Morning, everyone, and thank you for joining the 2026 H.C. Wainwright 28th Annual Global Investment Conference. My name is Ahmed Mahmoud, an Associate Research Analyst here at H.C. Wainwright, and I'm happy to welcome our guests for this fireside chat from Prelude Therapeutics, a biotech company developing precision medicines for cancer. Joining us today are Dr. Kris Vaddi, Bryant Lim, who's the Chief Financial Officer, and Dr. Peggy Scherle, the Chief Scientific Officer. Thank you for joining us today and, Kris, to get us started, and for those who may be unfamiliar with the Prelude story, could you please provide us a high-level overview? Yeah, absolutely. First of all, thank you for the opportunity to participate in the conference. Prelude, as you said, is a precision oncology company. We're clinical stage, and we're advancing multiple differentiated programs against clinically validated targets. Why is our patients with cancer need better therapies? We have the team that we've built over the years that have tremendous amount of experience in discovering and developing novel molecules, and we are really target-centric and modality flexible. Given our technical capabilities and expertise, we don't need to be a sort of a kinase or a degrader or any of the specific target types. We are able to go across multiple target types, and we really focus on mechanisms that are clinically validated, meaning that the biology is de-risked, and there is still a significant opportunity to improve upon what's out there. Our current pipeline is very much reflective of that, and I'll spend a couple minutes going over that. But over the course of next 12- 15 months, we have a number of very important data catalysts and potential value inflection opportunities, and we are laser focused on executing on what's ahead of us. Our lead program, or the one that's farthest along, is our JAK2 V617F selective inhibitor. It's a kinase inhibitor. The space is MPNs or myeloproliferative neoplasms, where there is three of them, and there's 200,000 patients in the U.S. alone that have these disorders, and the first-generation molecules, one of which we, our team, helped develop, Jakafi. They're good. They're very effective from the symptom and other standpoints, but they really are not very disease modifying, right? Because they don't target the very mutation that is involved in driving disease in majority of these patients. Our team, based on our not only discovery experience, but understanding of the clinical problems that these patients face, developed a very interesting molecule that is currently in the clinic, and we're enrolling patients. We are going after both PV, polycythemia vera, which is one of the largest number of patients within MPNs, as well as more serious disease called myelofibrosis. We can talk a little bit more about that. Our second program, a KAT6A selective degrader, we just recently announced we cleared IND, and we are about to start enrollment in the fourth quarter. This is something that is very exciting in breast cancer, HR-positive breast cancer, more specifically, where we are seeing more and more oral SERDs that are actually coming in, but really not meeting the goal of earlier stage therapies where earlier lines of therapy where you need to be active in all patients and not just only ESR1 mutant or those specific populations. KAT6 emerged as a really exciting novel mechanism. The clinical data with Pfizer, PF-07248144, demonstrated very good response rate and PFS, but it comes with a significant hematological toxicity. That is a problem because if you want to be able to deliver a drug with full dose intensity and combine with earlier lines of therapy, such as CDK4/6s, you need to be able to have cleaner hematological safety profile. We believe our KAT6A, based on the biology, genetics, has the ability to really do that and significantly expand the opportunity to create value for patients across all lines of therapy. That is about to start clinical trials. The third one, which we are really excited about but still in the discovery phase, is our mutant CALR degrader antibody conjugate. Again, it is a clinically validated target. The antibodies that inhibit the signaling of CALR receptor in ET or essential thrombocythemia, as well as MF can have significant clinical benefit for these patients. They appear to be primarily the benefits coming from type I mutations. There are almost half of ET patients have non-type I mutations who do not seem to be benefiting just by signaling inhibition alone. We developed a degrader antibody conjugate where we can deliver a very potent payload that we designed to be safe and can really kill the disease-initiating cells. We will be giving a little bit more detail on that program relatively soon. Basically, we have these three assets that are going to be generating very meaningful data and have the opportunity to leapfrog the ones that are ahead of us, and we have the capital to advance these to key inflection points. 2026, rest of 2026 and 2027 will be pretty exciting years for Prelude. Thank you. I think to start, we want to focus on the PRT3789 asset that you have. In the second half of 2025 or in back half of 2025, you entered into an exclusive option agreement with Incyte for your JAK2 V617F inhibitor asset, PRT3789. Can you explain the precise governance triggers and timelines dictating what Incyte must opt in and what capital inflections those triggers represent for your balance sheet? Yeah, I'll start, and I'll let Bryant, our CFO, go through the mechanics of that. The idea behind that option agreement is that Incyte was in the clinic with their lead JAK2 V617F inhibitor program. We believe that they have the ability to develop these assets well. We entered into this option agreement where they can It's a time-based agreement where they can make a decision in terms of acquiring our entire program. Currently, we are responsible for running the phase I trial of our lead program, PRT3789. But if they opted it, they could take it over. Bryant, you want to talk a little bit about that? Yeah. Just in terms of the mechanics, it was a $60 million upfront, broken into two parts, $25 million in cash, $35 million in equity. As Kris just mentioned, there is a time-based option of 15 months, not about 15 months, that expires in February of 2027, with a potential for a three-month extension, so that would take you to May call it, and that would trigger a $100 million milestone payment. Then we move into the milestones section of the agreement, which is up to $775 million in milestones together with low single-digit royalties on the back end. Yeah. Just to add to that, these milestones are primarily- Clinical and regulatory Clinical and regulatory. They're not something sales-based or a later stage. Got it. Thank you. Speaking of Incyte, they discontinued development of their INCB123667 program following comprehensive review of their data and prioritized next generation targeted pipeline. Given that disclosure, is there any read-through to the option agreement you have in place, in your view? No. There's two aspects to it, right? One is, a question that we often get asked is that, is there any read-through to, because of the technical challenges, issues that they had to our molecules. Answer to that is no. Because we're fundamentally completely different scaffold, completely different molecules. Our program is not built on Incyte's chemical scaffold. So there is no read-through at all related to that. In terms of what Incyte might or might not do in terms of option exercise is really dependent on their own progress with their programs and their need to have actually a viable molecule to go forward. So, I don't think that specifically that particular decision to discontinue has anything to do with what we're doing or what they might do with our program. Got it. Your phase I trial for PRT3789, which started enrollment mid-2026, encompass high-risk polycythemia vera and intermediate to high-risk MF. Given the biological differences between those MPN phenotypes, how are you allocating your initial dose escalation cohorts? Can you help set investor and our expectations around the early data reads in first quarter of 2027? Yeah. In terms of the trial design, these are enrolling patients in parallel. Basically, the design itself allowed for enrolling patients independent of each other, right? The trial is open. Anybody who meets our inclusion criteria will be screened, and if they meet our eligibility criteria, they get enrolled. If they are PV patients, they go into the PV arm, and if they are MF patients, they go into the MF arm. Then once we establish the safety of that particular dose, then we move to the next dose independently. There is really no company allocation of patients to one or the other. It is just basically enrolled in parallel. In terms of what we are looking for is really our ultimate goal for this program, the reason why we chose PV and myelofibrosis is that in PV, greater than 95% of patients have the JAK2 V617F mutation, right? That is important. You do not really even have to look for mutant positivity ahead of time. The second aspect of it is there is no approved JAK inhibitors in PV in front-line settings. That represents a significant opportunity for us. We will look for complete hematological response rates, any symptom improvements, and change in the mutant allele burden are the ones that we are looking for as key indicators of clinical activity. For myelofibrosis, these patients would have failed other JAK inhibitors because there are four of them approved. You are basically looking for really see if we could actually demonstrate clinical benefits like spleen symptoms as well without the hematological toxicities that the first-generation compounds have. That would be a win there. Got it. Speaking of those readouts, you already touched on this, but could you give us a little bit more color on what benchmark for each indication are when it comes to decide whether or not to advance the program further? The benchmarks are not having hematological toxicity like the first-generation compounds have and demonstrating clinical activity, like the ones that I described. Achieving complete hematological response rates, and spleen symptom benefits, and movement of allele burden. Those are the ones that we are looking for. I think it is hard to come up with a benchmark when there is none right now that really can do that. Right. Thank you. Speaking of benchmarks, it's a bit of a competitive landscape right now. We have Relay Therapeutics on our radar, Cogent, as well as Ajax Therapeutics, who has a platform for similar allosteric targets. Could you explain the specific structural or PK properties that differentiate 396 from these other rivals? Peggy, you want to take that? Sure. When we designed our compounds, we really designed them to reach into that pocket where the JAK2 V617F mutation actually resides. We call it the deep pocket, and our chemistry effort was really to bind in there and basically touch that mutation. We don't think the other companies have that same binding feature as ours, so we think that's really unique and really important for getting that mutant selectivity. We've also worked really hard to build in the PK and other physical-chemical properties of the molecule so that we can achieve target coverage of the mutant but spare the wild type. We think those are really differentiating features that we're taking into the clinic now to look for that translation. Got it. Thank you. Late last week, the FDA cleared your IND application for PRT3722, your first-in-class oral KAT6A selective degrader for HR-positive and HER2-negative breast cancer. Currently, there are around 13 KAT6A and B inhibitors in clinical development. Could you explain to investors and to us why selective KAT6A inhibition would be preferential to non-selective A/B inhibition? Yeah, let me start, and then I will let Peggy explain the biology of it. The fact that there is 13 companies wanting to do this tells you how exciting this target is, right? But I think the key is that to our knowledge, because I do not think there is a full understanding of how each of these molecules actually do, but based on what we know, they all are KAT6A/B inhibitors, dual inhibitors. And that is because structurally, A and B are very, very similar, right? We are the first one to actually, and we have started down this path before Pfizer data even came out that there is a sound rationale for targeting A and sparing B to maximally engage this target and avoid or improve the therapeutic window. From that standpoint, we think we have a really good opportunity here to drive deeper biology and target inhibition without being that dose-limiting toxicity and where patients have to dose reduce to be able to stay on therapy. So I hope you want to take it. Sure. So, as Kris mentioned, we really think there are two important ways we differentiate. We are KAT6A selective, and we are also a degrader. In terms of the selectivity, there is strong preclinical rationale that KAT6A is amplified in a number of tumors and really drives that tumor biology, whereas KAT6B does not. However, they both contribute to bone marrow development and hematopoietic stem cell development. And we think, and again, there is preclinical data that supports it, that by sparing KAT6B, you can have much less effect in terms of bone marrow toxicity as read out in the clinic as neutropenia predominantly and anemia. So we think selectivity buys you a much better therapeutic window when we have selectivity for KAT6A. We chose a degrader approach really for two reasons also. One is that the homology between KAT6A and B is very high. With the degrader, you can have even greater selectivity because you are not only binding in the catalytic pocket, but you have the ternary complex to build that selectivity. It also buys you a tremendous amount of potency because of the catalytic nature of degraders. Thirdly, we know that when you degrade KAT6A, which is part of a complex, the whole complex can fall apart, which can give you the deeper biology, which is what we see preclinically. When we compare head-to-head in the preclinical models, we achieve regressions with our KAT6A selective degrader, whereas inhibitors tend to give more tumor stasis. We think that's really important, and in terms of the safety, we see less effects on neutrophils in our preclinical models relative to inhibitors. From both those standpoints, we think we're very differentiated. Got it. Thank you. That's a very thorough answer. You touched on this a little bit about the safety. The patient enrollment is slated to begin next quarter in Q4 2026. How should us and our other analysts benchmark initial safety and PK metrics against the non-selective inhibitors? Is there any particular go, no-go signal that you're looking for in order to advance into later products? Yeah. I think the trial is set up to really ask three fundamental questions, right? That based on what Peggy just described. Can we really see as a monotherapy significantly differentiated, meaningfully different hematological toxicity profile? Because if we do, that kind of reads through to many of these other things, not only combinability, which is important, right? To be able to move to earlier lines of therapy, so that's fundamental. But also even at that line of therapy, to be able to not have the dose reduced, which happens in greater than half of the patients with Pfizer trial, and that happens early. If we can actually see differentiated safety, thereby being able to see differentiated efficacy. In terms of timeline, we're just opening the trial in fourth quarter, and our goal is to drive hard, and we're being really specific to only HR-positive breast cancer. We're not waiting for reaching the recommended phase two dose to do combinations. A lot of these things will happen in parallel in 2027. We just have to see. We've guided to initial early data release in second half of 2027. That's really what we're laser-focused on and trying to drive to get there. Thank you. We're running very low on time, but I do want to ask about your DAC constructions because they're so novel and exciting. Could you tell us about the mechanistic rationale and what targets would be most suited for this type of approach briefly? Thank you. Yeah. The one that I alluded to early on, we're testing this with the mutant CALR positive MPNs. Those of you who are following CALR field, it's just also super exciting. It's also going to be very, very crowded, just like any interesting target class. But a lot of those are naked antibodies, right? What they do is they inhibit signaling of mutant CALR selectively. They don't inhibit wild type CALR. There's multiple mutations, so broadly classified as type 1 and then non-type 1. It appears that these naked antibodies are very effective in type 1, not so effective in non-type 1. It's shown in the clinical trials where you look at the mutant allele burden changes, they fairly stay flat with non-type 1, whereas they drop, right? That is important for disease modification. What we've developed, because we've been working on this for a number of years now, where we can selectively deliver a payload that is safe generally, right? So that only cells that actually receive this payload through this delivery mechanism, which is the antibody, CALR antibody would be susceptible. Here we're trying to not just inhibit the signaling but really eliminate the disease-initiating cells. By doing so, it should be equally active on all cells, all mutations. We've also selected the antibody that actually has equipotent activity on all mutations other than type 1. So it is, again, like I said, earlier stage, but it is an area where we think has the potential to be really meaningfully better activity for patients with MPN over what's currently out there or be in the development. Got it. Thank you. It's an exciting year ahead of us. I want to thank you, Kris, Bryant, and Peggy, for joining us today. I want to thank our audience for their attention and for being here today as well. Thank you. Thank you. Thank you.