All right, welcome everyone to Jefferies 2025 Healthcare Global Conference. My name is Roger Song, one of the senior analysts covering SMID Biotech in the US. It's my pleasure to have the next fireside chat with Prelude Therapeutics. We have the whole team here. We have CEO Kris and the president, then CMO Jane and then CSO Peggy. Welcome everyone. Thanks. Awesome. Yeah, thanks Roger. Thanks for the opportunity to participate in Jefferies. Kris, as always, excellent. Yes, Kris, why not you start with some recent updates for Prelude and then, you know, seems you have some recent data updates and then also what are the upcoming catalysts and then we can drill down some of the details afterwards. Absolutely. For those of you in the audience that are not familiar with Prelude, we are a precision oncology company really solely focused on discovering, developing novel small molecule and now even degraded antibody conjugates for the treatment of diseases, cancers that are very aggressive and need new therapies. Our lead clinical program is targeting chromatin remodeling complex called SMARCA2. We have developed a platform of very selective degraders, the first one of which is called 3789 that is now in the clinic. We presented some proof of concept data. It is IV once weekly targeting SMARCA2 in patients who have mutations in SMARCA4, different types of mutations, and Jane will go into more detail on that. We believe this is a very, very aggressive cancer in need of therapies. There are no existing therapies for these patients. And We've actually from the beginning took an approach of developing both IV and oral molecules. They're distinct molecules. The data that we presented and then we're going to talk more about is the IV molecule. Then the oral 7732 began clinical trials late last year and there's a lot of information we gained and knowledge we gained in this disease in the first in class mechanism with our IV molecule that we're able to leverage to rapidly advance our oral molecule. We're very excited about the progress that we've made so far. We recently indicated that we are going through fifth dose cohort. As you can see that it just started in October of last year. That's a very very rapid progress. There's a lot of enthusiasm from the investigators as well as need for this therapy from patient side. We're looking forward to actually talking about that further, both of these programs, later this year. Our research is still a very important aspect of Prelude. We recently announced at the AACR we presented some data on our new program called CAT6A degrader. It's a CAT6A, a selective degrader. We're going to talk a little bit about how it has the opportunity to differentiate from a validated mechanism that we just saw some data from Pfizer at ASCO. We think that our approach has some benefits over that. We're continuing to make a great deal of progress on degrader antibody conjugates in collaboration with Arcellera and We are in a very good place as a company and looking forward to the discussion today and further data updates later this year. Excellent. All right. My understanding, you recently presented some data in Japan, JSMO. Maybe give us some highlights there because that's from your program for the IV SMARCA2. Yeah. Yes. At our presentation we showed that the molecule 3789, which is our IV molecule, continues to have a very clean safety profile with very few related AEs that we are able to continue to dose escalate, thus proving our preclinical hypothesis that if you have a very selective degrader that you're able to avoid significant toxicity. We showed that the response rate in doses greater than 283 is 23% in the lung upper GI tumor types that have loss of function. We were very, very happy. We've chosen our dose at 500 mg since then for both combination as well as monotherapy. Good. You have the RP2D for the, or at least therapeutic dose for the next step. 500 milligram. What's the key criteria when you design, choose this program? Because we see the PD and then the PK, and I think in the past we talk about the depth and the consistency of the reduction of the SMARCA2. Yeah. With a very safe molecule you could technically keep a dose escalating if you're not seeing any DLTs. What we did was look at the totality of the data between safety, activity, the depth and duration of SMARCA2 degradation, and put that together, and we felt that the 500 was where we should land in terms of getting the maximum benefit. How do you think about considering this loss function, different class of the SMARCA2s, do you see is necessary to go even higher? Or you think this is because you may expand this population to different population? Yes. The lowest hanging fruit for us is in the tumor types that we've seen the most tumor shrinkage, which is the upper GI, esophageal, gastric, as well as non-small cell lung cancer. In fact, in that study, we saw three out of three responders in the upper GI. We are carefully thinking about juxtaposing this against where we are with the oral and where the lowest hanging fruit is. What we've learned from this phase one is we want to first target those two tumor types, non-small cell lung as well as upper GI, as well as target the loss-of-function patients. It doesn't necessarily mean that there isn't activity beyond that, but this is where we're seeing the strongest signal to pursue as aggressively as possible. Yeah, okay. Yeah, that makes sense. You have to have something to focus for now and then maybe you can expand later to others, maybe using different dose. It seems you are picking the RP2D from here and then at least for the next step. Next step for the dose, and then you're ignoring those patients. I believe you will have some data updates second half of the year from that dose cohort and then just tell us what's the expectation from that data update? Yeah, we're planning to give the totality of the information from the phase one since we have completed it. Again, demonstrating like at the JSMO, we also demonstrated that there's no overlapping toxicities with other potential partners, like with a chemotherapy with docetaxel. There will be a reasonable number of patients, you know, the 10-20 at dose across these tumor types. 10-20 at the 500, and then across those two tumor types. Two tumor types with loss of function. With the class one loss of function. Got it. Okay, that's great. In then how about the combination? You say you already also enrolling the patient. It seems we also have some updates from the Adiza docetaxel. That's correct. The same number of patients with docetaxel so, today we presented the activity of the combination where we've seen, again, as I just mentioned, very little overlapping toxicity. The toxicity we see is with the neutropenia from docetaxel. In terms of the activity, you'll see your 10 patients at dose with a final data presentation. Got it. Okay, great. This is the IV portion and then we're going to see some data later this year. Before we talk about the oral, what will be the next step for the IV program? Yeah, so it's sort of linked to the oral because obviously. Depending on the oral data as well. So the beauty of this is that we were able to learn so much from the IV to set the stage. I can say that when I started the program two years ago, not only patients, but physicians, investors, nobody even knew what SMARCA4 was. We made a very good effort to be able to hone in on the patient populations we want to go after as well as establish this as a biomarker because we got it on every single NGS panel that is available. With that knowledge, we are able to really rapidly advance the oral and really hone in on the populations, as I mentioned, the lung as well as upper GI from the get go, also those patients with loss-of-function. The oral only started in October and we are enrolling in the sixth dose cohort. We have been very efficient. We will be able to make some important decisions about how we move the program forward into registration. Obviously, there is a propensity for both patients and physicians to like oral, particularly in lung. That would be the natural way to go. Got it. That just leads into the next step. Right. You will have some data updates from the oral later this year as well. You know how much data we should expect from there. We would like to give some qualitative updates, I would say toward the end of this year because we are still in dose escalation, and then give you the most robust data set we can at a medical meeting next year. Got it. Okay. How are you going to make a decision from the initial data, deciding between the IV and the RO for the next step? Yeah, so we're making comparisons across where we are with the greater degradation of the SMARCA2. Right. The depth, duration, how much coverage we are getting. As you might expect, a daily oral is giving more sustained degradation over the course of the week than an IV once weekly. We're continuing to get tissue biopsies so that we can understand the relationship between the blood and the tissue. What we found out from the IV at the end was that there's, at the higher doses, good recapitulation of our preclinical models. We think we understand what the oral should look like as we approach dose and want to get to that essentially 24/7 coverage. Yeah, got it. And the, I think you have a couple of slides talk about the indication overlap and then overlap between the oral and the IV. So do you need to choose one or the other for the next step? Or you can develop them in parallel and then maybe in a bit different indication not to cannibalize with each other. I mean, we want to use our capital as wisely as we can and as efficiently and effectively as we can. I think, as I mentioned, there's probably a natural propensity to lean towards the oral for multiple diseases. If in Asia, there's some thought about for upper GI esophageal, the IV might be preferable. There would be a consideration for this. If we can have one holistic program, it would be to gravitate toward the oral. Okay, yeah. Just to add to that, we brought both programs forward. These are very, as we talked before, distinct molecules. Really discovering a highly selective oral degrader has been actually quite challenging. We are very gratified that the molecule we ended up bringing forward to the clinic not only demonstrated that you can actually safely go after this pathway by sparing SMARCA4. The selectivity is very key, and we learned a lot of lessons from IV that we were able to apply. We had to be very careful in terms of thinking about the program, capital allocation, and patient allocation to get the right answer so that we can actually create a very cohesive development strategy going forward. This is a question that often gets asked, you have two molecules. How do you go? We thought clearly, for patients for whom IV might be appropriate, that's a path for an IV, if you could do that. Given where we are with oral, if there is a clear path we can define for that, that would be optimal from a company standpoint at the moment. It does not mean that we will never develop IV in the future, but at least for now, it gives us a place to really focus the company. We have been efficient, so we have been able to catch the oral up essentially to the IV. Yeah, yeah. It's a good problem to have if you have both program viable and then you can pick and choose for. And again a lot of things had to be learned in terms of the depth of inhibition, duration of inhibition, what the base level SMARCA2 are in these patients, how that might or might not affect the dose you need and the concentrations you need. There is a tremendous amount of learnings that we were able to get from the work that we've done so far, and even from a diagnostics standpoint. Right. Like how, you know, how to select these patients, how to identify these patients. I think that positions the oral program really well, and it has the benefit of, you know, wider usage and, you know, front lines and adjuvant settings, et cetera. There is a number of, you know, benefits for that if that were to, you know, to be able to deliver what we're looking for from a Coverage standpoint. We've indirectly told you we're very happy with how the oral is proceeding. Yeah. You also told us the enrollment is so fast and you're already in the sixth cohort. That speaks to safety and also the enthusiasm there. Totally got that indication. Right now you are in the clinical proof of concept stage and relatively early, you're moving quickly into the next step. I think Jane, you mentioned you are even thinking about the pivotal as the next step. How should we think about the corporate strategy in terms of moving this forward by itself into the late stage? First approval or you will start to think about the partnership. Really will be dictated the data. We just have to. We can clearly execute, Jens, as the organization to be able to execute the studies. From that standpoint, we do not really need another partner or another strategy. We just have to see. There could be situations where it may be beneficial if you want to execute much larger frontline studies. We would be driven by the data that we are generating and make the decision appropriately. Yeah, it's data dependent and situation dependent. Okay. When we look at the landscape, seems we have another key kind of smart player out there. They have some recent data as well. Just not trying to let you to comment on other program but just in terms of you as the leader of the SMARCA2 degrader and how you think about the landscape and then what's to give you the confidence 3789 and then oral can be the best in class for the SMARCA2 degrader. I mean, you know, that clinic will tell us what's best in class. It's hard to claim that before you actually have the data. But we're happy that, you know, these patients really need new therapies and we are, you know, we're thrilled that we actually are able to bring a very, you know, potent and selective molecule to the clinic. And we were able to get the POC with IV and also demonstrate that this mechanism can be safe. Right. We'll just have to see how the data sets emerge over time. You know, there is in any active mechanisms, there's always more than one drug. You know, we're going to wait for the data clinic to tell us really, you know, how these are differential because one is a inhibitor, ours is a degrader. We just have to see what the clinical data looks like and it's probably going to be in 2026 by the time we will have initial readouts from both molecules to really get our first look at how they compare or separate. At the end of the day, from a kind of scientific standpoint, we still strongly believe that the degrader hypothesis, where you're very selective, will be critical for your safety profile and achieving the therapeutic index you need. Because these patients have very aggressive disease and you want to be able to get to dose really quickly. Patients are very intolerant these days with all the good molecules that are out there of side effects. Having a very safe selective molecule will be very important. Yeah, that's a good point. Maybe Peggy is also there. So when you design this program, at the degrader, selectivity, potency, any other parameters, when you design this program, you want to be a very good molecule, move forward. Yeah, I think as we talked about, potency selectivity was key for us, but also in the degrader space, building in those pharmacokinetic properties so that it really effectively can hit the target and has good oral bioavailability for our oral compound. All those things were key to us so that we could advance the best molecule into the clinic. Yeah, okay, very good. Yeah. A lot of work went in from Peggy Scherle and our chemistry group to be able to come up with oral molecule that we're happy with in the clinic. Yeah, absolutely. I think you move this oral program pretty quick now with all the good property that's the lead program, IV oral for the SMARCA2. Also, you have broad small molecule discovery platform including degrader and the inhibitor. What are the other earlier pipeline you want to mention to us? Any highlights in terms of the near term, the activity we're going to expect to see? Yeah, we had a recent disclosure at AACR of our new program, a CAT6A selective degrader that we're really excited about. We've been following the work from Pfizer with their inhibitor that inhibits two family members, CAT6A and CAT6B. They're advancing that in ER-positive breast cancer. It looks very promising, the early clinical data. They've had a recent presentation at ASCO that showed an overall response rate of around 37% in combination with Fulvestrant. They showed this was in patients that were resistant and had failed CDK4/6 inhibitors. We've been really excited about the data. We think when we started the program again, we thought a degrader could actually be advantageous in two perspectives. One, we again built in that high selectivity for one family member, CAT6A, as opposed to the inhibitors that inhibit CAT6A and CAT6B. We think from a tolerability standpoint, one of the dose limiting toxicities that the Pfizer compound has shown is neutropenia, grade three, four neutropenia. We think with a selective CAT6A degrader that we can mitigate some of those bone marrow toxicities. We have preclinical data that supports that. The second point, from a degrader standpoint, in addition to that selectivity, CAT6A is part of a complex. When you degrade the protein, the whole complex gets disrupted. We think that brings in better efficacy and deeper biological responses. We again see that in our preclinical models. Whereas the inhibitor leads to tumor stasis, we actually see complete regressions in the models. So We're really excited about that program and think again, very similar to the SMARCA2 selective degraders, that we have advantages over the inhibitors that are also in the space. Awesome. We definitely hear a lot of the buzz on the CAT6A at this ASCO and then. Glad you have that early pipeline. It seems you are differentiated on the safety and potentially on the efficacy side. Okay, we're going to stay tuned on that. What's the timeline on this? Yeah, we're hoping to have our development candidates selected this quarter. Just in a couple weeks and then we'll move to IND enabling studies and hope to have an IND in the early part of 2026. Got it. Yeah. Just to add to that, again, great deal of progress really leveraging all the work that the team has done on degraders. First market to selective degraders we were able to apply and again ask the question, a fundamental biological question about can you be more selective, can you go deeper biology and would that be clinically beneficial? Right. That is something from a scientific standpoint that the team has been able to do it and demonstrate. Also the molecules that we have are really very high quality molecules with excellent PK properties and they should be able to test the hypothesis in the clinic. We're looking forward to advancing our first one sometime next year. Beyond neutropenia, there's other potential side effects that we could circumvent with our molecule. That Pfizer molecule has a dysgeusia is also one of the challenges. We'll ask the question whether a completely different chemical entity, different approach, can offer a differentiated profile in the clinic. Excellent. Okay, great. I know you have a couple partnership, and in particular for the Arcellera for the ADC in the monoclonal antibody. Where you are with this partnership, and then what are we going to see from that? No readouts yet. Yeah. This was again, I let Peggy talk a little bit about some of the data that we presented. It started with the idea of using degrader antibody conjugates, right, to further expand initially our SMARCA2 for, you know, sort of expertise and to expand the reach of those molecules, those degraders, beyond those cancers that have just SMARCA4 deletions, right. The specific two degraders were really designed only for cancers with the 4 deletions. The pathway has broader applications. We also know that unless you are very selective for 2, you are not going to have tolerability profile. The team designed 2-4 duals and really conjugated them with the antibodies and asked the question, can you actually have the safety by tumor targeting a 2- 4 selective? Maybe Peggy, you can comment a little bit about the data we presented and then I'll come back to, you know. Yeah, I mean, as Kris mentioned, we had the concept that if you could conjugate these dual degraders to antibodies, you could build in that selectivity that way and really extend the types of tumors that back might be amenable to targeting the BAF complex through the dual SMARCA2/4 degraders. We did that. We had a preclinical presentation at the triple meeting last fall where we showed really compelling data that we could conjugate these dual degraders to multiple different antibodies that are validated and targeted selectively to specific tumor types, like a MET antibody or TROP2 antibody. We could show very good activity in tumor types that were positive expressing those antigens and no activity in tumor types that did not express the tumor antigen that the antibody was directed to. Preclinically, very strong proof of concept that targeting these dual degraders had activity and efficacy in the models and were very well tolerated by coupling them selectively to a specific antibody. I think again, really strong data that provides proof of concept for the idea that you could increase the number of patients that would be susceptible to these dual degraders. Yeah. We have another oral presentation at European Hematology next week on SMARCA2/4 conjugated to a CALR antibody. You know, we're doing a lot of work on it, but in terms of timelines, we work, you know, we work with our partner Arcellera, and you know, we'll have some announcements to make, but it is something that we'll do together. Great. Okay, last minute we can talk about the cash position and then you have a couple things going on how this the current cash is supporting the operation plan. Yeah. As of end of last quarter it was $103 million and we guided that the runways into second quarter of next year. You know, some of the work that we're doing in our SmartCare program, we expect to have meaningful, you know, readouts later this year and we have a number of options and opportunities we're looking at in terms of capitalizing the company. We're in very good shape as a company. The science is really, I'm excited to have the opportunity to advance these agents in the clinic as well as the preclinical and look forward to updating this treat on all the progress we're making. Excellent. Thank you team for being with us and thank you everyone for listening.