All right, good afternoon, everyone. Thanks for joining us on day three of the Morgan Stanley Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce John Valliant, CEO of Fusion Pharmaceuticals. Just a reminder, the format is a fireside chat. But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. And with that, John, thanks for joining us today. Really appreciate it, and maybe to start, I could just hand it over to you to give us just a brief background on Fusion. Sure, happy to. So, Fusion is a targeted alpha therapy company working in the radiopharmaceutical space. We have an extensive pipeline, which we'll talk about today, four clinical programs and a real exciting manufacturing investments we've made in manufacturing. So we're focused on a number of different disease areas. Our lead program in a phase II, we have three phase I's, as well as a big collaboration with AstraZeneca. And again, we'll get into that in a little bit more detail, I'm sure. But radiopharmaceutical certainly very exciting at the moment, and we're excited to be at the forefront of that field, particularly in this targeted alpha therapy subset. Yep. Great. Thanks for that introduction, and maybe we can just continue with, with sort of big picture questions just on radiotherapy. Field's obviously evolved quite a bit over the past few years, and you're working with targeted therapies, so maybe just talk about some of the advantages of, of that approach. Sure. So, I mean, people are often very familiar with external beam radiation therapy, where you're shining radiation from outside a patient onto one or two tumors. It's a very effective therapy for that, but when you start looking at metastatic disease, the ability or the opportunity to bring radiation on a cell-by-cell basis to the cancers, was really very intriguing. Another part of this field that I think gets people quite excited is you can see where your drug is going. You can image a patient, select them, to make sure they have the right target, before they go on to actually get the treatment with the same basic form of the drug. So that's driven a lot of excitement. I think what's happened recently is with the Novartis drug Pluvicto in prostate cancer, the fantastic clinical data, as well as, I mean, the sales have been fantastic, and a billion-dollar radiopharmaceutical drug, that's where it's trending in its first year. I think people are now starting to see the potential of the field for far beyond just prostate. Yep. It's really, again, an exciting time, and it's based on a very simple mechanism of action. You're prodding a tiny bomb inside a cell, and it's proven to be very effective, so it's an exciting time. Yep. Can you talk about targeting and the different ways you can do that? You obviously have a couple different approaches, so maybe walk us through some of those, and are there advantages or disadvantages of some or certain applications where one approach might make more sense than another? So in a radiopharmaceutical, the strategy is you identify a target on the cancer cell and then a molecule that you attach your radioactivity to. In our case, we use actinium, which is the alpha emitter. And the molecule's job is to get to the tumor, drive the radioactivity into the tumor, and really clear from other parts of the body. And there are many different targeting molecules you can use. The three larger classes are antibodies, peptides, and then small molecules. And interestingly enough, lots of people tend to gravitate toward one or the other. There's been actually products approved and great clinical data from each of the classes, so the approach we take at Fusion is we look at the cancer type, the target, and what would be the best way to interrogate the target. So two of our programs are based on small molecules, one is based on an antibody, and another is a bispecific antibody. So it's really, there are pros and cons. There's no one universal targeting concept. It's really driven by the target, and that's why we took the approach of diversifying the targeting molecules based on the target of interest. Makes sense. Maybe you can also talk about your focus on actinium, and maybe there seems to be a shift in the field, more towards actinium. Maybe talk about why that is and maybe how it's different from the more, I guess, traditional beta emitters. Right. So the early days of targeted radiopharmaceutical therapy really were on beta emitters, which were much more widely available. Certainly the data that came out on lutetium agents, like Pluvicto, as I mentioned before. But betas are electrons. They're small, they travel a fairly large distance, and they cause single-strand DNA breaks, and so you need a larger amount of injected radiation to actually create double-stranded breaks. Alpha particles are large, they're highly energetic, they travel about one-three cells, but they cause direct multiple double-stranded DNA breaks, and so very potent kill mechanisms, but there's a limit of the supply early on. Mm-hmm. But what's emerging now is clinical data showing that patients who won't respond to a lutetium agent, you take the same drug, you remove the lutetium, you put in the actinium, those patients can respond to the more potent alphas. And so what we're seeing, and, again, with nearly three decades of experience in this field, tremendous excitement about the field, but a real shift from betas to alphas because of the potency, but also the ability to really target and go that sort of very selective- Mm-hmm ... tumor kill. Yep. I guess maybe just to follow up on that thought. In general, is alpha will generally be better than a beta in whatever sort of application you're thinking about? Or could there be areas where maybe a beta makes more sense, for example? So one of the original sort of dogmas in the field was because a beta travels farther, it should be better in larger tumors. Okay. And that alphas would be better for smaller disease. But it turns out that, when you move from the theoretical whiteboard into- Mm-hmm In the clinic, the alphas are actually working in even very large tumors. In some of the data that we showed from our lead program, there were some very large lesions on those patients. And the drug Xofigo, which is an alpha emitter, they were also treating quite large lesions. And what we're learning is that the alpha, not it travels a short distance, but it really causes what's called the halo effect. It's a damage that spreads out, so it's more than just how far it travels. And there's an immune component because you're creating tumor neoantigens. So I, I think the differentiation based on path length is really not bearing out in the clinic. It's the enhanced potency of the actinium, which is really driving people from lutetium to alpha emitters like actinium. Makes sense. Maybe just talk about the supply and access to actinium, because that's, it's an important aspect in terms of radiopharmaceuticals. So maybe just talk about, you know, how you've sort of solved for that challenge. So when launching Fusion around 2017, we would take a targeting molecule, and we would put a beta emitter on it, we'd put actinium on it. Again, from that potency we were just talking about, the actinium continually produced great results. So we decided strategically as a company, focus on actinium and alpha emitters. But what we knew was there was a limited supply. So we have a great relationship with the Department of Energy, who provides us actinium from their generator. But if you want to move into large market, late-stage trials, we knew we needed greater supply. So we've made strategic partnerships and entered into strategic partnerships with three groups, BWXT, Niowave, and TRIUMF. And these are groups that have tons of experience producing, distributing, medical isotopes, and they've actually produced actinium and sent it to us that we've used. So we invested early to have a strong actinium supply chain, which we can actually also tie to our manufacturing, capabilities. So we built our own manufacturing plant that's now open. We have CDMOs that we work with, because certainly there was some supply shortages with Pluvicto because of the demand. Mm-hmm. And so we want to be in a place now that we have the supply to support our advancing portfolio. Is there a way you can give us a sense of that supply, you know, in terms of, you know, you're looking at a couple different studies that are ongoing now? Like, can you get to supplying the next stage of development for those, or like, how far does the supply go at this point, or are you continually sort of trying to expand the supply at this point? We invested early to sort of grow the supply with our partners. Okay. When we took over the phase II actinium PSMA program, we knew that that's a large market opportunity, so we wouldn't have done that if we weren't comfortable that we had the actinium to support that development pathway. The manufacturing facility that we opened, it can produce 100,000 patient doses per year. We've built the capacity to be able to really meet what we expect to be, a large and growing market. Yeah. What's the status of your, your manufacturing plant currently? Yeah. So construction finished. We had the grand opening. Okay. It's in the process of going through the validation steps, so we expect to be manufacturing next year. Great. Maybe we can shift to FPI-2265, your PSMA-targeted product. Maybe just give us a quick background there. You acquired the asset earlier this year, so maybe just talk about some of the reasons for that and maybe what was attractive to you. So the Fusion's thesis as a company is really to go into areas of high unmet need and be the first to market. That's really the core of what we're trying to do. We saw in the literature, through a number of investigator-sponsored studies, some pretty impressive response data from patients, whether they pre-Pluvicto or post-Pluvicto and lutetium. We're really kind of wondering, why is this drug not advancing if that data looks really good? The answer largely was the actinium supply. So we had actinium supply, we have manufacturing, and then a phase II U.S. IND opened and we acquired that IND because, again, there's a growing market for patients post-Pluvicto who don't- Mm-hmm. relapse/refractory, so unmet need, and an opportunity to really be first to market. So we, we felt that it was a great fit for us, as a company. Yep. You mentioned early on with actinium that you can kind of see a response post abeta. When you look about through the investigator-sponsored data in naive patients, how does that compare to, for example, a Pluvicto? Is it similar? Is it better? Yeah. So the trial that we took over, one of the reasons we liked taking over the TATCIST trial was it actually is treating both Pluvicto-naive and post-lutetium patients, so we're actually collecting data on both patient populations. But there's data now coming out as recently as this year in very early lines of treatment, so pre-lutetium, as well as other therapies. And the PSA50s and response rates are actually really quite impressive. So we're gonna focus on the post-lutetium patient population, because I think that's the highest unmet need, fastest path. But the data we feel for patients who have received less lines of therapy, there's a real opportunity, I think, to compete for those, that earlier line setting of patients. Yep. You mentioned the TATCIST trial. That's your phase 2. Maybe talk a little bit about the design there, you know, number of patients you plan to enroll, key endpoints, et cetera. So it's patients can receive up to four cycles. They're spaced eight weeks apart, and the unit's 100 kilobecquerels per kilogram per cycle. That trial started off as an investigator-sponsored study that allows both, as I mentioned before, Pluvicto naive patients, as well as those who are relapse refractory. We've now taken over that IND, and it's under our direction. And the plan is to enroll 100 patients by the end of 2024, 60 post lutetium, about 40 who are naive. And when this trial really got off the ground was during the sort of lutetium shortage. So that first group of patients are really largely gonna be lutetium naive, but will have had many lines of prior therapy. So in terms of refractory patient population, it's a great sample for us. And we'll report the data on the first 20-30 patients in the Q1 of next year, and then the idea is to finish the trial by the end of 2024. So the initial update in the 20-40, 30 patients, will—you said mostly naive and some? Yeah, that's right. Okay. Yeah. All right. How should we think about, you know, expectations, on activity in those two subgroups? Is there a particular bar you, you're looking for, or how are you thinking about that? So fortunately, for this, the way that we look at this asset as being quite a de-risked asset is, this class of molecules, the actinium PSMA small molecule, has been in about 250 patients, with about, with 100 being sort of post lutetium. So we'd like to see the activity to being in line with that. So you're looking at PSA50 levels between 40% and 50%. And you'd like to see sort of ORRs in this roughly around the 30% range. So, we have targets, but we also can compare that data to the literature. And we also, from a safety perspective, xerostomia, dry mouth, is really the sort of tolerability issue that we have to keep a close eye on. We saw that in the first 10 patients coming out of the TATCIST study. No patients stopped therapy as a result of it, but it's certainly something we have to identify and manage as we go forward. In the initial update of patients early next year, 1Q next year, will you have ORR data at that point, or will it mostly be PSA50? No, we expect to report ORR, rPFS- Okay in that group. Okay. Once you share that update, maybe walk us through next steps for the program. Is it another update later in the year, or how are you thinking about that? I mean, our plan is to finish the enrollment by the end of 2024, so that's the 100 patients, 60/40 split. And then we'll obviously identify the right timing to report that data. We really see the opportunity growing in the post Pluvicto space, so data is gonna come out, we expect relatively shortly, on patients being treated pre-chemo with Pluvicto, so earlier line. And because certainly from the VISION study, a large percentage of those patients go on to another therapy, the market for an actinium PSMA agent will continue to grow. Mm-hmm. And so we want to move as aggressively and as quickly as we can to really fill that high unmet need. And again, our goal is first to market, and really with being the only phase II U.S. IND in this space, we think we have a great opportunity. For the previously treated population, do you think... Can you get approval off of phase II, or do you think you need to run phase III? So traditionally in prostate cancer, they've really been randomized controlled Phase III type trials. I mean, there are some exceptions, but really, the radiopharmaceutical development pathway has been sort of well established. So I think, you know, we'll work with the FDA, and we are working with the FDA to sort of finalize that, and we'll obviously, once we have agreement, share that more broadly. Okay. I guess, is it you'll go after the later stage, previously pretreated, then try and move upstream into naive patients? Yeah. I mean, again, if you look at some of the data from the investigator-sponsored studies on earlier line patients, you know, the PSA50 responses and the radiographic responses are really quite striking. Another area that Fusion looked at early on was on combination therapies. And so when we were combining our other program, 1434, with drugs like olaparib, which effectively is like a radiation sensitizer, we could really decrease the administered dose of our drug, and still see the comparable efficacy. And so we see an opportunity in the combinations to really also move earlier lines as well. And this is an area where we filed IP early on because we think that's obviously part of the treatment strategy as you move earlier lines. Do you think you can get beat with Pluvicto in the naive patient population? Or do you need to be differentiated there somehow, or? I mean, what I would say is that consistently, we see when we compare actinium and lutetium, that actinium has the greater potency. Yeah. We also believe that in combinations, because of that potency-... The massive damage that the actinium creates, the ability to synergize with, DDRIs or checkpoints really gives it a competitive advantage. Yep, got it. Maybe just quickly, you know, IP around the program, maybe just remind us there. I think there were some recent updates as well. So there's a broad method of use patent on the actinium PSMA, and when we acquired the IND, we filed an IPR challenge. There's two main steps to that challenge to invalidating that patent. The first one is whether the PTAB takes up the IPR. And so in August 15th, they have made the decision to take up based on the merits of the argument. So we'll know about a year from now in terms of the final decision, but it's consistent with the sort of strategy we took in sort of understanding that there was prior art in validating that patent. Gotcha. And maybe just last question on 2265. Maybe just talk about the market opportunities in, in the two buckets and maybe what, what that looks like. Based on the current label, it's a $500 million market in the U.S. alone. Pretty significant in the radiopharmaceutical space. What I would say, though, is with the data that's gonna come out of studies like PSMAfore, which is in pre-chemo setting, we think that market is gonna grow significantly. From my perspective, patients obviously have really adopted Pluvicto as a treatment, so have the clinicians, and for those patients that then go on and relapse, administering the same type of radiopharmaceutical treatment now with an alpha in this very much the same way, fits very nicely into the treatment paradigm. You know, we think there's gonna be high demand for that drug and a growing market quite significantly. Do you think if you, if you become a first-line agent and you relapse, could you get treated again and have a benefit, or you think that's unlikely? So in the case... People have thought about this. I think the idea is, if you have the option between retreating a patient with a less potent form of the drug, versus the alpha, I think you're gonna opt for actually going forward with the alpha. Yep, makes sense. Maybe we can shift to 1434. Maybe just give us a quick background there, and highlight some key takeaways from your recent phase I data. So 1434 is an antibody that targets IGF-1R. And, you know, interestingly enough, if you go back and look at the PSMA space, PSMA was a failed target for ADCs, and it wasn't until you replaced the toxin on the ADC or a small molecule drug conjugate with radiation, that you really saw, took some responses and really elevated to what you see with Pluvicto. So we see the opportunity to create next generation ADCs with an alpha emitter, and one target that came up that really caught our eye was IGF-1R. It had been in the clinic, lots of antibodies targeting it, expression on lots of solid tumors, but the efficacy underwhelmed. And we thought, we're not trying to block the target, we just want to use it to bring the alpha inside the tumor. So we started that study with a single ascending dose. We then moved to multiple dosing, and again, very early days of targeted alpha therapies with antibodies. What we discovered is that if you add a small amount of cold antibody, you can actually block endogenous binding sites, increase the exposure, but actually get a better safety profile. Part of the exciting part of that early data was people were worried that antibodies circulate too long. A lot of that data was based on beta emitters, which travel a long distance. Mm-hmm. With alphas, which only travel one-three, having them in circulation longer is actually not the same risk as what you would have with the beta from our perspective. Sure. So we see that the company who can crack the code of how best to dose with antibody-targeted alpha therapies, is opening a whole new next generation of ADCs. It's part of our collaboration with AZ. So this early IGF-1R 1434 data, we're very excited about. I guess you're gonna give an update, I think, is it later this year? So we've dose escalated. So we had 15 kilobecquerels was our first dose cohort. It was a 3 + 3 design. Great safety. Two patients had stable disease, one patient had five cycles of therapy over eight months. So we've now dose escalated to 25 kilobecquerels per kilogram. And then we're gonna, much like we did with the fifteen, we'll share that data with the street, around the end of the year. So imaging, safety, dosimetry. Can you remind us where, what's the active range in terms of the dosing? Are you, are you there with 25? So we don't know... So this is an all-comer solid tumor study, so it really depends on what's the expression of the IGF-1R in the patient. What we wanna know is, can we keep increasing the exposure and get the right safety? And then we will drive the study into specific patient populations that have the highest IGF-1R expression. In trying to select the dose, is it to push as high as you can till you hit some safety issue and then back off a little bit? Or what's the strategy, when figuring out the dose? Yeah, I mean, it's really about getting to the maximum tolerated dose, and then with radiopharmaceuticals, you also look at what's the dosimetric limits to the body. So it's... You're on sort of both sides of that- Yep. that you're looking at the same time. Yep, got it. Maybe we can just shift, you know, to your partnership with AstraZeneca and, and maybe just remind us a little bit about how that's structured and, and where the focus is there? Yeah, it's a phenomenal partnership with two parts. One is, so AZ, who's a leader in the, obviously the ADC space, had lots of success with drugs like Enhertu. We jointly identify targets of interest, and we can actually develop up to three novel targeted alpha therapies based on their antibodies. The first of those is the EGFR c-Met program that we just announced, FPI-2068. The other and that's, that structure, that deal is we co-fund, co-own, and we have 50/50 global profit share, and we have the right to co-commercialize in the U.S. So lots of, I think, value for the company and leveraging the strength of both AZ and Fusion. On the other half of that deal is the combinations I was talking about. So AZ is a leader in the DNA damage response inhibitor space, like PARP inhibitors, and also in checkpoints, and so they're fully funding up to five combinations of our drugs with their checkpoints or DDRIs. And we only have to repay our portion upon approval. So it's a very broad, large collaboration, one of the very few radiopharmaceutical companies with such a big pharma collaboration. So we're excited about now that the first program coming out of that, the IND is cleared, we're looking forward to getting the first patient dosed. Okay. Maybe just last question, if you can talk about your current cash position and what the burn looks like going forward. Yeah. So our cash position is $225 million as of the last earnings release, and that takes us into Q2 2025. Okay, great. Well, we just end it there. Thanks, John. Appreciate your time, and have a good day. Thanks, everyone.