the alpha comes. If you do not chelate and hold that lead-212 and the bismuth together really tight, then you run the risk of off target with bismuth.
We have published data showing that 60% of bismuth of any kind, if it is free bismuth in the body, it does not matter which daughter byproduct from actinium or lead or whatever else it is, 60% of bismuth will actually accumulate in kidneys. That is the normal biodistribution biochemistry of bismuth in the bloodstream. You need to really make sure you hold that tight. The other bonuses we see from actually having a smarter or more thoughtful chelator is really understanding the fact that there is a net zero charge from the chelator we have designed.
The PSC is not Perspective's specific chelator. It is a lead-specific chelator. We've designed this with really thinking through any chelation chemistry, any metal pairing, there's all kinds of different optimizing energies and several metals will cross-chelate without getting too much in the weeds on that. What we found is that with DOTA and TCMC, the sort of generic chelators, you can actually get leakage of the bismuth and you have a net charge on the molecule.
Getting back to what's best for a patient is having a medicine that gives best possible biodistribution onto target. If we can minimize kidney retention, we can do that by not having a charged protein, right? Kidneys pick up charged proteins. Our chelator has a net zero charge on the protein, which makes it easier for renal clearance. It also makes a few other things easier too in terms of radiolabeling and some other things that relate to how these medicines get taken up.
Great. Yeah. That renal clearance obviously being a concern as people wrestle with tumor to kidney ratios and things of that sort. I guess the last few months for you guys have really been a story of clinical data for the stock. You know, looking at both clinical data for VMT-01 targeting MC1R and VMT-α-NET, obviously targeting neuroendocrine tumors.
You know, setting the stage for VMT-α-NET, Lutathera is obviously approved for neuroendocrine tumors with the NETTER-1 study having, you know, a really low overall objective response rate, around 13%. Can you talk a little bit or frame the scenario for your VMT-α-NET program and how to think about these populations, the different response rates that have been shown for NETTER-1, NETTER-2, and then what the opportunity looks like for an alpha emitter in these scenarios?
Sure. If we think about the neuroendocrine space, you know, it's, and there's a lot of background here and all these images are available off of our website. These are patients where their disease progression is a slightly unusual course. You know, the tumors are slower growing and the patients will be treated mostly symptomatically for quite a while. The question that shows up, what do you do with a patient if they've had tumor and they're starting to progress?
First and foremost, the physicians want disease control. If they can get disease control, then which is what they had before probably on some somatostatin analog of some kind, how do we actually kind of make sure we maintain disease control and what's possible? If we think about kind of how things sort of track through on the response rates, you know, the fact that we can actually go in and target these tumors directly, we're targeting SSTR2 expressing tumors.
We're really, in our case with our study designs, targeting the first time a patient actually gets treated with or addressed with a radiopharmaceutical therapy. If we look at sort of our study design, we want patients coming in that are going to be advanced unresectable NETs that were progressing on prior therapy and were PRRT naive, so naive to any kind of radioactive drug. These are patients that would otherwise be Lutathera eligible, similar to the NETTER-1 population.
If you look at the package insert for the standard of care for Lutathera, it implies a 13-14% overall response rate. The developers did not look like they actually wanted to go any higher on the dosing and there may be dose-limiting toxicities that prevented that, but no real push to go any higher on that. That sort of four doses, you know, it is certainly better than nothing and it gives some sort of disease control.
As we look at how we are dosing, we went to the FDA and said, we would like to actually get a fast-track designation to patients that have failed Lutathera, failed lutetium. The FDA came back to us and said, no, we would actually encourage you to look at this in the alternative to Lutathera. You know, these sort of newly progressing patients, so previously diagnosed, but they've had disease for a while, they've had a prior therapy and now they're starting to progress. We're actually in dose escalation here.
When we look at how the results initially came out, you know, looking at the waterfall, we were really excited. You know, we had one patient with progressive disease in the far left, but disease control in all the other patients.
The data, as we track these patients through, you know, between November last year with the NETs presentation and the ASCO GI update of the data, now they're getting three out of seven patients responding and they'll put little asterisks and say two of these patients are at unconfirmed response, meaning we need another scan to make sure that they are confirmed responders.
We're also seeing things tracking in the right direction. Certainly when we look at the waterfall plot, this tells us their patients are, we think are absolutely benefiting. In this kind of framework, if these were previously progressing patients to then get all these kinds of curves, really has got us excited. I have to say, Jeff, there's a big disconnect between the investigators and the investors.
The investigators are really, really excited. We've had a spike of interest in interest for our program, both before and after the NETs and after, before and after the ASCO GI data, where physicians even around the world are saying, we would love to get access for this drug for our patients because the safety profile looks so great and the sort of eight and nine so far disease control is also terrific.
Let's talk a little bit about that disconnect. Obviously the big hit for you guys to the stock from the investor community came on the NETs data. You're showing here the ASCO GI update, which was just a week or two ago. What's changed between NETs and ASCO GI? From my perspective, there were a couple of outstanding questions raised by the NETs data, some of which were answered by the ASCO GI update.
Also interested to hear your perspective from the investigator community, what's really getting them enthusiastic about the data and the opportunity to participate?
You know, this was the data that we showed at NETs. There's a lot of questions here. For example, was there a weight-based dosing component? We look at previous experience of lead-212 with another program targeting SSTR2. At the lowest doses, they were not showing any responses at all and only at their sort of, you know, MAD-4 dose were they actually getting responses in a weight-based dosing parameter. We started our trial in the U.S. with a fixed dose.
Therefore, if you divide fixed dose by weight, you get a, you know, you need to figure out what the weight-based dosing looks like. We also had this other thing in the background, which was what was happening with some investigator-initiated work and their compassionate use setting overseas, where at a fairly consistent high, you know, higher dose per kilo than we're dosing here, what their response looked like.
The initial NETs data, you know, implied that the only patient that really had a strong response out of the gate was someone that initially was getting 84.5 micro curies per kilo. Then things, the shape of the curves tended to drop off if you just try, if you label these and looked at, you know, micro curies per kilo. Doesn't mean it's the only way to go. Where things really kind of may have that wow impact for everyone is seeing that, well, that story didn't necessarily track all the way through.
It's not just weight-based and there's other things at play. This is why it's so important to look at the overall signal. What was consistent across the board is that we're not seeing any major safety concerns at anything we can measure at the acute level. As we looked at safety across the board, we didn't see any major issues. What the investigators were seeing with this kind of chart is that they can get pretty quick disease control and not just disease control, they can then start to see responses kicking in.
Anecdotally, we're getting such amazing feedback about patients feeling better and about sort of having more energy and all these things where the treating physicians in the study feel very encouraged about getting more of their patients enrolled into our program.
The word of mouth is that this is a very compelling program to get into. The patients themselves are also highly educated and they're reading that in Germany and Australia and India and other parts of Europe that alpha-emitting drugs for SSTR2 can actually have a stronger response rate in some cases than lutetium. There is a lot of interest to really explore what's the safest way to develop this kind of program.
All right. Now, are these patients, you know, you saw some of these later responses, you're still seeing trends down in a number of these tumors or these patients in terms of, you know, tumor size at these later time points. Could that be a factor of neuroendocrine tumors being a slower growing tumor? Are you continuing to follow these patients as you have obviously for the low-dose patients there with scans continuing over time?
To answer the last question first, we're definitely following these patients as they move on their journey. We do want to see what's happening with the scans. The patients come in routinely in any kind of, you know, clinical trial and/or under cancer care to assess tumor status and see how well they're doing. We will continue to follow these patients and, you know, when reasonable, be able to update, you know, the industry about what's happening with these patients along their journey.
There are various hypotheses at play and I don't want to, we want to see how the data pans out. There is a hypothesis that a higher dose out of the gate may give an earlier deeper response. That's something that we have to sort of test through. We don't know if that's weight-based or absolute dose or how that tracks through.
There are also, with the slower growing cells, as you said, it may be a situation where even at lower doses, if there is damage to the double-stranded DNA, that's only going to really manifest in cell death if the cell tries to undergo mitosis. You have to wait for that first mitotic event before you start to see a reduction. There are various theses that we're trying to play out.
At the end of the day, we're trying to find what's the best medicine that we can provide and what's going to be the most straightforward way for a clinician to actually go and treat a patient. One of the things that we have this relentless focus on from your very first question about why we like Lutathera with our chelator is that we're trying to develop a broader therapeutic window.
What we've seen with some other programs out there, there's very, very tight windows between what's a minimum effective dose from an efficacy basis and what starts to induce grade three plus dose-limiting toxicities or DLTs. So far with the limited number of patients we've seen so far, we feel like we may actually have a broader therapeutic window, which then hopefully we can then turn into better response rates.
Okay. Obviously you've talked before that you've actually, that you've continued enrolling patients into this cohort. There are another 11 patients out there, which we may get data on at some point in the future. This data set should get more robust over time as well.
We think it should. And certainly as we watch these patients through, you know, one of the things that we've done is reopened this cohort two. The safety monitor committee, you know, gave us the go-ahead to and recommended both dosing higher. That's going to be predicated on FDA agreement and interaction. They also recommended that we reopen cohort two and add more patients there. We've had incredible interest there.
The 11 patients we announced that came in as of December 31st. We've had quite a bit of interest since then as well. Reopening cohort, the 5 mCi should give us a lot more data points.
As you noted, the safety board suggested dose escalating. I know you had agreed with the agency that you'd go sit down with them before dose escalating. I believe one of your recent slides disclosed that you've submitted your materials to the agency for those discussions. Can you say anything about how you were thinking about dose escalating originally?
Cohort three is, you know, as shown right here, is 7.5 mCi. There's also been discussion about going to weight-based dosing. How are you thinking about the different options for dose escalation?
We're pretty passionate about the idea of following the data where it takes us. We need to get more data across the board to understand what's happening from safety and efficacy. The fastest way actually for us to get to think about if weight-based is the way to go is to actually collect a lot more patients on the fixed dose setting because then we actually get a whole scatter of different sort of activities per kilo across the spectrum. More patients in is helpful given that we haven't seen any major safety issues show up at all.
This implies that it's not inappropriate to go here, especially if these patients are being offered disease control effectively as we learn what different weight-based dosing could mean versus fixed. The other thing with the agency is that independent of kind of formal statements, it's an ongoing dialogue with any drug developer and the FDA in terms of really identifying where does the data take us and what do we learn from it, what do they learn from it, and how do we actually help patients in the best possible way.
Obviously that's a critical update for you guys to open that next cohort, whichever way, you know, whatever that cohort will end up looking like. You'll update when, I assume, once you have that guidance.
Yeah, we ask the question a lot and we do not live tweet our interactions with the FDA or any regulatory body. Suffice to say, we want to tell the investigators what to do. As we communicate with investigators, we will make sure we communicate to the street as well.
Okay. And then on the VMT-01 program on targeting MC1R for melanoma, that data update was last year as well or the initial phase one data. It was a surprise to folks in terms of, you know, what tumor to kidney ratio looked like, but some interesting observations there in terms of effects at low doses as well as potential for immunological drivers to response. Could you share some of your thinking there and where you guys are in exploring both combinations as well as lower doses?
You know, thank you. If we look at the immune system and if we look at radiopharms, things get non-linear pretty quickly. The immune system is such a complex, delicate, calibrated system within the body that you want to be very thoughtful for how you provoke or upregulate or change the impact in the tumor microenvironment.
Independent of actual numbers, if you looked at sort of the pink cohort and the blue cohort, you know, you'd say, all right, here's patients that are post-second line plus, they probably are on at least five different kinds of therapy and the expected PFS is in that sort of 2 to 5 month kind of range.
To have a blue cohort that tracks that as if therapy hadn't been administered versus the kind of pink cohort where 3 out of 3 patients, you know, had, you know, at 8 or 9, 11, 13 months out, really had the disease frozen in time. Speaking with one of the oncologists helping us develop the drug, they said the disease literally frozen in time is extraordinary in melanoma as being normally such a hyper-aggressive disease.
The fact that the 3 mCi dose seemed to get this phenomenal response rate well above what the expectations were of best possible standard of care tells that this is really interesting. The other thing to remember is that in drug development combinations, it's always helpful to lower down the dose and to really think through if you're stacking together different therapies, how do you do it so in a way that you don't inadvertently stack safety signals on top of each other?
If we think about sort of where we are with this program right now, we are looking at a combination cohort at a lower dose. The preclinical data does support kind of lower doses as well. If we, this sort of pointing towards some of the early data that we've published in the combination setting, if you look at this dark blue cohort in mice on the far right, the 1.9 MB was lower than 3.7 and 5.6 and had the best response.
Everything about the preclinical and good drug development combination setting, you know, tells us that you really want to be thoughtful about raising or lowering doses and getting things at the right level, you know, sort of with how you sort of treat. We are very keen to get into combination though. Looking at this graph in the middle, the black line here is immunocompetent mouse model with sort of cold tumors untreated.
The light blue line is effectively Ipi-Nivo. The dashed blue line is monotherapy. The animal data supports that monotherapy response is at the right level, which we're very pleased to see. The combination looks extraordinary. You know, combining a checkpoint inhibitor with the neoantigenic alpha emitters, if you can hit hard and fast and then disappear quickly the way that lead does, we think actually provides a lot of rationale to study this in patients.
We're thrilled to have a partnership with Bristol Myers Squibb, or collaboration, excuse me, with Bristol Myers Squibb, where they're supplying Opdivo. What that means then is that patients that are coming into the program now will be in a cohort where we're actually looking at a combination where they're getting 1.5 mCi of our dose in combination with nivolumab, as well as looking at the monotherapy 1.5. We saw the three looked really good. The five seemed like it may have been too much for the immune system.
You know, let's dose find, which is what you're supposed to do in drug development.
Are both of those arms now, the lower dose and the combo arm, recruiting now?
Yep. We have these, both these cohorts are open. We want to get into the pattern of sharing with everyone, the external world at our quarterly earnings calls updates, what the enrollment status looks like across our programs.
Got it. Last one I wanted to touch on is your FAP program, which has sort of been, it's been an interesting target in the radio farm space. A huge amount of excitement as a sort of broad-based tumor agnostic target. A lot of work done on the imaging side, but challenges to translate that to the therapeutic. You know, we've seen that in results from Lilly and Point and others.
I guess what in your view, and you guys have a FAP program that's rapidly advancing to the clinic. What in your view has been some of the key challenges for folks addressing FAP in human studies and the advantages you think you bring to the table there?
Without getting into why we think FAP is so interesting right now, I'm showing you on screen here three different molecules, each with an affinity for FAP. To say you have a FAP drug is almost like saying, like, I bought food. What does that mean? You need to break it down a bit further and say, like, what are you actually, how is your FAP targeting? In the far left image, you see sarcoma in the animal's right shoulder and you see kidneys.
In the middle, you see sarcoma and kidneys. In the far right, you see very high tumor uptake and very little kidney retention. These are all FAP targeting agents, but I think if you were to ask a clinician, would you rather inject into a human, the one on the far left where you're going to get a lot of kidney exposure or on the far right where you shouldn't expect it? It's a rhetorical question. You really don't want the extra exposure. We actually do show all of our images over time.
It's really important with any FAP therapy and without commenting about anyone else's program. Some of the early work I've seen with other programs, broad stroke, is that they didn't have a consistent enough tumor uptake and retention to imply a broad enough therapeutic window to make it interesting for us.
We have developed this drug, which I think is a lot more interesting because looking at a human image, now jump away from mice, get to humans and say, what's this doing in a patient? The 1 hour and 18 hours, that's initial uptake. When the dose rate is the highest coming off of the radioactive medicine and versus 18 hours, which is two half-lives, so 75% area of the curve, you can predict where that radiation is going.
Radiation is incredibly damaging. If it's hitting tumor, great. If it's hitting healthy tissue, not great. That's the secret here. Can you get it on tumor fast enough as FAP and stay long enough to deliver all the energy into the tumor without causing adverse issues? We have consistently tried to show as part of our development process what gives us confidence.
Okay. Now, one of the challenges with FAP or theoretical challenges with FAP and alphas has been that in some tumors, it's on the cell surface and other tumors, it's in the tumor microenvironment. With the shorter path length of an alpha, do you need to be on the cell surface or does your target need to be on the cell surface or can you be active in the tumor microenvironment? As you guys are getting ready to run your study, how are you thinking about that equation as you think about the patient population?
I mean, we want to think about it on both metrics, which is really both stroma and tumor expressing. Tumor structure is really messy. It is really convoluted. These tissues are interwoven like a sponge. Getting things into the sponge, we think, is fundamentally going to be helpful for the patient. I just want to be mindful of time here, Jeff, as well. We are going to see what the data takes us. The animal data looks very compelling. The human imaging looks very, very strong. We will have to wait and see what the clinical responses look like.
Okay. So will you be targeting tumor classes where it's known to be expressed on the cell surface in addition to those where it's in the tumor microenvironment?
We're trying to learn as much as we can about how this targets. We'll be looking at both because we think there's implications in both, sort of pure play, if you want to lack a better term, you know, sort of FAP versus stroma versus tumor. The answer is we want to learn as much as we can. We've learned as much as we can from the animal models. It's time to really make this available for humans.
Yeah, it would be great to have some answers to some of these questions I've heard people asking for the last 2 of years. Thijs, I think we are up on time. It has been a pleasure as always. Thank you very much. Good luck with all the rest of your meetings today.
Great. Jeff, thanks so much. Thanks for having us at your conference.
All right.