Good afternoon. My name is Michael Guba. I'm the healthcare sector specialist here at Wells Fargo. And I'm joined with Kris Vaddi, CEO of Prelude Therapeutics, to close out for day one of our conference. We're gonna keep this relatively informal. I got a couple questions, and we'll just kind of run through the background of Prelude. So right off the bat, can you just provide a little bit of background on the company, just for those who might not be as familiar with the story? Yeah, of course. Just thank you for the opportunity to participate in the company. Can you hear me okay? Good now. Yeah. So, you know, we all know someone who faced this frightening diagnosis of cancer, particularly those that either don't have good therapies or have therapies, but they don't work as well, right? Once it's faced with that sort of a scenario, the most important question that comes to the mind is, "What's next for me?" Really, the mission of Prelude is to create options, create hope for patients who are asking that question, "What's next?" And the way we go about that is really by discovering and developing very potent, selective, small molecule therapeutics that can intervene in the pathways that the cancer uses to really evade treatments or resist, develop, resist, or relapse. And that's really our core mission. You might ask, you know, "Why does Prelude think they can do that?" I can tell you what really gives me the confidence that we can do that is really three things. The team that came together at Prelude, really, as a leadership team, we've done this before. We were able to put together a team of exceptional drug discovery scientists, clinicians that have created those what's next options. For example, I worked on Jakafi from the idea of really targeting a pathway and developing, registering, developing, and really bringing to patients very important medicine. Same thing with Jane Huang, our President and CMO, brought BRUKINSA, which is a, you know, the most successful BTK inhibitor that's being developed. So we've done it, and we have the passion to do it again. So I think the team is really what gives me the confidence. And our strategy really is also very, very patient-focused in the sense that we've developed our capabilities to go across target classes, across technology platforms, to be able to create those molecules that the patients or the cancers, you know, to intervene in the pathways that the cancers might use. And finally, the progress. You know, we've been a public company for three years now, and we've brought multiple molecules, first-in-class, best-in-class care potential, to the clinic. And they're currently going through the important phase of phase dose escalation and on their way to potentially demonstrate multiple POCs. So that, that's what really gives me the confidence that the Prelude is on its way to really be the company that provides what's next option, you know, for patients. Awesome. Well, building on that, you've got four pretty interesting programs in your pipeline. Just to kind of give a baseline of how should investors look at prioritizing those four programs? Yeah. So, again, you know, if you think about the strategy, right, like with the team we put together, it is by design that we identify important pathways that have the potential to change the course of a cancer, right? So, worked diligently, brought these molecules to the clinic, and it's kind of embarrassment of riches, if you will. But, what it actually does is it gives us the optionality to be able to select the programs to resource and move, right? So, you know, we don't have to work on a program any longer than we need to if the data are not supportive. And so, having that optionality is really key. The way we think about prioritizing is really, fundamentally, the strength of data is what we're generating, and the ability to differentiate from if there are others ahead of us, are we really generating data that is sufficiently, you know, improved and better, you know, than what's out there for these patients? And, you know, the clinical development path and regulatory strategy is very, very important because, you know, depending on what you have to prove that you're better than, right, may actually set a different hurdle, so that's important. And the landscape out there is changing, evolving, so we need to make sure that, not only that we have a attractive molecule, but it is actually serving the needs of patients in an effective way and creating commercial opportunities, right? We continually evaluate, and we make those prioritization decisions really based on the data that we are generating, you know, over the course of next 6-12 months. ... Oh, that's really helpful. And then kind of doing some background on our pre-call, the team called out the SMARCA2 program. Can you tell us a little bit more about what this program and, you know, why there's so much interest in it? Yeah, absolutely. Again, you know, every program really starts with the patient's need, right? So if you actually just, I'll get into the science of the SMARCA2 shortly, but there are up to 10% of patients in multiple cancers, including non-small cell, esophageal, colorectal, that have mutation in a related protein called SMARCA4, right? So when you have these mutations in SMARCA4, many of them or some of them will result in loss of the protein. So most important thing is, these patients who have these mutations really have no effective options. They don't actually overlap, these mutations, with other actionable mutations like EGFR or ALK or other things. And they respond... They don't respond well at all to Pembro, or chemotherapy, or chemoimmunotherapy, immunotherapies. So they define a group of patients who have the highest unmet need in these cancers, right? So that's kind of what made us think about how can we develop a potential therapy for these patients. And that's, you know, there is, again, a lot of this data is published, and it's well known. So we basically evaluated all of that data and decided to pursue this program as one of our internal discovery efforts. Got it. Helpful. Why have you chosen inhibitor approaches for some targets and degraders for others for SMARCA2? Yeah, it's a good question. So in terms of our R&D strategy, it's by design being able to go across target classes because cancers really don't use a platform. They find different mechanisms, pathways, and you need to be able to, you know, build an inhibitor of a kinase. In some cases, we know very, very successful kinase inhibitors. We have protein-protein interactions. Venetoclax, for example, is a very, very successful drug in AML that disrupts that protein-protein interactions. Degrader is a new class that actually is allowing us to go after targets that we couldn't do using inhibitor approach. So we built those capabilities to be able to really go across target classes, you know, to really change the cancer, if you will. And for... In the case of SMARCA2, we've really carefully evaluated the best opportunity to really go after it. There are two proteins. There's the SMARCA2 and SMARCA4, and these proteins are required for normal cell function, right? So if you're not able to build that selectivity, you would not have the tumor cell, cancer specificity, because you would also hit the normal cells. And so we felt that going after SMARCA2 with the degrader approach might allow us to really build that selectivity and spare SMARCA4, and as a result, spare normal cells, right? Because cancer cells don't have the SMARCA4, and you hit SMARCA2, you can hit both only in the cancer cells, but not in the normal. No, and that, that kind of leads to my next question, which is, you know, why have your SMARCA2 program been successful versus others that historically have not been? Do you mind just kind of giving us a little background there and, you know, other assets that are out there, and where PRT3789 fits relative to those other as, or programs, sorry? Yeah. So, the question about why we were able to advance or be the first-in-class SMARCA2 degrader is, you know, we've taken on this project about three years ago when we first recognized there is a high unmet need in these patients. And once we recognized that, and we've evaluated different options and decided on a degrader, we really, for this program as well as others, really, you know, look at them from the lens of a drug developer. What does that molecule need to be? Not just biochemical potency, selectivity, but what makes it drug-like? And that's what the team's expertise is. So we were able to rapidly make progress in building those properties that would go from really highly selective potent molecule to something that we can take to clinic, and ask the question of what happens to these patients who have SMARCA4 deletions, you know, if you degrade SMARCA2. And along with that, we developed really a molecular understanding of how to build that selectivity. I'm sure others are making a lot of progress as well. There's a number of companies that we know have interest based on published patent literature and, or stated interest. And we really don't know where they are at this point, so I can't assess how far ahead we are or where we are. The only thing we know is that, to our knowledge, our 3789, our SMARCA2 degrader, that is in the clinic right now, is the first one to enter. The other thing I'd like to make a point about is because it is the first-in-class, and high unmet need, there's a very high level of interest from investigators. We now are in multiple sites, in all major sites in the US, and beginning to open ex-US sites as well. So, investigators are very encouraged to really, you know, enroll patients in the trial. And we hope the learnings that we are actually having as part of the clinical development, because there are a number of mutations. It's not one mutation. There's a Type 1 and Type 2. There's two kinds of mutations. We know more about Type 1, that results in loss of protein, which is the set therapeutic hypothesis. But there's a number of Type 2 mutations that may also confer that sensitivity to our molecule. So that's something we're learning, you know, in our clinical development approach. And to truly take this mode of action, if you will, further, we're developing an oral SMARCA2 degrader as well. And we hope to bring that molecule to the clinic, you know, in early 2024. No, that's, that's very helpful. And then just kinda, you know, I sit on the market side, so in terms of timelines and when, you know, the investment communities will see data on this, any, any color you could provide, that would be great. Yeah. So we are enrolling in our phase 1 dose escalation, and it's a biomarker-selected patient population. It's often that because it takes longer to enroll biomarker patients, many companies, including us, we've done it before, is to enroll all comers early on and then be much more biomarker selected later. So we've taken the approach of actually selecting patients from the beginning here. We are including all mutations, right, all SMARCA2 mutations. So any cancer type with a SMARCA4 mutation or deletion are eligible to enter, right? So that this study is enrolling really well. And the design of the study also allows us to be able to, when we think that we are at a pharmacologically active dose, we can backfill, right? Meaning we can add additional patients with a specific mutation. So there's a range of mutations we can select, specific loss of function mutation and a specific tumor type. So that, we believe, will give us additional information to be able to refine our biomarker strategy, you know, should the data support more rapid, readily move into the next phase of development. So by the end of this year, we will provide an update on where we are in the dose escalation, potentially give the guidance on when we think that we could move to a dose confirmation or a recommended phase 2 dose, which is the old terminology. But more meaningful data set will be presented at a medical conference in the first half of 2024. Got it. Thank you. Super helpful. Moving on to the other programs in your pipeline, do you mind giving us a, you know, high-level overview of those three other programs, including the CDK9, CDK4/6, and the MCL-1? Yes, happy to. So, with this program, I'll go through one by one, but collectively, they, you know, we've guided at the beginning of the year that we will be providing updates and medical meeting presentations on all three programs, and we intend to do that, you know, in the second half of this year. And so starting with CDK9, the molecule itself is 2527. Why CDK9, right? So this is really focused on this as well, CDK9 as well as MCL-1, they're related programs, so maybe I can speak about them in a somewhat combined fashion. So, you know, a significant number of hematologic patients with hematological malignancies need new therapies. These, you know, blood cancers really are not as well addressed, right, as some of the solid tumors. And so, we felt that the mechanisms that could be targeted, you know, would be amenable to our CDK9 and MCL-1 program. So MCL, CDK9, the 2527, we've demonstrated, we presented data earlier this year, that in solid tumors. So we've taken both of them into solid tumors because there is an opportunity in solid tumor for these. But the real, low-hanging fruit is really, the patients who are most likely to benefit our hematological malignancies, right? Solid tumors allowed us to move through the development, establish the profile of these molecules. For example, 2527, we've presented the data that it is very, very potently inhibits the two key pathways in hematological malignancies, that are known and validated. One is MYC, which is an oncogene, and an MCL-1, which belongs to this family of proteins called BCL-2. You know, venetoclax is actually an inhibitor of BCL-2. MCL-1 drives resistance to BCL-2, so it's well known. So, so CDK9 gave us the opportunity to hit both pathways.... Right. But the challenge with this is, in the past, when inhibitors of this particular target were developed, there were a lot of side effects. There's a lot of gastrointestinal side effects and other side effects that did not allow them to really reach their full potential. So our goal with 2527, one, we've demonstrated that we have a very well-tolerated molecule, very potent and selective molecule, and we're, in the middle of, dose escalation for hematological malignancies. We also have a clinical trial supply agreement with BeiGene, where we get BRUKINSA. And the combination of BRUKINSA and CDK9 is believed to have actually, as a pathway, already a proof of concept, right, from other companies. So we have the opportunity to have two best-in-class combinations in aggressive lymphomas. So we will present, you know, additional solid tumor data later this year, demonstrating the safety, target engagement, overall profile, and give an update on the hematological malignancies later this year, with more data from the dose escalation at a major medical meeting in the first half of 2024. MCL-1, on the other hand, is a different problem we set out to solve, which is the competitive molecules all had cardiovascular toxicities that basically precluded their further development. We've presented data earlier this year in solid tumors that, you know, at a dose that we saw similar degrees of target engagement and inhibition as others, did not have the cardiovascular toxicities. And that's because the way we designed the molecule, you know, is the overall profile of the molecule, is what we believe allowed us to avoid that toxicity. So we will, we are in the hematological cancer dose escalation, which we expect to complete and present the data this year as well. And the last program, which actually is our next generation CDK4/6 program, that we've initiated this year. And, you know, CDK4/6 is an approved path. There are approved agents that target this mechanism. They're well entrenched in ER-positive breast cancers. When we look at all of the data and design our molecule, we've taken into consideration a number of factors that would allow us to potentially expand the reach of CDK4/6, you know, not only in breast cancer, to other cancers where there is potential opportunity. So it is an early program, and, we, you know, we expect to get to a recommended phase 2 dose, this year, and be able to present, some of the data at a medical conference later this year, and also provide a, a data update, a program update from the company in the second half as well. Got it. Thank you. Yeah. Just to recap, all four programs will show something before year end? Yeah. So the programs are advancing as we guided, right? So they are in the right patient populations, generating the data. The challenge for us really is to... I think this is a question that you asked early on, as to how do we prioritize and how do we resource these programs in a way that they're positioned for success? We don't think that taking all programs to the next phase of development is the most prudent thing to do. And we need to generate the data and evaluate the data to be able to make those decisions. And the next step of development could be our internal development or other strategic options that we might use to advance the programs, or deprioritization, if they don't meet the bar we set. when I say the bar we set, we, we set a very high bar for these to be moving, to be really deserving additional capital allocation. We don't take that lightly. Not only that there has to be data, but there, there has to be compelling enough to, to really make a meaningful difference to our patients. So, so that's our guiding principle, and that's how we, we plan to, you know, advance this. Prudent approach. You got to let the data lead. All right, so in this kind of final minutes, is there anything I missed or anything you'd like to touch on, just to kind of close out? No, I think we've covered, we covered all the programs. What I would like, you know, your audience to leave with is that, you know, Prelude has really evolved to a multi-program, multi-stage product company, where we are generating meaningful data sets over the course of the next 6-9 months, and that will guide us to really take the company to the next phase. Our intent is to become a fully integrated oncology company. That was our company when we launched it, and that remains our focus. And we are very excited about the opportunities we have to be able to execute on that mission, and look forward to updating, you know, on all the progress over the coming months. We look forward to hearing it. Yes, so just to close out, Kris Vaddi, Prelude Therapeutics, and I'm Michael Guba from Wells. Thank you very much for joining us and, now the day is over. So- Thank you. Glad to hear it. Thank you.