Good afternoon. Welcome to 2024 Jefferies Global Healthcare Conference. Last day, my name is Roger Song, Senior Analyst covering SMID Cap Biotech in the US. It's my pleasure to have this fireside chat with Prelude Therapeutics. We have CEO Kris and CFO Bryant here. Welcome, gentlemen. Thank you. Awesome. Yeah. So we have a lot to cover in terms of your pipeline. I think you have a lot going on there. And then before that, maybe Kris, if you can give us some kind of intro remark, what's happening for Prelude in the recent months, that would be appreciated. Yeah, great. Thanks, Roger. Thanks for the opportunity to participate. For those investors in your audience that are not familiar with Prelude story, we're a clinical stage biopharmaceutical company with sole focus on oncology and really with a mission to expand the precision oncology options to every patient in need. We know that despite all the advances, far too many patients are still receiving ineffective and unsafe, untargeted chemotherapies. And our focus is to develop selective, potent inhibitors of key pathways that have the potential to be first in class or best in class against very challenging targets, and with the hope of creating safe and effective medicines. And the reason why we believe we can do that is because we've put together an exceptional team of medicinal chemistry, cancer biology, and clinical development, including late stage development, with the leadership and the team that has done it before. And we're excited to do it again. And our pipeline is quite compelling. We're going to talk more about it today. But our SMARCA2 program really has the potential to be a pipeline in a single program. We are in the clinic with our IV SMARCA2 degrader, very highly selective molecule. We started that dose escalation last year. And we have an oral also exquisitely selective for SMARCA2 over SMARCA4 and other proteins that is expected to start in the clinic in the second half of the year. And our CDK9 program with 2527 has the selectivity and potency profile that has the potential to be best in class. We're really focused on driving these two clinical programs to POC this year. The company is laser focused on that. We're excited to be at a time where the industry's first SMARCA2 degrader data, clinical data, will be released later this year. Really hoping to advance beyond just the initial phase one should the data support into registration programs in 2025, 2026 timeframe. So really excited to talk more about these programs today. Absolutely. Maybe before we take a step back and before we talk about the SMARCA2 and the CDK9, which is your lead program right now in the clinic, Kris, you have a track record as a leader for the discovery and the medicinal chemistry. Tell us what's the secret sauce for Prelude, why you can come up with those molecules really can differentiate it because those targets are not easy targets. A lot of companies have been working on them, but why do you think you have the team to be able to generate the best-in-class molecule? Then we talk about the clinical. Yeah, of course. Of course. Maybe part of it is that by design, the teams we put together at Prelude, from the inception, we never created the company as a technology or a target class company. Everyone we recruited from the very beginning were true drug hunters. We always set a profile that has that potential and drive the program through collaboration between discovery chemistry, discovery biology, and strive to identify the molecules that have the best chance of success in the clinic. Not all mechanisms will eventually work. We know that. There is a certain attrition that is expected. But every single molecule that we've taken to the clinic has done what it is supposed to do, hit the target and have the safety profile. Very proud of what the team has been able to do. I think the secret sauce is that the teams have worked together over two decades. Our head of chemistry and head of biology and myself have been through four companies before. It's the whole process we set in place that we know works. So I'm excited to see that translate to hopefully meaningful medicines for patients. Absolutely. And then all of those components coming from your internal discovery platform. Yeah, absolutely. I think that is Prelude through and through is an R&D company. We don't need license. We really design, ideate, design, and develop all the molecules we have internally. Excellent. Okay. Now we can move on to the clinical program, which is always the key focus from the investors. I would like to focus on the SMARCA2 first because that seems to be the most exciting and generate a lot of interest in the field. Where are you for the phase 1? What's the enrollment? What's the dose right now? Understanding you will have the POC data later this year. So how much we should expect from there? Yeah, sure. So just again, as a very, very high level overview, SMARCA2 has been of interest to our industry for a long time. And the reason for that is patients who have these mutations, SMARCA4 mutations, two things are important. One, it confers susceptibility to a selective SMARCA2, either inhibitor or degrader, because you need one or the other. You don't have four. And if you hit two, you can kill the cells. Number two, which is probably the most important, and this is the reason why we started to work on this, is that there's a high unmet need. These patients do very poorly on current therapies. The median progression-free survival in frontline chemoimmunotherapy setting is under three months for these patients. That's very, very important to know because when you talk about the potential in those patients, it's really the context has to be understood, number one. So we've had a 3-year program on discovering highly selective SMARCA2 degraders. 3789 is the first molecule that we started the trial. Just as a trial overview itself, it started about a year ago. And it has a standard dose escalation component, but it also has a backfill component, which is very, very important. And the standard dose escalation component has every patient needs to have a SMARCA2 mutation. It doesn't have to be loss of function. About half of all SMARCA2 mutations are known loss of function. So they can have any mutation. And number two, they can be any tumor type. And the primary objective of this is to establish that we are achieving the levels of target degradation that we were hoping to see based on the preclinical data. It has a safety profile that supports continuation as the PK and PD and clinical activity right from this. The backfill cohorts, which we initiated this year, and those were initiated at a dose where we believe there is pharmacological activity, the drug, but you need a more homogeneous population, really enriched for loss of function. 10 patients can come into each of these cohorts. Six of them are non-small, have to be non-small cell lung. The purpose of the backfill program is to give you that more homogeneous population where you can calculate the ORRs, et cetera. What we're hoping to present this year is all the data that we collect to that point on monotherapy dose escalation and describe safety, target engagement, both depth and duration of target engagement, as well as any clinical activity that we see to date across multiple tumor types. So that's kind of what we hope to show. Then we have also initiated our docetaxel combo escalation this year. And so. You're going to see some signal there. How should we think about the data coming from that cohort? Given that it's only initiated this year, so you can't expect enough datasets to be presented this year from that. Having said that, there are those patients with loss of function and the right tumor types in the initial escalation cohort as well. But the focus of this year's presentation is going to be dose escalation. We said publicly that the data will have 30 or more patients' worth of data. And so it should be a pretty robust dataset that gives us a lot of confidence in terms of what the next steps are, what the dose might be to take forward. Got it. In the second half of this update, you will give us 30-ish patients. You will decide the dose. And then probably what is the enrichment for the patient population and small cell lung and the loss of function, and then moving to the expansion cohort. I think it's more of a you should think about this as really a backfill cohort data that to come next, which is the more homogeneous population. So yeah, I mean, we still are a few months away, so we can't really exactly describe. But we're very pleased with the way the study is going, very pleased with the safety profile of the molecule so far. Again, it is a validation of what the years we spent in perfecting this compound that the premise here is that you need the SMARCA4 selectivity against SMARCA4 to be able to be safe. And we've said that we were in the sixth dose cohort in March timeframe. So that tells us that, A, that happened within nine months of starting. So the compound is obviously well tolerated without dose-limiting toxicities. That there's a high degree of enthusiasm from investigators and patients because these patients don't have other actionable mutations. They're not candidates for other targeted agents. All of that bodes well for us to be able to generate meaningful data to guide us as we think about the next steps. Okay. Just clarify this second half of the data update will come in mostly from the dose escalation. And then the decision coming out of that data readout is really inform the RP2D or the expansion cohort. And then the next data update will be mostly coming from the backfill. And then you also start to enroll the expansion will be next coming. Got it. Okay. Good. That's pretty clear now. And then so for this SMARCA2, another thing for the SMARCA2, maybe we talk a little bit about the field. So we have a couple of companies working on this and taking different approach. Like we said earlier, you have a platform, medicinal chemistry, and some people want to do inhibitor versus the degrader. So what's your approach? How do you view your compound versus the others? How should we think about the compound, the design of the compound compared to others? Yeah. So obviously, there is an ATPase pocket, which is the business end of the molecule. So if you could inhibit selectively ATPase, you could inhibit the function of SMARCA2. That's one approach. The approach we had taken was to degrade it so that the target is gone. It's not there. If it's not there, it can't function. So we've considered both approaches. We decided to go down the path of degraders because simply we felt that it gave us more flexibility. We've learned a lot from many, many TKIs that were developed. The things about inhibitors are that not only that you need to achieve high levels of inhibition, but you're likely to need high levels of inhibition around the clock. So that would require, depending on what the human PK looks like, et cetera, as you're optimizing the molecules, there's different parameters that need to be considered. Whereas with the degraders, you can measure it. We have very sensitive assays, mass spec assays to measure if the target is there. If the target is not there, the protein half-life of this SMARCA2 is long enough that you don't need to cover it around the clock. You have to hit it and the target is gone. So there are certain benefits. But if you just look at the field in general, if you look at many kinase inhibitors now moving into degraders like BTK, IRAK4, so degraders seem to be the next stage or next generation. So we said, why not start with the next generation first? Yeah, you want to be the best in class as always. So the same target, you want to be the best in molecule. Yeah. Not to say that a good inhibitor, that we have great inhibitors that inhibit the target around the clock and safe and all of that. That's possible too. Yeah. Yeah. Got it. Okay. And then so, yeah, anything else related to oh, so you also have the oral SMARCA2 upcoming. So tell us why you want to design the oral version and what's the difference between the IV versus the oral? And And in terms of the design, what you specifically want to address in the oral kind of format? Yeah. No, good question. So our oral molecule 7732 is on track to be entering clinic later this year. And we've always had, from the very beginning of the program, we've taken multi-pronged approach of developing highly selective molecules, whether IV or oral. 3789 happened to be the first one to be developed. And we have about a year of clinical experience that we gathered with that. There's a lot of learnings that we can apply into the oral program. And we think that different tumor types, different lines of therapy, and just a degree of SMARCA2 degradation and sensitivity of tumors could be different between IV and oral. So it gave us the best optionality to tailor the medicine that we're developing to the patients. We know certain patients, certain types of patients, we know esophageal has 8% patients have the SMARCA2 mutations. They may not be able to swallow pills. So an IV could be a great option for them. So we just kind of have to see how the data plays out over the course of next 18 months, 24 months with both IV and oral and make decisions. But at the moment, we plan to take 3789 full steam into whichever indications where the data supports. Just structurally, in those two, the same thing, or it's just a different formulation for this? It seems that they are both degrader, but structurally also slightly different. Why did you design them differently? Yeah. So they are very different structurally in the sense that one is a VHL-based ligase and the other one is a Cereblon. Because historically, it's been very difficult to get high oral bioavailability with the VHLs. So there are different challenges, but they're completely different chemical entities. So the binding site is different. The linker is different. The ligase is different. So it was an independent project. In fact, it is a fairly challenging project to optimize the oral bioavailability and selectivity. And we presented some of the data at AACR where you could see that it is exquisitely selective. There's this flat line for SMARCA4. So we feel like that could actually be quite interesting molecule to study and see where we can best apply that. Yeah. And then so in terms of the development paths, you're going to full steam for your IV and then catch up with the oral going to catch up in different tumor type, not try to overlap those two. It's hard to really game all of that at this point because it's different lines of therapy. We know that oral agents, for example, if you look at TKI experience, they can be used in advanced cancers and adjuvant, neoadjuvant settings, maintenance therapies. So oral may be more suitable in that same tumor type based on the line of therapy. So there's a number of options that the team is really thinking carefully. We also brought a Chief Business Officer, Sean Brusky, who comes from Genentech with a number of years of commercial experience in this space. So we will let the data drive our ultimate downstream decisions. But at the moment, all we can say is that there are potentially unique non-overlapping options for both molecules. Yeah. Got it. Okay. We spent a significant amount of time on the SMARCA2, which speaks to the interest and the focus. But still, CDK9. So it is a challenging target. A lot of development there, a lot of unmet need. Why do you think you have a better what specifically you want to try to address? Why do you think you have best in class? And then also what's the clinical update we're going to see from that? Yeah. No. So CDK, yeah, we usually spend a lot of time on SMARCA2 because the biology is complex and first in class. So there's a lot more interest there. And it's in all tumor types. 5%, 10% of all cancers is huge populations. But CDK9, our conviction in CDK9 really comes from clinical experience of our own molecule, not extrapolating from others. So from designing the molecule, we felt that a highly selective compound with good properties, pharmaceutical properties, well-behaved will allow us to avoid some of the major challenges with CDK9 class over the years. There's a lot of intolerable GI tox, other issues. The patient can't be on therapy long enough. So we designed that compound to be highly selective and potent. And we took it to solid tumors trial. We were able to study the molecule, its safety profile, its PD effects, its ability to downregulate MYC and MCL1. So we've characterized that well in solid tumors. But the most compelling biology for CDK9 was and continues to be in hem. So there is the external validation of a combination of CDK9 and BTK in DLBCL, B-cell malignancies. There is emerging data. There's always been a very good rationale and strong preclinical data in myeloid malignancies, particularly when you develop resistance to Venclexta, which is a BCL2 inhibitor. It's always believed that MCL1 can further resistance because it is a resistance pathway. And we showed that with CDK9, our CDK9 inhibitor, we downregulated MCL1. So we've initiated an AML cohort with the hope that we could actually develop it in combination with Venclexta. So we view hem malignancies overall are very good therapeutic indications for CDK9. So our trial itself has started enrolling late last year in BCL malignancies. It's got three components. It's a monotherapy escalation first. Because of all the solid tumor data, we didn't have to start from the very low dose. We were starting at a reasonable dose. But we still have to establish the MTD. So that's ongoing. We've initiated the zanubrutinib combination because that's where most compelling external validation that is. And then we've initiated the AML cohort. So towards the later part of this year, again, at a major medical conference, we expect to present the results of the trial driving towards POC in probably 20, 30 patients worth of data we should have by then. And depending on what that data looks in what tumor type or what particular cancer type, we will make the plans for the next steps. Great. And then, so just you mentioned this for CDK9 and the SMARCA2, both of them, the second half update will come in from the medical conference, or that's something that coordinated. Okay. Got it. Good. So all right. We have a couple of minutes. The key thing for you are definitely is the R&D company. You do bring in some late-stage development expert. How we think about the late-stage development and commercialization for Prelude, or you want to do something like a partnership later on for those kind of pipeline? We let the data drive. It's very difficult at the stage where we are to have a very definitive plan. But our best efforts right now are focused on ensuring the optionality to have for Prelude the best option possible, either in the way of different modalities, IV versus oral. And in fact, we haven't talked about this. We've announced a collaboration with AbCellera last year. And we are developing a very potent SMARCA2 degrader as a payload. And we're excited about the collaboration. And we hope to really add to that what I said before, the pipeline in a program concept. But in terms of downstream activities, over the course of next 12 months, I think we're going to have a lot of data that helps us define where our IV could go, where our oral could go. If there are geographies in which we need a potential partner to be able to do that, we are resourced and infrastructurally equipped to execute this global trial. Currently, our SMARCA2 trial is enrolling globally. We can do that. Under Jane's leadership, we have the bandwidth to do phase three trials. Having said that, depending on where we are in terms of the program next year, we will entertain any options that come on the table. Excellent. So lastly, cash position runway, and then we can wrap this up. Bryant. Cash position as of our last Q was $201.9 million. Takes us into 2020.