Everyone, it's great to see you all. Welcome to the Citizens Life Sciences Conference here in Miami for the first time. It's my pleasure to introduce Prelude and the management team, you know, up here with me. Joining me on stage here, Kris Vaddi, CEO, Peggy Scherle, CSO, Bryant Lim, CFO. You know, I never know exactly who's in the audience, who knows the company or who's listening to the webcast and who may or may not know the company. I love to start these conversations off with maybe a two- to four-minute overview of what Prelude's about. Great. Thanks, Randy. Thanks for the opportunity to participate in Citizens Life Sciences Conference. Prelude is a precision oncology company, with a, you know, very differentiated pipeline of molecules that are targeting clinically validated pathways. You know, we've announced towards the latter part of last year a strategic shift in our portfolio, and I just wanted to give you a little bit of color on that. We were, like, towards the sort of the middle of the year looking at where we were with our lead clinical program, which was targeting SMARCA2 selective degrader program, which was in the clinic. It was advancing towards, you know, end of dose escalation. We also had significant breakthroughs in the two molecules that we'll talk about today, one targeting JAK2V617F and the other one targeting it's a degrader for KAT6A. We really looked at what the next 12-24 months are really gonna look like in terms of capital needs, the clinical catalysts. We made a difficult but an important strategic decision to pause our SMARCA2 program and really shift our focus to JAK2V617F and KAT6 program as the ones that we can get to the clinic in 2026 and also a very innovative degrader antibody conjugate program targeting mutant CALR, also in MPNs, which was in the discovery. As a result, now our pipeline is really the JAK2V617F and KAT6A are the two lead areas of focus for us in 2026 in getting them into the clinic and driving them to you know certain clinical milestones as well as advancing our CALR program. We're very focused on advancing these, and we have already announced clearance of our IND for the JAK2V617F in January, and we're in the process of actually getting the clinical trial initiated and advancing that program forward. On KAT6, it'll be sometime middle of the year is when we're targeting our IND. Again, we can get into more detail, but it's a very attractive degrader molecule that highly selectively targets KAT6A. We've also announced or made a decision to enter into a business development deal with Incyte on our JAK2V617F program. It's an option to buy the program at certain, you know, point in time. That extended the runway for the company into second quarter of 2025. Seven. We're very well positioned right now with you know with our focus on these programs to really make meaningful progress and demonstrate the value of our pipeline to our investors. Let's jump right into it. I'm gonna truncate JAK2V617F to just JAK2 so you- Yes. You know what I'm saying. Yes. Let's just jump right into it with the JAK2, you know, inhibitor program. Why is this different? When I think JAK2, I automatically think ruxolitinib, which is at, like, a $3 billion run rate in the U.S. alone. You know, why is this unique and what's differentiated about your molecule? Yeah, absolutely. We certainly know a thing or two about ruxolitinib as, you know, we had, you know, been part of that development of that program. Let me step back a little bit and really talk about the diseases that we're interested in in developing these agents for, the so-called myeloproliferative neoplasms. There's three of them. There's polycythemia vera, where you have too many red blood cells and white cells that potentially lead to myelofibrosis and AML. There's essential thrombocythemia, which is too many platelets. There's myelofibrosis, the most advanced and most sort of life-threatening of all three, which is, you know, the myelofibrosis. This V617F or JAK2 mutation is present in nearly all of polycythemia vera, greater than 90%, 95%. About half of ET or essential thrombocythemia and half of MF, right? When original JAK2 inhibitors were discovered, they were all targeting this catalytic domain of the JAK2 enzyme, which is exactly the same between wild type and mutant, right? As a result, the first generation JAK2 inhibitors really didn't differentiate between mutant and wild type, and I'll tell you why that's important. The reason why they also couldn't develop them is because the mutation itself is in a different part of the molecule. It's not in the, you know, where the business end of the molecule is. And the structure of that domain was not very well known at that time. This is already almost 20 years ago that this original mutation was discovered. Ever since, you know, everybody had been really looking to develop a mutant selective inhibitor because you want to preserve the normal bone marrow function, right, which is driven by normal or wild-type JAK2. Whereas abnormal hyperproliferative state is driven by this mutation. We, you know, having worked in the space for a long time, had been looking at ways of going after this mutation, the domain in which the mutation exists. Peggy can go into a little bit more detail on the scientific side of things, but the idea is that if you had a molecule that could spare the wild type and hit the mutant, you can actually change the disease course. Because the previous generation JAK2 inhibitors are very good in addressing symptoms and spleen and some of the, you know, aspects, some of the debilitating aspects of these diseases, but really have not shown compelling, you know, disease modifying potential, which is what we're trying to get with these mutant selective compounds. Maybe Peggy can take it and talk about our compound. Sure. As Kris mentioned, the V617F mutation actually resides in a separate domain called the JH2 domain, and that phenylalanine residue with two other phenylalanine residues forms what we call the deep pocket. Our medicinal chemists were able to synthesize molecules that bind in that deep pocket where the mutation actually resides. In doing so, it helps to inactivate or hold the protein in an inactive conformation. We think, you know, binding in that deep pocket is really unique to our molecules and allows us to have the mutant selectivity that Kris mentioned is so important for having that therapeutic window, and also to kind of modulate the disease. We've really worked hard, I think, to build in not only potency and selectivity for the mutant, but also all of the other properties that are needed for a drug in the clinic. Protein binding, PK, solubility, all those things that are really important for delivering a drug. We've, as Kris mentioned, just filed the IND and are moving into the clinic. I think by our count, we probably saw about six, maybe five-six, other inhibitors all targeting, you know, the V617F, right, mutants. I'm you know kind of curious, right? Like one of those developers is actually Incyte, and then they did a deal with you for your inhibitor, right? They have their own inhibitor. They now have an option for your inhibitor. Clearly, you know, there are things that are happening in the space that you're probably aware of. Can you help just excuse me, maybe differentiate your molecule from the other competitors that are out there? And then maybe even while you're answering that, answer kind of why Incyte would partner with you guys when they have their own inhibitor. Maybe I'll just start. Yeah Turn it over to Peggy. You know, again, one of the major breakthroughs in this field is really the elucidation of the structure of the domain. Naturally, you know, that would lead to different groups trying to make molecules that would attack. I'm not surprised at all that there are a number of companies, you know, making good progress, which ultimately is beneficial for patients. Again, with, you know, having been involved in the development, discovery, and development of Jakafi, there's a lot of learnings in the clinic, in the preclinical stages that we really could use to guide the discovery of our own molecules, right? Doing head-to-head comparisons and etc., to really convince ourselves just not only we have, you know, the selectivity profile needed, but actually have the overall properties. I don't know, you can comment on other molecules, but we just believe that we have a really good molecule that we think has the potential to really, you know, make a difference for patients. Yeah, you know, we saw the data that was presented at ASH as well. We don't know a lot beyond that. A lot of the structures haven't been published, and then really until you can, you know, do that cross comparison, it's sometimes hard to understand the specifics of the molecule. As Kris said, we worked really hard. We compared across multiple cell lines to get our selectivity. We looked in primary cells to ensure that selectivity translated and also in vivo and built in the properties, you know, that we think make it a really good drug. As we think about you mentioned that the IND's been filed. You guys had your 10-K today, and I believe you said that you'll be in the clinic by the second quarter. I think you're gonna beat it. You know, that's just me. Can you talk a little bit about the clinical development plan, right? What is this, what does this phase 1 study look like? What are the efficacy and safety parameters that you'll be looking at as you kind of you know elucidate the? Yeah. No, absolutely. We've thought long and hard, and we're fortunate enough to have the advice of some of the key opinion leaders in the MPN space that helped shape the development of many drugs that came out. The design that we ultimately ended up with is a parallel design. You know, in some of the JAK inhibitors are being developed or were developed in myelofibrosis first, followed by, you know, others. Here, we've taken a position of advancing the molecule three nine six into both myelofibrosis as well as polycythemia vera. The reason for that choice is PV, or polycythemia vera, is about, like I said, more than 90% of patients have the mutation, and this is a mutant-selective inhibitor, so it made sense to do that. Similarly, you know, myelofibrosis offers a rapid development path, right? Being able to do both of them in parallel and actually convincing FDA to allow us to do it, I think is a significant differentiator for us. Also the scientific reason and disease biological reason is that, you know, the doses that you need for a disease like PV where you have too many red blood cells, too many white cells, could be very different from a disease like myelofibrosis, especially if they are later stages, they've already experienced, you know, other JAK2 inhibitors. I think from a design perspective, that is I think is a very important distinction, number one. Number two, we were also able to, you know, write the protocol in a way that would allow us to enroll the right types of patients and not have to come always behind a JAK2 inhibitor, right? We're hoping that we could actually have some patients who could potentially be eligible for our trial that are not eligible for other JAK2 inhibitors, you know, that would allow us to study this drug in earlier stage of disease. I think that's important too. We have the right investigators, you know, we have global trial, U.S., Europe and Australia, and a lot of enthusiasm from the investigators. We are very hopeful that we actually not only enroll the trial, but enroll the trial with the right patients that could give us meaningful information in the early development. There's the potential for JAK naive patients to If they're ineligible, they are. If the patient is deemed ineligible. Yep for other JAK2 therapies, then, you know, they can be enrolled into our trial. Perfect. Okay. As we think about clinical data and readouts, is it possible that we'll get kinda early clinical data this year, or is this really like an early 2027 sort of event? Yeah. It's hard to predict as we're just about to get started, so we'll just wait until we have some meaningful data. Maybe you also asked about why Incyte- Mm-hmm as part of your question. Again, you know, as we were thinking about the two programs that we had, both are very, very attractive, the KAT6 and JAK2, and looked at potential partnerships that we could do with either of the programs. Incyte was a natural partner as they have a strategic focus on MPNs. They have their own program, but, you know, as they said publicly that they are doing some medicinal formulations, and they also wanted to. They approached us, and we thought that, you know, of the different things that we could do, it's a really meaningful collaboration or, you know, agreement with them that not only provided us the upfronts to extend our runway, but also has the potential to bring in a meaningful influx of cash should the program advance, you know, meaningfully. Before leaving this, I think I'd be remiss to not kind of explore your involvement in ruxolitinib development. Maybe very quickly. A lot of people say like, "Hey, I was involved in, you know, this development or that development," and it could be tangential. I think it's very important for people and investors to understand this kind of going back to the roots approach at Prelude. How actually involved were you with ruxolitinib development? Sort of tangentially or like, did you discover the molecule? Kinda where are we? It's hard for me to speak about that, but I started the program. I was always very interested in the JAK-STAT pathway. I started the program and, you know, Peggy led the pharmacology of the program. At Incyte. At Incyte. Right. We were involved all the way through advancing it into the clinic and through registration. We had multiple discussions with FDA. I would say I was pretty central to the discovery and development of Jakafi. Terrific. Okay. With that, let's switch gears to KAT6, the KAT6 degrader. Can you talk to us about that target? Clearly, there are other KAT6 inhibitors that are out there, right? Right. Maybe you know how your molecule is differentiated and kinda what's the opportunity? Yeah, I'll just start and then let Peggy. Peggy's a real expert in that space. Again, like I said, as we were looking at different ways of advancing our pipeline prioritization, KAT6 really stood out because we were already working on KAT6 before Pfizer announced their KAT6A, B inhibitor data at ASCO 2024. We had the thesis that if you really targeted KAT6A which is actually the amplicon or the one that's amplified and avoid B, you could have a potentially you know a better safety profile. We looked at the inhibitor versus degrader and a lot of science went into and thinking and data went into making the decision to go down that degrader path but Peggy. Yeah. I think we decided on a degrader for really two reasons. One is it really allows us to build in the selectivity for KAT6A over KAT6B. We had seen that with our SMARCA2 program that, you know, you don't have to just have selectivity based on the binding site, but you can use the whole ternary complex that's part of a degrader to get that selectivity. And secondly, KAT6A is part of a complex, and we thought by degrading the protein, you could perhaps have deeper responses because you're eliminating the protein. And it's a target where, you know, if you look at the Pfizer data, they really have to cover it around the clock. I think for both of those reasons, we really thought a degrader approach was attractive for this. As Kris mentioned, KAT6A is clearly driving the tumor biology, and KAT6B plays a role in bone marrow. We thought by sparing KAT6B, we could have better tolerability, less bone marrow tox, and greater efficacy. When I think about your preclinical work, right, and the work that you do prior to getting into the clinic. Is there a comparison to, you know, like the Pfizer KAT6 inhibitors and others that might be in development that you have to, you know, replicate in order to move your molecules forward? Yeah. We usually if the structure of those other molecules are known, we try to do head-to-head comparisons in our own systems. We think that's the best way to really see if how comparable we are. With KAT6A selective degraders, we actually get regressions in all of the tumor models, whereas head-to-head with an inhibitor, it's more tumor stasis. That is preclinically why we think that we could potentially have better efficacy. On the same front, if we look at effects on neutrophils, which is what Pfizer's seeing in the clinic, right, the neutropenia, if we compare a dual inhibitor to a selective degrader, we see less neutropenia in the models. Preclinically, our hypotheses seem to be, you know, playing out. You'll be filing an IND by the middle of this year. How are you thinking about the clinical development program from a KAT6A degrader perspective? Are you a fast follower for, you know, Pfizer and their program? Do you go into different indications? Is there patient selection or biomarker selection in certain tumors? How should we be thinking about it? Our hypothesis is based on what Pfizer has seen, right? Differentiating on efficacy and differentiating on safety in ER-positive breast cancer. That's I mean, there's potentially other opportunities beyond that, but we're currently focused on that, right? We know what the neutropenia rates are and what the limitations with those dual inhibitors and what limitations that neutropenia rates pose, which is you know, really getting into earlier lines of therapy, being able to combine with CDK4/6s, which also have the same side effect profile, right? Our clinical plan is really, you know, because it's a degrader, we don't have to get to the concentrations, high micromolar concentrations that the inhibitors have to get because these are picomolar degraders. You know, we could be a hundredfold lower plasma concentrations than them. All the preclinical package so far you know, makes it. We still have to you know, wait for the final histopath data from the GLP toxicology studies. So far, the data is supportive that they should have no worse adverse event profile, generally speaking, and better hematological profile, right? Coupled with very low plasma concentrations, which in and of itself is an advantage, right? We plan to go to the clinic in ER-positive breast and rapidly you know, do the dose escalation. We don't expect to need, based on what Pfizer has seen, too many dose cohorts and go to fulvestrant combo, which is where there's a 35%-40% response rate in post-CDK4/6 setting. At the same time, we're actively working with experts to design our expansion cohorts where we could look at CDK4/6 combinations, which Pfizer has not been able to look at so far. I think that is something, a priority for us to be able to run potentially. CDK, fulvestrant for sure, because that's something that we can do a direct head-to-head comparison with the Pfizer compound, but also, at minimum, do a CDK4/6 combo, to see if we can actually demonstrate that better tolerability. As if you don't have an impressive enough pipeline, you also have a mutant CALR degrader as well. Can you just maybe in a minute just kinda tell us what's happening there? Yeah. You know, mutant CALR is a sort of a hallmark of a certain fraction of ET, essential thrombocythemia, and myelofibrosis patients. It's expressed on the cell surface where it is not expressed in wild type CALR in, you know, on the surface. It gives you an opportunity to target with an antibody. We've seen very compelling efficacy data from a naked antibody. Our idea, which we were also working on for a while, is to really have a degrader conjugate payload on it. The reason why that makes a lot of sense, at least preclinically for us, is that without having to saturate all the mutant CALR that you need to do with the naked antibody to inhibit signaling, you can actually kill the disease initiating cells with minimal receptor occupancy because you're delivering a payload. These payloads are extremely potent on MPN cells. It is an earlier stage program. It requires an antibody. There's multiple ways of differentiating from the previous. You know, there's lots of mutant CALR antibodies that are going into the clinic. But we think that we are. You know, this is an area where we focused on really building that know-how and expertise to create these degrader antibody conjugates. You know, we've announced a few years ago this collaboration with AbCellera that allowed us to build that know-how, that expertise internally, which we're able to leverage on this. There are clear areas of differentiation from the first generation CALR antibodies that we see in terms of, you know, having that, you know, up to 100x or more potency that allows, you know, potentially a down the road subcutaneous patient self-administration, that many KOLs actually like to see in a product for ET particularly, and being able to target all mutations and not only, you know, one of the two. So there are some real advantages, but we can talk about it more when, you know, when we actually have a development candidate. Yeah. I guess one of the questions that I'll just throw it out there, but you don't have to answer, is just how much data do you need before Incyte acquires you? No, I'm just kidding. Just leave it like that. Bryant, you're here looking handsome as ever. Let me have you answer a question. Sure. What's the cash position at the company? You got $60 million from Incyte. There's an option for an additional $100 million. Just kinda take me through, you know, how long this lasts. Sure. As you identified, we released our year-end results, and we announced $106 million in cash, taking us into second quarter of 2027. That taking us into second quarter of 2027 does not account for the $100 million potential option payment. From Incyte. Excellent. Yeah. Well, we've run out of time, guys. Thank you very much for coming. Really appreciate it. Thanks, Randy.