Hello, everyone. Welcome to our fireside chat with Y-mAbs. I'm Li Watsek, a biotech analyst at Cantor Fitzgerald. We have CEO Mike Rossi with us today. Mike, it's a pleasure to have you. Thank you. So why don't we start with an overview of Y-mAbs? What are you excited about, and what's coming up? So Y-mAbs is a commercial-stage biotech company. We've got a commercial product that is indicated in children with high-risk relapse refractory neuroblastoma. So we're very excited about the progress on our DANYELZA product in treating those patients. Also, we have a pipeline of radiopharmaceuticals focused around our SADA platform, with two products in clinical stage. So we've got the first product, where we're nearing the end of our Part A phase I trial- Mm-hmm. with our GD2 SADA product, and that was a basket trial focusing on sarcoma, melanoma, and small cell lung. We've recently added adult neuroblastoma into that trial. Mm. We've dosed the first seventeen patients. We've also opened up our sites for our 1201 trial, which is a CD38-focused SADA radiopharmaceutical in refractory non-Hodgkin's lymphoma. So a lot of exciting things going on and with both our commercial product as well as our radiopharmaceutical pipeline. Great! So I wonder if you can talk a little bit about your SADA platform. So that's the focus of Y-mAbs now, and obviously, you're in a area, radiopharma, which is, you know, really hot. So tell us a little bit about, you know, SADA, which I believe your approach is a little bit, you know, different from sort of the one construct approach that we've seen from the other players, and I believe you got this from MSK. So maybe tell us a little bit about the history, the background. Sure. So our SADA platform, SADA stands for self-assembling and disassembling. It's a tetramer complex that mimics a full antibody, but it also breaks down into monomers, so it actually is eliminated quickly from the blood. What makes it different than the commercial radiotherapies in the market and much of what's in development, it's a two-step approach. So we actually inject the SADA construct as a non-radioactive drug, and we then, on a second step, we inject the radioactive material separately. That allows for an in vivo tag in the patient. And why this is novel and why it's important is there's three areas in radiopharmaceutical development and administration that become very challenging. So the first is targeting the tumor and minimizing off-target toxicity. So we know historically some of the products that were administered as a pre-tagged conjugate have a long circulating life, and they irradiate areas in the body that you don't want them to. And the theory behind the SADA complex is, you inject the drug as a non-radioactive, it paints the tumor, and leaves open sites for the radioactive material to grab onto, which then decreases the off-target toxicity and increases the on-target, or on-tumor toxicity. The second component's physician participation. You know, physicians like to treat their patients, and when you deal with radioactive materials, it's really limited to authorized nuclear physicians that can prescribe and administer the products. So historically, there's been a challenge with oncologists, urologists, endocrinologists, being able to treat the patients themselves and have to refer them away. The third is all around infrastructure and logistics. So there's not enough infrastructure in the hospitals today or in the clinics to be able to administer all of these radiopharmaceuticals that are available and under development. We see constraints with things like the prostate cancer agents today with finding enough space to administer these. And also from a radiopharmaceutical manufacturing perspective, these products aren't manufactured in conventional pharma manufacturing facilities. They need to be specialized to handle the radioactive material, and that becomes very challenging. And the logistics on an isotope, it's constantly decaying, so you're actually shipping what's the equivalent of a melting ice cube, not under refrigeration, because you can't stop the decay of the isotope. So a lot of that gets burned up in time and in transit. So with our platform, oncologists, urologists, endocrinologists can actually infuse the drug in standard infusion centers. So this way, they can utilize the existing infrastructure that they already have for chemotherapy, for IO, for CAR-T, and they're able to administer this as a non-radioactive. They then go to the nuclear medicine department, and two, three days later, they'll get the isotope injected, and it becomes a much faster injection, a better throughput, utilizing that infrastructure, and the patient can then go home, and the tag or the assembly of the drug and the isotope actually happens in the patient. So for us, we don't need a production facility to combine the two because the patient is actually the production facility. It also saves on logistics of the drug- Mm-hmm. -on the isotope, so it's not getting transported around, and also allows us to be isotope-agnostic. Since the isotope comes after the drug, we have proprietary chelators in development that will chelate multiple different isotopes but all link back to the same drug. So as we move forward with PET diagnostics as well as alpha and beta therapies, the drug doesn't change, the isotope and when it's injected into the patient changes. So it's a much cleaner use of existing infrastructure, existing personnel, knowledge, and also puts us in a position where more physicians can participate in a cross-functional or multidisciplinary approach to patient care. Great, so let's talk about your first SADA program, which is GD2. Tell us why you picked this target. Yeah, so I get that question a lot, right? People don't see GD2 as being a target that they have a lot of experience with or something that is validated in the radiopharmaceutical world. But we in-licensed this technology, and it was a combination of MIT and MSK that developed the SADA technology. We already had our DANYELZA product- Mm. our naxitamab, which is an anti-GD2, full humanized antibody. We were able to take the knowledge from that, and in under three years from in-licensing preclinical technology to actually being in the clinic and treating patients, by utilizing that naxitamab and the knowledge of the GD2 to attach it to the SADA. So for us, it was an opportunity to expand our the product we already had, utilize that knowledge to increase the speed, and I'll say it was speed to failure, right? Mm-hmm. So anytime you're coming into a new technology, it's either succeed fast or fail fast. Mm-hmm. And it gave us the opportunity on a target that we had a lot of knowledge on to move it forward. It also gave us the opportunity to continue to invest in the space that's extremely important to our organization- Yeah ... and the patients that we treat, to give them another alternative. And for us, you know, there's several different indications that express GD2, but right now, the only validated treatment is in neuroblastoma. Mm. By doing a basket trial and expanding it beyond neuroblastoma, we were able to image receptor expression as part of this, as we moved into the treatment of the patients that were GD2 expressing. Great. So let's talk about your clinical plan or trial, which is phase one. So I believe this is a three-part design. So obviously, you have two steps here, so there are more parameters perhaps for you to optimize. So walk us through how you approach the optimization in terms of the doses for both the protein and the isotope. And I believe right now you're in part A. Maybe just tell us a little bit about, you know, the design, the expectations. So it's designed. You're, you're 100% correct, because it's designed as a three-part study. So part A is really designed to show the safety of the protein. Most drug trials, you'll inject the protein, scale it up till you'll see some toxicity, potentially scale it back a little bit, and then move into some efficacy studies. For our side, we knew we didn't necessarily need to inject a lot of protein to the point where you were going to see toxicities because we're just trying to paint the tumors. We're not trying to treat with the protein. The effectiveness or efficacy actually comes from the physics of the isotope breaking the DNA strands within the cells. So for us, the first parameter is: determine the safety of the protein. Mm-hmm. and how much do you need that's just enough to paint the tumor, but not so much that you have these residual high PK levels in the blood that you're waiting to clear before the isotope comes in? So the first thing we want to determine is the safety of the protein. Second is, what is the optimal protein amount? What is just enough? And then the third parameter that we're looking for, and again, we have several variables, is what is the right optimal window to inject the isotope so that you're maximizing what is on tumor and minimizing what is off tumor. And if you inject too early, while you have too much circulating in the blood, you're gonna tag what's in the blood, not what's on the tumor. So ideally, you let the blood clear out, so the majority of the receptors that are remaining- Mm-hmm ... are painted on the tumor so that the isotope ends up on the tumor. Great. So how do you determine that sort of, you know, the optimal protein dose? How do you even measure that? Yeah, so there's two things. One is, we started looking at the PK levels. Mm-hmm. So seeing a spike in the PK, as you would with any drug after you administer it, but also look for the trough. Look for it, how quickly is it eliminated from the blood? Because that is the ideal time when you see it get down to near zero or below, in our case, a thousand nanograms per ml, because what you're doing is what you're tagging is going to be on tumor. So it's as much art as it is science, but at the end of the day, you have some room there. Mm-hmm ... where it's not the Goldilocks scenario where it has to be perfect. It just has to make sure that you have enough on the tumor to create these open receptors for the isotope, but minimize what's in the blood. And then add enough isotope to saturate what's in the blood, get beyond that, and saturate what's on the tumor. Mm-hmm. In the tetramer complex, there's four binding sites for the tumor, and there's four binding sites for the isotope. And why that's important is, even if that tetramer grabs onto the tumor at one of the... one point on the, the tumor with one anti-tumor, it still leaves the opportunity for four molecules of the isotope to bind onto that tetramer. So you're increasing the amount of activity focused on that cell fourfold by having multiple binding sites, versus a pre-tagged conjugate, which is a one-to-one scenario. I guess for part A, you're using lutetium. My understanding is you have a low imaging dose before you move into therapeutic dose. Tell us a little bit about, you know, what information you can get from that. Yeah. So what we did was, a lot of radiopharmaceuticals are developed as diagnostics first and then to therapeutics. Since this was a novel platform and really doing something novel, an in vivo tagged radiotherapeutic, we wanted to understand if we had a therapeutic. I'd say, not that it's easy, but the burden to develop a diagnostic is much different than the burden to develop a therapeutic. So what we opted to do was go straight to the lutetium, which is the therapeutic isotope, and image that therapeutic isotope in the patient, utilizing the secondary gamma emission that comes off the decay of lutetium. And you could use a standard nuclear medicine gamma camera to visualize that. What we did is, since we did not patient select for GD2 in advance, because there's not any validated IHC to determine GD2, we injected the protein into the patients, and that was giving us the safety data we needed for the protein. We then injected a 30 millicurie DOTA caged in or lutetium caged in DOTA in all of the patients at the given interval for the cohort they were in, and we imaged those patients. We did planar images, and we did SPECT images with the gamma camera, and we determined which patients actually expressed GD2 by imaging them and seeing the uptake within the tumors. For those patients that did not express, they were done. We had safety data based on, you know, dose-limiting toxicities, adverse events that we needed to move forward. For those patients that did express and we did see concentration in the tumor, we came back and gave them a second protein dose at the same level, and then a therapeutic level of the lutetium isotope, somewhere between 100 and 200 millicuries. So we would then have four data points on those patients that were expressing, to narrow in what the optimal window potentially would look like and the optimal isotope amount in order to get more and more on the tumor. So some of our patients expressed, some did not. All gave us safety data that we needed to be able to close out Part A and move into our Part B, which is our scale-up of our isotope. You have dosed 17 patients so far in your Part A. I wonder if you can share some of the findings there. Obviously, the full data is going to come a little bit later, but to the extent that you can maybe just, you know, big picture, what you're seeing from your initial experience. Yeah. So I think what we're seeing is what we expected to see in that we have a very safe protein. Mm-hmm. That's what is paramount to developing the platform, is making sure that what we're injecting is safe. So we haven't had any dose-limiting toxicities in our first 17 patients, and we haven't had any indication that we need to alter or slow down anything, so that's extremely good. We've also seen where some patients express GD2 and some do not, right? Mm-hmm. It is a heterogeneous expression within GD2. Yeah. That was what we expected to see. I think what is enlightening for us as a GD2-based company was finally being able to see GD2 expression- Mm-hmm ... when we haven't seen it before. Mm-hmm. So, you know, it's been satisfying to say: Yes, we can do an in vivo type therapeutic. Yes, we can get concentration in the tumor. Yes, we can see what GD2 expression looks like. And that's extremely important as we even further develop naxitamab, if we want to go into additional indications beyond neuroblastoma- Right ... is there a way to patient select for those patients who express GD2? I think the other side of this is really understanding the variability- Mm-hmm ... between how much protein's enough, because in traditional drug development, you think more is better until you hit toxic levels. In our case, in nuclear medicine, that's not the case. You only need just enough to paint the tumor, because the radiation itself, as the isotopes begin to collect onto the tumor, create a radiation field within the tumor that allows you to visualize it and also gives you the, the exposure within tumors. And we're getting to see that real time, which is also very exciting. So your Part A data, so you should be able to finish Part A by the end of the year and gonna share the data either later this year or early next year? It'll probably be just based on timing- Yeah ... because we're opening a sixth cohort. Yeah. In that, we added in neuroblastoma. So it'll take a month to two months to recruit and treat those patients, and we'll have a six-week DLT period following that. Mm. So it'll run us right up to the end of the year. Mm ... in collecting the data and maturing it. The report-out will be in early 2025, and that will be all of the patients that we've done in Part A, what our learnings are, and what parameters we've fixed moving into Part B. Our Part B is taking the two variables and turning them into constants. We'll have a fixed protein amount that we take into Part B, and we'll have a fixed interval in which to inject the isotope. The variable we'll introduce into Part B is adding more and more radioactivity in a single dose- Mm-hmm ... up as high as 750 millicuries, which right now, our highest is 200 millicuries. And with that also, we can do up to two repeat cycles on those patients. So if we wanna do a second dose and get, in essence, what would be six data points, because we would have the dosimetric- Mm ... the therapeutic, and then a second therapeutic. Mm-hmm. And then you'll be sharing some dosimetry data as well. So coming out of that Part B, there, we should have some very good dosimetry data. Part A will show the scans, will show some of the dosimetry, some of the elimination data. Okay. And then Part C, which will take the learnings from Part A and Part B- Yeah ... and move into multiple cycles up to five cycles. Mm. We know with the radiopharmaceuticals, we need multiple cycles because these are relatively small doses of, we'll say, micro-dosed radiation systemically delivered right at the cell membrane. For us, we know as we look at some of the existing products in the market, they're anywhere from four to six cycles to show efficacy in the clinical trials. We're looking at splitting the difference and doing up to five cycles, and that should give us some good indication on what it's doing within the tumors. So it sounds like we may get some efficacy read when you move into maybe part C of the study. Part C is designed to show efficacy. Mm-hmm. Potentially you'll see some signals in part B with two cycles- Yeah, yeah. Especially at the higher dose, 'cause we opted to go with higher doses than existing studies in some of the current trials, because we really feel that it's so important to deliver that dose and deliver it early while you have the most receptors collecting these, as well as when the patient's radiation naive. So getting that in and getting it early. We'll then monitor those patients in both part B and part C for any changes in their lab values and their tumors, any early indicators that something has changed within the disease state. I guess for GD2, you're looking at some tumor types. For instance, I thought a small cell lung cancer is quite interesting, and we've seen some other sort of radioligand going into it, maybe looking at different targets. How are you thinking about, you know, what the bar is, and then relative to some of the other targets in the field, how do you feel about GD2? Yeah, I think GD2 is a good entry point to validate the platform. We'll learn more about what that receptor expression looks like and what the potential efficacy is, and that was part of doing a basket trial and learning more about small cell lung GD2 expression, as well as sarcomas, melanomas, and neuroblastoma. The other part of this is we do want to do the pediatric trial. Mm. So including the neuroblastoma and gives us some good data to then take in and refine our pediatric trial, to make sure we're maximizing that for the patients. I think as we look at the overall target universe, we've got four targets that we've disclosed in development. So the GD2, CD38, a HER2, and a B7-H3 as well. Mm-hmm. There's several targets we've been working on in a preclinical setting that we'll disclose at a later date. But right now, one of the processes we're running through is looking at the overall target universe in both oncology and immunology to say, what are the right targets- Yeah ... to move forward with from a radiotherapeutics point of view? So what you'll see from us later this year, early next year, is a prioritized target list and timelines of what targets we plan to bring forward and when. Also, what isotopes we plan to bring forward and when. Yes, so that's a good point. I do want to get your thoughts on how you're thinking about different isotopes, because, Mike, you sort of mentioned in the beginning, this platform can be very modular, right? You can just swap out the radioisotope, which I thought was really cool. So tell us a little bit about the work that you're doing here, because obviously the field is very interested in the alpha emitters, right? Actinium, Lead. So what are you doing there? Yeah, so we're working on our chelators and our linkers for things like lead and actinium- Mm-hmm ... as well as an additional chelator for lutetium. Mm-hmm. Because binding affinity is extremely important. The better your binding affinity, the more effective it's going to be. I think adding PET isotopes into that, both short and long-lived, are also extremely important. The short-lived isotopes are very convenient for qualifying patients in for therapy, and we see that with the gallium-68 and the fluorine products today, which have a one and a two-hour half-life. But in order to do dosimetry and look at resonance time on tumors, look at latency, how long it's going to be there, where the decay is, where else it goes, using some of the longer-lived isotopes like copper or zirconium allows you to look at it over several days versus- Mm ... several hours. So for us, that's extremely important in then selecting the right therapeutic isotope. So if it's going to be on the target for a short period of time, you may want to go with a very short half-life, high energy alpha product that's on and off the target and delivers its punch in a very short period of time. If it's going to be on the target for a very long period of time, you may want to go to a lower dose, longer-lived alpha, like an Actinium- Mm-hmm ... or even a lutetium, because you can deliver more dose over a longer period of time and potentially kill those cells. So I think for us, it's looking at the energy levels of the isotopes, looking at the half-lives of the isotopes, what the potential daughter compounds are- Mm ... because you need to know what it's decaying into and- Mm-hmm ... where that is going. Mm-hmm. And then selecting what's best based on what you're learning from the PET imaging on that particular target. So there, there's a few variables. Ideally, as you develop these clinical studies, you have multiple arms. You'll have an alpha arm and a beta arm, as well as- Mm ... using a PET to do the dosimetry and the diagnoses. That then allows physicians to select, based on efficacy, tumor burden, location, which isotopes are best for them and that particular patient. And that's truly where... You know, I'd say the word personalized medicine got overused early on, but this really allows you to do dose, dosimetry on patients- Mm-hmm. -and be specific on that particular patient, where the metastases are, where the primary is, what the overall tumor burden looks like. Do you want to go to a beta first that creates a larger radiation field with deeper penetration? Or do you want to go to an alpha first because there's more micrometastatic disease that you think you can clean up with the alpha emitters? So, I think as we get forward and we do better on diagnoses- Mm. and we have the PET isotopes that can actually see micrometastatic disease, I think that'll also change based on individual patients, what the therapy looks like. So when, you might, I guess, bring alternative isotopes into the clinical testing? You know, our goal is to get the PET isotopes in as quickly as possible- Mm-hmm. so that we can do more of that dosimetry. Mm. -and follow shortly behind with the alphas. For us, it was important to validate the platform first- Mm And validate as we come into the next targets. I think the thing with alphas that we have to be careful with is when the alpha damages DNA, it's generally a complete double-stranded break, which is great if it's targeting the malignancy. It's not great if it's targeting some healthy tissue. Mm. So we see that with certain side effects, where we saw lacrimal gland and salivary gland accumulation with some of the other products where you had high levels of xerostomia. We just wanna make sure that as we move into the alpha and you can't see the alpha itself, that you want to be sure with using your PET isotope where it's going to go into, so that when you bring the alpha in, you're doing it in a safe and efficacious way. Okay, so I wanna switch to your second setup program, which is CD38. Obviously, you're going into heme indications, so the space is quite crowded. What is your sort of plan for CD38? Yeah. So initially out of the gate, the goal was to get a circulating tumor targeted- Mm. and into clinic rather quickly. Mm. We have a brand-new platform. We're seeing the solid tumors in the GD2. We have the opportunity to take a lot of internal knowledge from people that helped develop previous CD38 antibodies to convert that into a SADA complex. And for us, we're targeting non-Hodgkin's lymphoma, mainly T-cell and mantle cell, staying away from multiple myeloma for now, since you know, radiation can cause bone marrow toxicity. If you're targeting bone marrow, you may see toxicity that you don't want. Mm. Because the product is very good. So in this case, you know, validating this in a circulating tumor then opens up a world of opportunity to treat other heme and circulating tumors. For us, we know that the non-Hodgkin's space is crowded. Yeah. However, there is an unmet need in refractory non-Hodgkin's. So, you know, post-CAR-T, there are patients that don't have a lot of alternatives, and there isn't a lot going on necessarily in the radiation space. Yeah. We know non-Hodgkin's is radiation sensitive- Mm-hmm. -from the work that was done thirty years ago with Bexxar and Zevalin. Yeah. So, moving into... And that was a CD20 base. Yeah. This is CD38, but it puts us an opportunity to really validate the platform, and then we can make a decision on whether we take it forward as a commercial product, we use it for validation, or potentially partner with somebody who does have a CD38 product, or is in the CAR-T space that wants an alternative post-CAR-T- Mm if the patient doesn't respond. So I guess on, you know, strategic partnership, obviously, we have seen a lot of activity in radiopharmaceutical space, and I feel you have a very unique and differentiated platform, SADA, and then you can go after a lot of different targets, right? So maybe tell us a little bit about, you know, what are you thinking on the BD front, and when might be a good time to start that conversation? Yeah. So there's a lot of BD opportunities here. We've got a platform that can develop a lot of drugs and develop them rather quickly. So for us, you know, we can in-license targets- Mm which there's a lot of interest in. There's partners out there that have targets and don't have the capacity to develop them. There's others that we are developing, knowing that they're probably best suited in somebody else's bag- Mm-hmm as they go forward. But then there are products that we're focusing on bringing to commercial end ourselves. So it's a mix of all three. I say we have a lot of interest in the space. There's a lot of big pharma that has recently gotten in that need to backfill their pipelines. There's other pharma that aren't in yet that necessarily don't want to get into manufacturing- Yeah a pre-tag conjugate, where this allows them to get in without having to do it. But more importantly, we haven't rushed this because we wanna get the platform right, and we wanna get it done well, and we have a commercial product that's funding the company, so we're not in a hurry because we're in a bad cash scenario. The most important thing to us is get this right for the platform and for the patients, and then do the BD deal secondary to that. Okay, so maybe just last question on your commercial side of the story. Obviously, GD2 antibody, it's you know, on the market, and you've discussed there may be some competitive headwinds here. So maybe just help us understand in terms of you know, growth for that franchise? Yeah, so we've. We're in our third full year of launch, so we've had a very successful launch. We have roughly a 20% volume market share. Our value market share is higher than that. We've got a great product that can be used in both the outpatient and inpatient setting- Mm-hmm. Where the competitive product today is, is inpatient only. So there's a lot of flexibility with our products, and whether the parents want their kids to come home at night or whether they want them in for a longer duration of stay, on the inpatient setting. We've also seen, some additional products coming in to maintain response. So, you know, there is some additional opportunities for parents to- Mm-hmm ... choose how their children are treated. But ultimately, we have a great product that's well differentiated, that really targets bone and bone marrow disease. And also, when we look at the opportunity here, the. Our product is the only humanized antibody. Mm. It also shows efficacy beyond the use of other anti-GD2 products. We're continuing to move it earlier, continuing to position it well, looking for other opportunities for label expansion and other indications like osteosarcoma. We've seen solid double-digit growth, year-over-year. We expect to continue double-digit growth moving forward. Although it'll slow down as the product matures, we are investing in label expansion and moving the product earlier and earlier in the positioning. We've also had a good opportunity in an ex-U.S. perspective. We've got partnerships outside the U.S. We launched in Mexico and Brazil last year, China the year before, and that's continuing to grow. We just recently received approval in Hong Kong, so that'll be additional. We're working with additional countries and regions for additional launches and expansion. We are treating patients in Europe on a named-patient basis. Mm. So the product is continuing to grow both in the U.S. and the ex-U.S. environment. So we're very excited about where it is, what it does for these children, and more importantly, what it can do for more children across the globe. Great. Looks like we're out of time, so I wanted to thank Mike again for a great discussion. Thank you, Li.