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Good afternoon, everyone. Thank you for joining us today here in our Jeffries Healthcare Conference in New York. I have the pleasure today, joined by Chris Vardy and Peggy Shrill of Prelude Therapeutics. Why don't we go ahead and get started. Chris and Peggie, if you could introduce yourselves and a little bit about your company. Sure. I'm Chris Varty, founder and CEO of Preluded Therapeutic. And I'm Peggy Shirley, CSO at Prelude Therapeutics. Maybe I'll just take a couple of minutes to introduce the company. First of all, thank you very much for the opportunity to participate in your conference. Just to frame up Prelude, we're a precision oncology company with a very specific mandate. Go after cancers where the patients really do not have good therapeutic options today. they're underserved, and bring something better, genuinely better, to the table for them to move the needle. And, you know, why do we think we can do that? It's the team and the pipeline that the team built. Our discovery and development team has done this before. They actually designed and built molecules that matter, and they know how to move these compounds through every single asset in our pipeline was internally discovered they were not in license they were not bolt-ons but they were specifically designed to be better than what's out there and you know we have our well capitalized we have a number of data catalysts in the next 12 to 24 months and and these are we're not waiting for any binary data we have multiple highly differentiated molecules that were very excited to talk about today the first one is it's PRT 1 2 3 9 6 I'll call it it 2396. It's a selective JAK2V617F inhibitor. And probably you're familiar with MPNs, or myeloproliferative neoplasms. There are more than 200,000 patients, 300,000 patients in the United States alone and many, many more worldwide that have this mutation in JAK to enzyme. A majority of these patients have this limitation. And they currently live with the first generation. Some of them are treated with the first generation JAK2 inhibitors. In fact, several of them don't even have that option. And we know about those molecules because our team invented the first one called JAK-FI, which is still most widely prescribed JAK1 inhibitor. While they work great, they treat the symptoms primarily. They really do very little to modify the disease. And why do they do that? It's because they hit the normal JAK2 that your body needs and the mutated JAK3 that drive the cancer equally. So we designed 2396 to fix that. It selectively targets the mutated Jack2 and thereby eliminates some of the toxicities or potentially significantly reduce the toxicities. So better therapeutic window, potentially better responses, and most critically, the opportunity to modify the disease for these patients. And so we are in phase one, currently in dose escalation, enrolling patients globally for this trial. The second molecule in our pipeline is a CAT6A selective degrader targeting ER-positive breast cancer, and it's been shown that this is a pathway that is effective, you know, with Pfizer and others showing hitting CAT6As and Bs could be very effective for these patients. However, they also uncovered an important liability, which is hematological toxicity, And we designed our molecule to selectively degrade CAT6A to not only get that selectivity and reduce the potential hematological liability, but essentially dismantle the entire oncogenic complex. And we believe that this is a pathway, this allows this type of a molecule to be used much more widely, better combinably, and across all lines of therapy. The third molecule that we're very excited about targets CalR, again, back to the MPN that I mentioned earlier. And these mutations in Cal-R allow this particular protein to be expressed specifically on the disease-causing cells in about 30% to 40% of MPNs. And the first-generation compounds showed that you actually, these are antibodies, that you can demonstrate the proof of concept and showed that you can actually get good responses, but they leave a lot of efficacy on the table. And by delivering a payload, we deliver a degrader as a payload on this antibody to specifically the cells, the disease-causing cells, so we can drive deeper responses, be a better patient-friendly formulation, and truly be a best-in-class medicine for these patients. So that's the pipeline that we're building. You know, we're very excited about the next 12 to 24 months. I think we have the science, we have the capital, and we have to focus. So looking forward to the conversation today. Yeah, thanks for that overview of the pipeline. Focusing on your first asset, as we look at MPN, we know that some of those subsets, like PV versus MF patients, they do have some different baseline physiologies and then dose tolerabilities. So how do we kind of think about that phase one profile between those two? Yeah, sure. So, you know, the way we designed this program exactly for that reason, to be recognizing that myelofibrosis, where patients have a very compromised bone marrow function versus polycythemia vera, where they have hyper proliferative bone marrow, we designed our trial to independently dose escalate in each of these populations separately and be able to find the right dose for these patients. And again, at baseline, the mutant allele burdens are different between these two patient populations. The outcomes we're driving to are quite different. For example, myelofibrosis, where they have spleen and symptoms, have been the traditional endpoints and ultimately improving the outcomes and improving survival are important. For PV, they undergo phlebotomies as first line of therapy, so reducing phlepotomies is an important objective for the low-risk patients. Patients with high-risk PV, they have high levels of thromboembolic events, cardiovascular events, and most importantly, conversion to myelofibrosis. So we have to really understand what level of target inhibition is needed for each of these patient populations and, you know, be able to advance the, you know, beyond the dose escalation into these populations with the right dose. So we're well positioned to be able to do that with our phase one program. Thank you. And then also you highlighted the differentiating points of this asset. I guess as this phase one is continuing, what would get you excited? Any early signals that you would expect to see almost? Yeah. So, again, in MPNs, one of the good things is you can track the disease pretty much in real-time basis, unlike solid tumors. So what we would be looking, you know, early on is normalizing the blood counts in PV and then ultimately driving to complete hematological responses. That would be the earliest signal we think we'll see. Beyond that, we would like to see, as markers of disease modification, reducing the mutant allele burden, change in what they call variant allele fraction would be another marker we would be tracking. And also, a significant number of PV patients have symptoms, and so we would be tracking. In terms of MF, I think the spleen and symptoms are pretty well validated by a number of check inhibitors, and so we would be looking for in the early part of the trial. But between both of them, we would definitely be tracking the variant and the infractions to look for the early signs of, you know, disease modification. Thank you. And then I know that, so the early cohorts are focused in that high-risk population. How do you think about expanding this to the ET indication. Yeah. So we've thought quite a bit about that and actually consulted with a number of advisory KOLs in our advisory board. What we've ultimately decided was that is to really focus on PV because about 95% of patients with PV have this particular mutation. So that seemed like the most ideal first-in-man, first- in-human study. And MF is, again, still in need of therapies beyond the first-generation JAK inhibitors. But we felt that once a dose is identified for PV, that could be, you know, the grounds to actually open an ET trial and potentially be able to treat those patients at that dose. So that's coming, but that'll be part of our expansion program. Thank you. And as you guys are ongoing, Insight is advancing its own internal JAK2 along with the option in your program. I guess, any comments on your asset and how differentiated it is from others? Yeah, I'll start and I'll ask Peggy to comment on the molecule itself. um so um with regard to you know insight you know we only know what you know they present publicly and um you know based on what they said and actually based on the way we designed our molecule um we believe that we are in a very different chemical space than everybody else and different sort of mode of action if you will on the jack enzyme um so that would be the the major differentiation and, you know, just in terms of a mechanism of action. I don't know if you want to add. Yeah, I'll just add, as you know that V617F mutation is not in the ATP binding pocket, but it's actually in a separate GH2 domain. So we designed our molecules to bind deep into that pocket where the V618F mutation actually resides. And we think, as Chris mentioned, that that's a really unique chemical space that's different from what we know in patents and and what's been presented by other companies. We also really worked hard on the PK properties of the molecule, building in excellent solubility and protein binding properties. So we really think with the molecule we're taking forward, we can effectively inhibit the mutant and spare the wild type. Thank you. Taking a step back, we just came back from ASCO, and now focusing on the CAT6 area, We saw some long-term data from Pfizer as well as some efficacy data from another company, Alema. How do you see the read-through from these to your asset and anything differentiating with your Cat6 to greater? Yeah, I'll start with my own sort of learnings from ASCO and then turn it over to Peggy to speak about some other aspects of this particular target. So, yeah, the two important pieces of data with regard to CAT6 is, one, we saw more longer-term safety data from Pfizer. I think efficacy data was already presented before, and now they're in phase three. So, from safety data, it's still very clear that the neutropenia primarily and dysgeusia are the two safety parameters that we would be tracking. With regard to neutropeny, it seems like a significant number of patients had to be dose-reduced, so I think they've talked about neutropena within the first four weeks is something that emerges that leads to, you know, reducing the dose from the starting dose of five milligrams. And that's important because if you're not able to maintain the patients at the starting dose, then, you Know, that could be a challenge there. And majority of the dose reduction seem to have come from neutropenia. And Olema is another, you Now, a second molecule going into the same patient population. it to us numerically maybe there are some differences but this is early early data but again showing the same to safety you know aspects I think the tour lead to comment on the efficacy side but overall I think it strengthens the case for targeting cat6 but still points out the need for potentially better therapies yeah so i'll just add both those molecules that chris just described are are inhibitors of both cat6a and cat6b when we designed our program compounds we really thought it was important to selectively target cat6 a and spare cat6 b and and the reasons for that were twofold it's pretty clear from the preclinical biology that cat6ae drives the tumor biology It's amplified in ER-positive breast cancer, as well as in a number of other tumor types, and regulates a number key genes like MYC and cell cycle genes, as well as the estrogen receptor itself. Cat6B, on the other hand, as well as Cat6A, are both important for bone marrow cell development, hematopoietic cells. And what was shown preclinically is that if you knock out both Cat6a and Cat6B, the toxicity to those bone marrow cells is much more severe than if you knock out either one alone. So we really started the program with that in mind to build Cat6A selective degrader compounds to try to improve upon the efficacy and mitigate some of the toxicity. And our preclinical data supports both those aspects, I think. We show very strong anti-tumor effects, regressions, in fact, in a number of ER-positive breast cancer models, and we also show less impact on neutrophils in the preclinical models, so we think from both those standpoints, our Cat6A selective degraders are differentiated, and we look forward to advancing our molecule in the clinic. Thank you, and as we think about sequencing in this indication with other agents like oral SIRDs, PI3 kinase inhibitors, where is a degrader? How do you see a degrador fitting in, and what are you hearing from feedback from, like, physicians? Yeah, I mean, I think the breast cancer landscape is really evolving in different ways, right? So you have in the estrogen-targeted therapy space, the oral SIDs are slowly moving through, So far, the activity seems to be interesting in ESR1-mutated breast cancer, others unclear. And, you know, other biomarkers selected tumor types like PI3K mutation mutated, you know, obviously the selective PI3M mutant inhibitors are being advanced. So what's really interesting with the CAT6 pathway is that, you know, it was really shown by Pfizer that two things. One, this mechanism, which is sort of orthogonal to other mechanisms, seemed to be effective, or at least the early responses and PFS endpoints are similar, regardless of whether you have ESL1 mutant, wild type, small numbers, PI3K mutated or not. But more importantly, if you look at the ctDNA drops of either of these mutations, they're pretty dramatic, and you actually can see a good correlation for the responses and stable diseases in patients who can achieve those kinds of ctTNA drops. So, the way we see it is, obviously, we'll start based on the preclinical data that we presented recently. We think that this degraded approach could actually – has the potential to significantly improve on the efficacy and perhaps match the efficacy of what Pfizer and Olema have been attempting to do with the combination, and we'll see what happens in the clinic. And beyond that, we would be looking at, you know, fulvastrin combination early, but also try to combine with CDK4-6 early in development because that is the one thing that so far we haven't seen CAT6A inhibitor, CAT6AB inhibitors being able to do. So that's kind of what we're focused on in early development, monotherapy, fulpastrin, and CDK46, and then go from there. Thank you. And as we're thinking about the clinical development, as we approach phase one, how do you think about designing the dose escalation cohorts? I think, again, we have a number of biomarkers we can follow. It'll be, you know, because it is a degrader and because it's a very potent degrader, sub-nanomolar, we think that our initial starting doses would be in a pharmacological range, just based on the preclinical data so far, and if that's the case, that we would actually potentially start incorporating, you know, backfills and fulvestrin combinations earlier in dose escalation phase rather than wait all the way to finish the dose escalations and then start the combinations. So that's kind of what we're thinking. Again, we will be obviously guided by the data, which we don't have yet, but, you know, that's kind of our approach, to be able to really start to get the data – the combo data – sooner in the development rather than wait for the entire phase one to complete. Thank you. And then just the greater antibody conjugate class as a whole, how do we think about this is field moving and how it's differentiated from ADCs. Could you give us your views on it? Yeah, if you want to. Yeah, I can start with that. So we really think it's an exciting class and a really novel therapeutic approach. What it does is we take a degrader molecule that's targeted to a specific protein and couple it to an antibody that's also specific for a surface antigen that's on a subset of tumors. And that approach, unlike your standard cytotoxic ADCs, is really what we call precision times two. So you have precision from the payload being targeted as well as the antibody. So we really think it's a novel approach. We've been doing this in collaboration with Abcelera for several years now and have really been able to successfully design the payloads and the linkers to optimize that degrader antibody conjugate. The important point is that by using a targeted payload rather than a cytotoxic, we think that we can have better tolerability and be able to move into patient populations that may not be ableto be served by a standard cytotxic agent. And, you know, one of our examples of that now is our mutant Cal-R degrader antibody conjugate to SMARCA A2 degraders, SMARICA A2-4 degraders. And we're, again, really excited about that approach to be able to deliver specifically a payload to, in this case, patients with mutant Cal‑R. Yeah, just to add to that, you know, as, you know, this field is evolving, ADCs obviously are here to stay, and they've proven the important point that if you can deliver, you know, potentially a toxic agent for a tumor type, you know, selectively and specifically, you can really get very good efficacy and minimize the toxicity, right? But there's been a lot of innovation in terms of the antibody side. There are, you know, biparatopic, bispecific, you know, like different types of antibodies. So there's a tremendous amount of innovation there. But when it comes to the payloads, it's still, really, we still are using the same, broadly speaking, the payload that the field has used. So here is an opportunity to really bring in the payload diversity. And of all the classes of payloads that you could use, degraders are very well suited, right? Because they are catalytic. You don't need to be delivering huge amounts of molecule to the tumor cells. So as a class, we see tremendous potential for degraded antibody conjugates. And as Peggy said, beyond just simply being specific to the tumor cells and then actually further reduce the systemic toxicities, this approach actually makes it feasible to treat cancers or other diseases, actually, broadly speaking, that you couldn't otherwise target with ADC. So we think that this is going to be a really exciting new class that is here to stay. And, you know, we had the opportunity to be leading and shaping the way this class is going to evolve. Great point. I think at ASCO, a lot of us saw that, the over 200 topo1 payloads, you know, in development. I think a lot of us saw that slide. Now, again, on the degrader antibody conjugates, and I want to also make time for the mutant Cal-R. But anything we should know about the manufacturing and how you guys think about the manufacturing of them as a drug class and anything to know about the safety there also? Thank you. Yeah. I mean, again, in terms of manufacturing, if anything, it should be simpler than your cytotoxic payloads and chemotherapy agents. But yes, there are some new chemistries that you need to bring to bear, particularly from the linker side and even the payload side. But we have the opportunity to now engineer, you know, different properties, like if you want a high clearance or either cell permeable or non-permeable payloads, thereby you're completely eliminating exposure to any cell unless it is attached to the antibody. So those are the parameters that we can actually sort of add to the profiles of these degraded antibody conjugates. But in terms of issues or challenges, you know, the chemistries have to be solved. But beyond that, we don't really see anything else that would actually be problematic here. I don't know if you want to add. No, I think Chris is right. I don't think we see any additional challenges. It does take a little bit more time in terms of the preclinical side and the talk studies for antibodies versus small molecules. But other than that, we don't really see any challenges associated specifically with the degrader antibody conjugates. Thank you. And also, so on that mutant KLR, could you talk to us about why you're excited about it? Yeah. Yeah, so again, just keeping in the theme of our pipeline where we're really targeting validated pathways and looking for ways to make them, you know, better driver, deeper responses, better safety. or in this case, in addition to deeper responses and better safety, you know, we have the opportunity to really turn this into a truly patient-friendly population, which is patient-friendly formulation because this ET population is, you know, really, they would be on this drug. They essentially normalize their platelets, right? That's what the idea is, and reduce the mutant allele burden. but they have to be on it for potentially decades. So, you know, the ultimate product need to be amenable to be self-administered by the patient. That's our view. And I think that is the view of companies, other companies that are building these antibodies. And the first-generation antibodies, as good as they are, they do need to, they inhibit signaling. They don't necessarily kill the cells the way a degrader payload delivered to the cell could do. So as a result, we think that they are going to end up with challenges of actually truly patient self-administered formulation. Again, this is early days, but we think that given the high potency and very low doses we anticipate needing with this degrader antibody conjugate, we think this modality has the potential to be better. Chris and Peggy, thank you. Thank you.